Baicalin and CNS-related diseases: new insights into neuroprotective potentials based on underlying mechanisms

Abstract

Central nervous system (CNS)-associated diseases such as neurological (including cerebral ischemia-reperfusion injury and stroke, Parkinson's disease, Alzheimer's disease, traumatic brain injury, and spinal cord injury) and psychological (including depression, anxiety, attention deficit hyperactivity disorder, and dementia) diseases are known as serious problems for public health worldwide. These diseases contribute to the occurrence of several disabilities and even death in affected individuals, and also decrease their quality of life. Therefore, discovering effective complementary treatments is essential. Recently, baicalin, a multifunctional natural product, has attracted much attention because of its therapeutic potentials in various diseases. Moreover, it has been shown that this agent can regulate key cellular and molecular processes in human diseases. In the case of CNS-related diseases, this review article aimed to summarize and discuss the available data from in vivo and in vitro investigations on the therapeutic application of baicalin, based on underlying mechanisms.

Graphical abstract

Highlights

• •Baicalin modulates neuroinflammation in various CNS disorders.
• •It reduces oxidative stress via potent antioxidant activity.
• •Baicalin alleviates symptoms of CNS-related psychological conditions.
• •It offers neuroprotection by influencing key signaling pathways.

1. Introduction

The central nervous system (CNS) disorders are attributed to functionally based and structurally based problems of the spinal cord and brain. The global burden of CNS disorders is increasing, largely due to longevity and increased life expectancy [1]. It is currently estimated that over 1.5 billion people are suffering from neurological disorders [2]. The Global Burden of Disease Study (2016) report specified that the largest burden on the world was due to neurological disorders affecting approximately 276 million people worldwide. It specified that neurological disorders were the major causes of disability-adjusted life years (DALYs) overall. Cerebral vascular diseases (CVD) cause nearly 10% of the deaths across the planet, and these disorders are a group of neurological illnesses that are responsible the highest mortality risk. Other CNS disorders also create a high burden, including epilepsy, Alzheimer's disease and other dementias, migraine, and tetanus. The report concluded with the statement that neurological disorders were the second leading cause of death across the globe. The study stated that there were approximately 9 million deaths that resulted from neurological disorders [3,4]. The diagnosis and management of CNS disorders remain significant obstacles in contemporary medicine, particularly in the realm of targeted therapeutics and innovative drug delivery strategies [5,6]. Despite growing insights into the etiological and pathophysiological foundations of these conditions, their incidence continues to rise. The substantial burden associated with CNS diseases, especially in terms of chronic disability and mortality, emphasizes the need for timely and effective therapeutic interventions. Early-stage treatment is crucial for improving prognosis and clinical outcomes, a priority that is further underscored by the global trend of population aging.

Recently, supplementation therapy and natural compounds have attracted much attention in the treatment of human diseases [[7], [8], [9], [10]]. It applies beneficial effects through modulating molecular and cellular processes such as programmed cell deaths, angiogenesis and endoplasmic reticulum stress [[11], [12], [13], [14], [15]]. Several investigations have recently reported that baicalin possesses therapeutic potentials against CNS diseases. Therefore, this review aimed to assess the therapeutic properties of baicalin in the management of CNS-related disorders, with focus on underlying mechanisms.

2. Literature search strategy

This narrative review was conducted by systematically searching the electronic databases PubMed, Web of Science, Scopus, and Google Scholar for relevant articles published up to June 2026. The search strategy employed a combination of the following keywords and Boolean operators: “baicalin” OR “baicalein” AND “central nervous system” OR “neuroprotection” OR “neurodegenerative diseases” OR “psychological disorders” OR “cerebral ischemia” OR “stroke” OR "Alzheimer's disease” OR "Parkinson's disease” OR “depression” OR “anxiety” OR “ADHD” OR “dementia".

Studies were included if they: (i) were original research articles published in peer-reviewed journals; (ii) investigated the neuroprotective effects of baicalin or baicalein in in vitro or in vivo models of CNS-related disorders; (iii) reported original mechanistic, pharmacokinetic, or safety data; and (iv) were written in English. Conference abstracts, case reports, editorials, and studies not directly related to baicalin or CNS disorders were excluded. Two independent reviewers screened the titles and abstracts of identified records, and full texts were retrieved for potentially relevant studies. Disagreements were resolved through discussion and consensus. No formal quality assessment or risk-of-bias evaluation was performed, as this is a narrative review and the included studies varied considerably in experimental design, models, and outcome measures. However, we critically evaluated the methodological quality of the included studies and have acknowledged the limitations of the current evidence base throughout the manuscript. This search strategy aimed to provide a comprehensive overview of the available evidence on baicalin's neuroprotective potential, while acknowledging the inherent limitations of the current literature.

3. Baicalin and its various biological properties

Baicalin (C₂₁H₁₈O₁₁; 5,6,7-trihydroxyflavone-7-β-D-glucuronide) is recognized as the principal bioactive and pharmacologically relevant constituent of Scutellaria baicalensis [16]. Traditionally, the root of this medicinal plant has been employed in the therapy of a wide range of health circumstances, including but not limited to hypertension, diabetes, dysentery, atherosclerosis, hepatitis, diarrhea, menstrual disorders, insomnia, vomiting, ocular diseases, bleeding, inflammation, the common cold, and respiratory tract infections [17]. A growing body of research has demonstrated that both crude extracts and isolated constituents from S. baicalensis exhibit diverse therapeutic activities, including neuroprotective, anti-inflammatory, antimicrobial, antitumor, anticonvulsant, anti-diabetic, anti-hyperlipidemic, and antimutagenic, activities. To date, over 50 flavonoids have been extracted and characterized from this species, with baicalin and its aglycone form, baicalein, identified as the predominant pharmacologically active compounds [18,19]. Pharmacokinetic research has revealed the intricate in vivo behavior of baicalin, including its hydrolysis within the enterohepatic circulation, carrier-mediated cellular transport, gastrointestinal tract, involvement in multiple metabolic pathways in systemic circulation, and elimination through both urine and bile. Despite these dynamic processes, baicalin exhibits poor oral bioavailability, which may limit its therapeutic effectiveness in clinical settings. Additionally, its pharmacokinetics can be significantly influenced by co-administered medications and underlying pathological conditions. Several studies have identified potential drug–baicalin interactions, offering insights into the mechanisms involved and contributing to safer co-administration strategies in combination therapies [[20], [21], [22], [23], [24]]. Baicalin has demonstrated promising therapeutic potential across a range of systemic disorders, such as inflammatory, metabolic, ocular, and neurological diseases. These impacts are largely associated with its anti-inflammatory, antioxidant, anti-angiogenic, and immunomodulatory actions [[25], [26], [27], [28], [29]]. Furthermore, baicalin has shown anti-obesity, antiviral, and lipid-lowering activities, contributing to liver protection and the mitigation of hepatic disorders, thereby highlighting its hepatoprotective properties [26,30,31]. Baicalin has been revealed to possess multiple neuroprotective impacts within the CNS, notably by facilitating neural differentiation and reducing neuronal apoptosis [32]. In addition, it demonstrates antidepressant- and anxiolytic-like activities, along with the ability to enhance cognitive function [33]. Experimental studies have reported that baicalin offers protection against various neurotoxic insults, including ketamine, middle cerebral artery occlusion (MCAO), oxygen-glucose deprivation (OGD), hydrogen peroxide (H₂O₂), amyloid-β (Aβ) and thrombin, in both in vitro and in vivo experiments [[34], [35], [36]]. Evidence also supports baicalin's neuroprotective efficacy in preventing the progression of neurodegenerative diseases including Parkinson's disease (PD), AD, and cerebral ischemia. These effects are mediated via numerous mechanisms, such as attenuation of oxidative stress, inhibition of excitotoxic damage, enhancement of neurogenesis, suppression of apoptotic pathways, and downregulation of pro-inflammatory cytokine production [29,37,38]. Fig. 1 represents the baicalin structure and its properties.

Fig. 1.

Pathophysiological hallmarks of diverse neurological and psychological conditions. This figure provides an overview of the key underlying mechanisms associated with four distinct brain-related disorders. It highlights that depression and anxiety are characterized by common processes such as neuroinflammation and oxidative stress, with specific contributions from monoamine deficits and HPA axis hyperactivity, respectively. Similarly, the figure delineates the pathological foundations of Alzheimer's disease, including amyloid-β pathology, tau hyperphosphorylation, neuroinflammation, and oxidative stress, alongside the hallmark features of Parkinson's disease, which involve dopaminergic neurodegeneration, α-synuclein aggregation, neuroinflammation, and oxidative stress.

4. Safety and toxicity of baicalin usage

As research into the pharmacological properties of baicalin and its aglycone baicalein has progressed, questions about their clinical safety and possible side effects have also come to the forefront. For example, a randomized, double-blind study involving 72 healthy volunteers who received single oral doses ranging from 100 mg to 2800 mg reported no significant adverse effects, and lab tests found no evidence of liver or kidney toxicity [39]. Similarly, another trial that examined the oral safety of baicalein in 36 healthy participants, who received doses of 200, 400, or 600 mg, found that any side effects were mild and resolved without the need for medical intervention [40]. Fang et al. demonstrated that giving obese C57BL/6J mice an intraperitoneal dose of baicalin (50 mg/kg) led not only to reductions in body weight and improvements in insulin resistance but also to a noticeable easing of glucose intolerance and hyperglycemia [41]. Shi and colleagues showed that baicalin (40 mg/kg) significantly protected liver from acetaminophen-induced damage in mice [42]. However, these findings should not be taken to mean that baicalin and baicalein are entirely risk-free. Some clinical observations have reported that individuals taking baicalein tablets experienced increases in high-sensitivity C-reactive protein (hs-CRP) and triglyceride levels [43]. Importantly, current studies have not thoroughly investigated the timing or mechanisms by which baicalin and baicalein might cause liver or kidney injury. Therefore, more well-designed trials are needed to clarify their potential hepato- and nephrotoxic effects and to assess other possible long-term safety concerns. Given the limited scope of available clinical research, the use of baicalin and baicalein still involves uncertainties and possible risks.

4.1. Dose-dependent toxicity and therapeutic window

While baicalin demonstrates a favorable safety profile at moderate doses, dose-dependent toxicity signals have been observed in preclinical studies. For instance, Yi Cai and colleagues reported that high doses of baicalein (800–1600 mg/kg) administered over eight weeks induced kidney toxicity and fibrosis in rats, accompanied by histopathological changes and upregulation of TGF-β/Smad signaling [42]. Notably, these toxic doses far exceed the therapeutic range typically used in CNS disease models (50–200 mg/kg), suggesting a potential therapeutic window that warrants systematic characterization. However, the therapeutic index—the ratio between toxic and effective doses—has not been formally established for baicalin, and the translation of these dose-response relationships from rodents to humans is complicated by marked interspecies differences in pharmacokinetics, metabolism, and bioavailability.

4.2. Lack of long-term human safety data

A critical limitation of the current safety literature is the absence of long-term human safety data. Most clinical trials have been limited to single-dose or short-term administration (days to weeks), with no studies evaluating the safety of chronic baicalin administration over months or years—a scenario that would be relevant for the management of chronic CNS disorders such as Alzheimer's disease, Parkinson's disease, or depression. Furthermore, the potential for cumulative toxicity, drug-drug interactions with commonly prescribed CNS medications (e.g., antidepressants, anticoagulants, or antiepileptics), and the effects of baicalin on hepatic and renal function during prolonged exposure have not been adequately investigated. The observation of increased hs-CRP and triglyceride levels in some individuals taking baicalein [41] further highlights the need for systematic metabolic monitoring in future long-term studies.

4.3. Priority research questions for safety evaluation

To address these knowledge gaps, we propose that future safety research should prioritize the following questions: (i) What is the no-observed-adverse-effect level (NOAEL) for baicalin in relevant animal models? (ii) Can innovative delivery systems (e.g., nanoparticles, exosomes) improve the therapeutic index by enhancing brain targeting while reducing systemic exposure? (iii) What are the potential drug-drug interactions between baicalin and standard CNS pharmacotherapies? (iv) What biomarkers can be used to monitor early signs of hepatotoxicity or nephrotoxicity during clinical development? Until these questions are adequately addressed, baicalin should be considered a promising experimental agent rather than a clinically established therapy, and its use in clinical settings should be accompanied by careful monitoring of liver and kidney function, metabolic parameters, and potential adverse effects.

Finally, it is crucial that future studies carefully evaluate participants’ health status, particularly liver and kidney function, before and during trials to ensure safety and minimize the chance of adverse reactions.

5. Bioavailability of baicalin

Bioavailability means the degree of drug absorbed into the systemic circulation, reflecting the percentage of drug absorbed by the gastrointestinal tract to the oral amount. Wu et al. reported that baicalin has low water solubility and permeability determine and cannot be transported by passive diffusion into the host cell lipid bilayer, which results in poor absorption and the low bioavailability [44]. Based on these studies, baicalin was characterized as having low oral bioavailability (∼ $2.2\pm 0.2\%$), attributed to limited aqueous solubility and permeability, an unfavorable distribution profile, and instability under physiological conditions [45]. After oral consumption, baicalin undergoes different processes like gastrointestinal hydrolysis, enterohepatic recycling, carrier-mediated transport, etc. [46]. Additionally, due to its glycosidic structure, which makes baicalin highly polar, it cannot easily cross lipid membranes through passive diffusion, resulting in poor absorption in the intestines. In contrast, baicalein, the aglycone form of baicalin, has better permeability because of its high lipophilicity, allowing it to be well absorbed in the gastrointestinal tract [22]. While baicalin shows moderate absorption in the stomach, its absorption is notably lower in the small intestine and colon. On the other hand, baicalein is absorbed more effectively than baicalin across all sections of the gastrointestinal tract. Baicalein is significantly more lipophilic than baicalin (cell membrane permeability (Papp) of baicalin is 0.037 × 10⁻⁶ cm/s vs. cell membrane permeability of baicalein is 7.29 ± 0.70 × 10⁻⁶ cm/s) [47]. Interestingly, after the oral administration of baicalein, baicalin remains the predominant form found in systemic circulation. Intestinal bacteria hydrolyze baicalin to baicalein via β-glucuronidase, and circulating uridine 5′-diphosphate (UDP) glucuronide transferase (UGT) can convert baicalein back to baicalin [20,48]. This dynamic conversion is vital for maximizing baicalin's pharmacological effects. Specifically, the conversion of baicalin to baicalein by intestinal bacteria is a critical step for baicalin absorption, as baicalein is absorbed more efficiently. Studies in germ-free rats revealed significantly lower intestinal absorption of baicalin compared to conventional rats, underscoring the essential role of intestinal microbiota in facilitating baicalin's absorption and utilization [49]. Thus, while a small fraction of baicalin is absorbed directly, the majority is transformed into baicalein by gut bacteria and then absorbed. Due to baicalin's inherent low bioavailability, innovative delivery systems utilizing nano- and micro-scale formulations have demonstrated enhanced absorption and increased bioavailability in preclinical investigations, suggesting potential for future clinical use [46]. In order to enhance its bioavailability, various formulations have been created, including cyclodextrin complexes, self-nanoemulsifying systems, micelles, nanocrystals, and gels. Recent studies show that the absorption of nanoemulsions is much greater than that of suspension forms. Furthermore, it has been documented that baicalin nanoemulsions enhance the saturation solubility of baicalin and improve their interaction with the mucin layer in epithelial tissues, resulting in greater absorption in the intestine [50,51]. The process of nano-sizing bioactive compounds from herbal medicines has attracted increasing interest in recent years. Nanoformulations, including nanoparticles, nanoemulsions, and liposomes, are colloidal systems with particle sizes ranging from 10 nm to 1000 nm. The nanoformulation of herbal medicines offers several advantages, including better solubility, increased bioavailability, enhanced absorption by the body, lower doses of medicinal herbs, and the ability to maintain consistent therapeutic drug levels over a longer duration compared to conventional herbal medicine preparations [52]. In conclusion, baicalin's low oral bioavailability is a major hurdle for its development as a therapeutic agent. The interplay between its poor physicochemical properties, gut microbiota-dependent metabolism, and active efflux are the core reasons for this challenge. Advanced formulation technologies offer a promising path forward to overcome these limitations.

6. Pharmacokinetic limitations and delivery strategies: a critical perspective

The clinical translation of baicalin is severely constrained by its poor oral bioavailability (approximately 2.2%) and limited blood-brain barrier (BBB) penetration [46]. While baicalin can be detected in the brain following systemic administration [53], its hydrophilic nature and active efflux by P-glycoprotein and other ABC transporters at the BBB substantially restrict its CNS accumulation [54]. To address these limitations, a range of advanced delivery systems have been developed, including liposomes, nanoparticles, exosomes, and nanoemulsions, which have shown enhanced bioavailability and brain targeting in preclinical models of CNS diseases [55,56]. However, the clinical adoption of these strategies faces considerable challenges. These include manufacturing scalability and batch-to-batch reproducibility, long-term safety and biocompatibility concerns, high production costs, uncertainty regarding translation from acute animal models to chronic human diseases, and a complex regulatory approval pathway. Therefore, while these delivery systems are promising, their success will depend on rigorous preclinical and clinical validation, cost-effective manufacturing, and careful risk-benefit assessment. Until these challenges are addressed, conventional baicalin formulations remain limited in their clinical applicability, and novel delivery strategies should be viewed as experimental rather than clinically established approaches.

7. Baicalin and neurological diseases

7.1. Cerebral ischemia-reperfusion injury

Ischemia-reperfusion injury (IRI) is a critical pathological process characterized by an initial period of blood supply limitation followed by sudden reoxygenation and perfusion restoration. This cycle frequently exacerbates tissue injury and triggers profound inflammatory responses, contributing to significant morbidity in conditions such as acute kidney injury, ischemic stroke, and myocardial infarction [57,58]. The activation of this inflammasome is often driven by mitochondrial signals, such as mitochondrial DNA (mtDNA) and mitochondrial reactive oxygen species (mtROS), which serve as key triggers for sterile inflammation. Inflammatory injuries possess crucial effects on the cerebral IRI pathogenesis and may become a therapeutic target [[59], [60], [61], [62]]. NLRP3 inflammasome, a fundamental tissue-damage sensor, is critical in sterile inflammation induction. Among its numerous agonists, injured mitochondria and produced mitochondrial signals, including mitochondrial DNA (mtDNA) and mitochondrial reactive oxygen species (mtROS), cause the activation of NLRP3 inflammasome [[63], [64], [65]].

Among all CNS indications, the neuroprotective effects of baicalin in cerebral IRI are supported by the most robust and well-replicated body of evidence, with consistent findings across multiple OGD/R and MCAO/R models establishing AMPK-mediated NLRP3 inhibition and antioxidant effects as key mechanisms [29,66]. Some studies suggest that baicalin decreases the NLRP3 inflammasome activities and suppresses cerebral IRI via activating the Adenylate-activated protein kinase (AMPK) signaling (a modulator of cellular energy), and efficiently improves the ultrastructural alterations of cortical nerve cells damaged by IR [67]. Preliminary evidence indicates that baicalin has protective effects on OGD-damaged human cerebral microvascular endothelial cells and represses the inflammatory response, probably through suppressing the toll-like receptor 4 (TLR4) signaling pathway [68].

While the antioxidant and anti-inflammatory effects are broadly supported, several other mechanisms remain more speculative or are currently restricted to specific experimental models. For instance, the role of the gut-brain axis is an emerging area of interest; recent studies in mice suggest that baicalin's neuroprotection may be mediated through the remodeling of gut microbiota, as antibiotic-induced depletion of microbial populations appears to attenuate its therapeutic effects [69]. Activation of mitochondrial succinate dehydrogenase (SDH) results in an extreme ROS generation through reverse electron transport under situations of IR or OGD/R, leading to an increase in proteasomal degradation and carbonylation of glutamine synthetase (GS) in astrocytes. Baicalin decreases SDH-mediated oxidative stress and decreases the subsequent GS loss. This impact enhances the glutamate disposal by astrocytes and has protective effects on neurons against excitotoxicity in response to IR insults [70]. In a neuron–astrocyte co-culture experiment, baicalin was shown to play beneficial roles against OGD/R–induced injury. It was demonstrated that baicalin at optimal concentrations (∼34.38 μg/mL) preserves astrocyte morphology and enhances BDNF–TrkB signaling. Blocking TrkB attenuated these protective effects, highlighting that baicalin exerts antioxidative, anti-apoptotic, and anti-inflammatory actions via the BDNF–TrkB axis and downstream PI3K/Akt and MAPK/ERK1/2 pathways. This supports the pivotal role of BDNF-linked signaling in baicalin's neuroprotective profile against [71]. While these findings provide a compelling link between baicalin and neurotrophic support, further validation in diverse in vivo models is required to confirm whether these specific pathways constitute a primary mechanism of action in clinical stroke pathology.

A high-throughput screening of the FDA compound library identified baicalin as a potent upregulator of TREM2, a receptor expressed on microglial membranes that plays a critical role in reducing inflammation and oxidative stress. In MCAO/R mouse models and OGD/R-treated microglia, baicalin effectively inhibited microglial activation, ROS production, and inflammatory responses while suppressing neuronal apoptosis, leading to improved neurological function and reduced infarct volume [72].

In a rat model of MCAO/R, baicalin treatment significantly attenuated neuronal damage by modulating proteins involved in energy metabolism, myelination, and neuroinflammation. Proteomic analysis revealed that baicalin mitigated MCAO-induced decreases in adenylate cyclase type 1 and solute carrier family 25 member 12, while reducing elevations in C-reactive protein, apolipoprotein C-II, and other inflammation-associated proteins [73]. At the mitochondrial level, baicalin protects neurons against I/R injury by regulating the PDK2-PDH axis. SDH activation-induced excessive ROS production altered LonP1 and HIF-1α expression in the early stage of I/R, leading to PDK2 upregulation and decreased PDH activity. Baicalin treatment prevented these alterations and ameliorated neuronal ATP production and survival [74].

In addition to studies investigating baicalin as a free compound, several studies have evaluated its effects using advanced formulation and delivery strategies. Where such approaches are discussed, we have clearly distinguished between effects attributable to baicalin alone and those resulting from the delivery system or its synergistic actions. Beyond direct molecular targeting, recent research has focused on optimizing the delivery of baicalin to overcome pharmacokinetic limitations. For instance, the development of liposomal formulations, such as borneol-baicalin liposomes (BO-BA-LP), has been shown to significantly improve brain infarction volume and neurological outcomes in MCAO rat models compared to standard baicalin [75]. These findings underscore that the therapeutic efficacy of baicalin is highly dependent on its bioavailability and delivery systems [76]. In line with this study, BO-BA-LP were developed to improve drug entry into the brain. It increased baicalin concentrations in plasma and brain tissues, improved neurological function and brain edema, and protected blood-brain barrier integrity by regulating the HIF-1α/VEGF/eNOS/NO pathway (6). Furthermore, baicalin liposomes (BA-LP) attenuated cerebral ischemia-reperfusion-induced acute lung injury (CIR-ALI) by modulating inflammatory responses, potentially through the PI3K/AKT/mTOR pathway [77]. It should be noted that the enhanced efficacy observed in these formulation studies is attributable to the combined effects of baicalin and the delivery systems, rather than to baicalin alone.

In the next part, we discuss the therapeutic actions of baicalin in the therapy of ischemic stroke, with a focus on possible action mechanisms.

7.2. Ischemic stroke

Stroke, a prevalent neurological disease related to a high risk of death and disability [78,79], contributes to the disruption of the BBB, where it can mediate neuronal damage via inflammation and cerebral edema [80]. There is mounting evidence that inflammation drives ischemia-mediated secondary cerebral damage, resulting in aggravated BBB dysregulation and cerebral edema [81,82]. Consequently, to achieve more effective neuroprotection against ischemic stroke and find out the mechanisms, discovering novel therapeutic approaches is essential to combat this pathology [83].

In ischemic stroke, baicalin's therapeutic potential is substantiated by a substantial body of preclinical evidence across multiple animal models, consistently demonstrating infarct volume reduction, oxidative stress attenuation, and BBB preservation [84]. The clinically relevant observation that baicalin mitigates hemorrhagic transformation associated with delayed tissue plasminogen activator (t-PA) therapy further strengthens its translational promise [85]. In a recent study, baicalin administration immediately after MCAO surgery reduced oxidative stress markers (ROS and LPO), attenuated histopathological lesions, and prevented apoptosis by modulating Bcl-2/Bax expression and reducing caspase-3 activation, thereby exerting potent neuroprotective effects through its antioxidant and anti-apoptotic properties [86].

Baicalin also improves neurological outcomes by inhibiting astrocyte activation and neuroinflammation. In tMCAO mice, baicalin administration significantly mitigated neurological deficits and reduced the activation of astrocytes, along with decreasing the production of pro-inflammatory cytokines including IL-1β, IL-6, TNF-α, and MCP-1 in vivo and in vitro, with concurrent suppression of NF-κB activation [87].

Additionally, baicalin mitigates excitotoxicity through the SDH/GS pathway, as previously described in the context of cerebral IRI [70].

Beyond direct antioxidant effects, baicalin appears to modulate the neuroinflammatory cascade, though these pathways often involve complex, multi-step signaling. Recent studies suggest that Baicalin inhibits the NLRP3 inflammasome and subsequent pro-inflammatory cytokine production (including IL-6, IL-1 $\beta$, and TNF-$\alpha$) via the SIRT1/NF-$\kappa$ B signaling pathway [88]. Li and co-workers studied the neuroprotective impacts of baicalin in a mouse model of MCAO-induced ischemic stroke. The research showed that baicalin (50 mg/kg) considerably ameliorated neurological outcomes and decreased infarct volume by inhibiting the NLRP3 inflammasome and subsequent inflammatory cytokine production (IL-6, IL-1β, TNF-α) via the SIRT1/NF-κB signaling pathway. Baicalin also enhanced BBB integrity by upregulating tight junction proteins (ZO-1, claudin-5) and mitigated oxidative stress through increased Nrf2/HO-1 expression, reinforcing its potentials as a therapeutic compound for ischemic stroke by targeting inflammation, oxidative stress, and BBB disruption [88]. Consistent with the findings in cerebral ischemia-reperfusion models, baicalin attenuates NLRP3 inflammasome activation and enhances AMPK phosphorylation in the context of ischemic stroke [67].

Furthermore, baicalin plays a critical role in preserving BBB integrity. It has been shown to upregulate essential tight junction proteins, specifically ZO-1 and claudin-5 [89]. A particularly clinically relevant finding is baicalin's ability to mitigate t-PA-induced hemorrhagic transformation. By scavenging peroxynitrite and suppressing the expression of matrix metalloproteinase-9 (MMP-9), baicalin stabilizes the ischemic brain during delayed t-PA therapy without interfering with the drug's primary fibrinolytic activity [89].

In addition to single-agent studies, several investigations have evaluated baicalin in combination with other bioactive compounds or within herbal formulations. In the following studies, we have distinguished between effects attributable to baicalin alone and those resulting from the combined actions of multiple agents. In research carried out by Ma et al., RQKL (a mixture of hyodeoxycholic acid, cholic acid, geniposide, and baicalin) was shown to inhibit astrogliosis and microgliosis, and protect neurons from IRI. It also suppressed apoptosis by affecting the B-cell lymphoma-2 (Bcl2) and Bcl2-associated X (Bax) ratio. Moreover, RQKL contributed to activate phosphatidylinositol 3-kinase (PI3K)/Akt signaling and block inflammatory responses by increasing the anti-inflammatory mediator IL-10, reducing the generation of pro-inflammatory factors including TNF-α, IL-6, and IL-1β, as well as chemokines including Cxcl3, Cxcl2, and Ccl2 [90]. Both jasminoidin (JA) and baicalin are active compounds in Chinese herbal medicine. They have been revealed to display additive neuroprotective actions in ischemic stroke models. In a study, the baicalin and JA-specific mechanisms were connected to apoptosis and cancer-associated signaling, as well as hormone regulation. In animals treated with the combinational therapy of JA and baicalin, their synergistic effects were based on increased actions in virus-induced immune responses [89]. It has been shown that co-therapy with baicalin considerably decreases the mortality rate, and improves the t-PA-induced hemorrhagic transformation and BBB disruption. Moreover, baicalin scavenges peroxynitrite and suppresses the activity and expression of MMP-9 in the ischemic brain with the delayed t-PA therapy. Baicalin does not influence the fibrinolytic activity of t-PA, as demonstrated by t-PA activity assays. In summary, baicalin has the potential to reduce t-PA-mediated hemorrhagic transformation and ameliorate the therapeutic outcomes of ischemic stroke, likely by inhibiting the activation MMP-9 induced by peroxynitrite [85].

Aside from studies on baicalin alone, considerable attention has been directed toward formulation-based strategies to overcome its pharmacokinetic limitations. These approaches have shown that the resulting neuroprotection often arises from the interplay between baicalin and the delivery system, rather than from the compound in isolation. Baicalin has demonstrated a consistent ability to mitigate oxidative stress through the activation of the Nrf2/HO-1 pathway, a finding replicated across both in vitro OGD models and in vivo MCAO models. In a recent study, novel brain-targeted baicalin-loaded macrophage-derived exosomes were designed to mediate neuroprotective effects against ischemic stroke in vivo. The findings showed that, with the exosome's help, the baicalin solubility was markedly increased. Additionally, exosome-baicalin showed better brain targeting properties compared to free baicalin, as they mediated the transfer of more baicalin into the brain. Exosome-baicalin considerably decreased the ROS generation and activated the Nrf2/HO-1 signaling in neurons compared to free baicalin, hence remarkably attenuating brain ischemic injuries in a stroke model [84]. Huang et al. further supported the efficacy of baicalin-loaded macrophage-derived exosomes in a mouse model of MCAO-induced ischemic stroke. Baicalin (exosome-encapsulated, 10 mg/kg) remarkably ameliorated neurological scores, decreased infarct volume, and attenuated brain injury by enhancing antioxidant defenses. The exosomes facilitated targeted delivery of baicalin across the BBB, activating the Nrf2/HO-1 pathway, decreasing lipid peroxidation and ROS. In vitro experiments with OGD-treated neurons confirmed that baicalin-exosomes mitigated oxidative stress and neuronal apoptosis, highlighting an innovative delivery system to enhance baicalin's therapeutic efficacy in stroke [84].

Overall, these findings indicate that while baicalin exerts intrinsic neuroprotective effects, its therapeutic potential is significantly enhanced when combined with appropriate delivery systems or synergistic bioactive compounds. Accordingly, the distinct contributions of baicalin itself versus those of the accompanying formulation should be carefully considered when interpreting the results of such combination studies.

7.3. Multiple sclerosis and demyelination

A recent study demonstrated that baicalin can directly promote CNS remyelination through activation of the peroxisome proliferator-activated receptor gamma (PPARγ) pathway. In this work, oligodendrocyte precursor cells (OPCs) were treated with baicalin in vitro, showing significantly enhanced OPC differentiation into mature oligodendrocytes via PPARγ activation; pharmacological inhibition of PPARγ abolished this effect. In vivo, a demyelination mouse model received baicalin at a dosage of 100 mg/kg/day, which resulted in improved remyelination and better preservation of myelin integrity compared to untreated controls. These findings indicate that baicalin exerts a dual action by suppressing inflammation and directly stimulating oligodendrocyte maturation, underscoring its promise as a therapeutic candidate for demyelinating disorders including multiple sclerosis (MS). Nonetheless, the study recognizes certain limitations, such as the necessity for dose-response validation, a comprehensive assessment of long-term safety, and further investigation of its translational potential in human models [91]. Recent studies have broadened the scope of baicalin's potential applications to include demyelinating diseases. The findings indicate that, in a cuprizone-induced demyelination mouse model, baicalin (50–100 mg/kg) facilitates remyelination by promoting the differentiation of OPC and inhibiting microglial activation via direct targeting of the TLR4/MD2 complex. This mechanism downregulates the PI3K/AKT/NF-κB axis, reduces pro-inflammatory cytokines, and increases IL-10 production, supporting baicalin's dual anti-inflammatory and remyelinating activities [92]. Song et al. (2023) investigated the improving roles of baicalin in a rat model of chronic cerebral hypoperfusion (bilateral common carotid artery occlusion) to simulate vascular dementia. Rats received baicalin orally at 100 mg/kg/day for 4 weeks alongside behavioral assessments (Morris water maze) and histological, molecular, and immunohistochemical analyses. Baicalin significantly improved cognitive performance, reduced CA1 pyramidal neuron damage, and mitigated white matter demyelination—evidenced by elevated expression of MBP and Olig2, preserved oligodendrocyte numbers, and enhanced regeneration in the corpus callosum. The compound also shifted microglia toward an anti-inflammatory phenotype, lowering pro-inflammatory cytokines. Mechanistically, baicalin activated Wnt/β-catenin signaling—as shown by increased GSK3β phosphorylation and β-catenin nuclear translocation—while inhibiting NF-κB expression. Limitations include reliance on a single dosage, short-term follow-up, and unknown translatability to humans. Thus, baicalin appears to promote remyelination and suppress neuroinflammation in chronic hypoperfusion, highlighting its potential for vascular dementia therapy [70].

The evidence for baicalin in multiple sclerosis and demyelinating disorders is limited to a small number of preclinical studies, primarily in cuprizone-induced demyelination models and chronic cerebral hypoperfusion models. These studies have reported that baicalin promotes remyelination through PPARγ activation and reduces neuroinflammation via TLR4/MD2 targeting. However, given the limited number of independent replications and the absence of validation in additional demyelinating models, these findings should be considered preliminary and hypothesis-generating.

7.4. Spinal cord injury

Spinal cord injury (SCI) can result from various causes, including traumatic events, medical conditions, or congenital abnormalities, and often leads to significant neurological impairments ranging from partial dysfunction to severe disability or death. This condition predominantly affects young adults between the ages of 15 and 29 and imposes a substantial healthcare burden due to the extended duration of hospitalization required for management and recovery [93]. SCI typically unfolds in two phases: the initial or primary injury caused directly by the traumatic event, and the secondary phase, which involves a cascade of pathological processes occurring over time and is categorized into acute, subacute, and chronic stages. The acute and subacute phases are marked by ischemia, apoptotic signaling, and infiltration of immune cells that release pro-inflammatory mediators and cytotoxic elements, such as ROS, ATP, and fragmented DNA, which collectively worsen the injury site's microenvironment [[94], [95], [96]]. Mounting data also underscores the crucial role of gene expression changes in glial cells, immune cells, and sensory neurons in the initiation and persistence of neuropathic pain following SCI [97]. Now, the SCI therapy consists of pharmacotherapy [98], physical therapy [99], stem cell transplants [100], and reparative surgery [101]. Drugs are utilized to decrease the deleterious impacts caused by the second moment of SCI. For instance, the synthetic glucocorticoid methylprednisolone has been administered to reduce inflammatory responses and lipid peroxidation. However, it has some unwanted side effects, including gastrointestinal diseases, hemorrhage, and infections. Moreover, there is no preventive method for the formation of glial scar, compromising local axonal regeneration [102]. Because there are no effective treatments for inhibiting the aforementioned adverse effects or glial scar formation, the quest for novel SCI treatment options is important.

In SCI models, baicalin has shown promising effects in reducing blood-spinal cord barrier permeability and attenuating neuronal apoptosis through PI3K/Akt activation, although the evidence remains limited to a small number of studies [103]. Zhao et al. further confirmed baicalin's neuroprotective effects in a rat model of SCI using the Allen's weight-drop method. Baicalin (100 mg/kg) administered post-injury reduced BBB permeability, decreased neuronal apoptosis, and improved motor function recovery over 28 days. Mechanistically, it activated the PI3K/Akt signaling pathway, which inhibited caspase-3 activity and promoted neuronal survival. Histological analysis showed reduced lesion size and enhanced axonal regeneration, reinforcing baicalin's CNS applicability through its BBB penetration and PI3K/Akt-mediated neuroprotection [103]. Additionally, baicalin has been shown to protect against neuronal apoptosis induced by spinal cord ischemia. Its administration remarkably reduced the levels of glutamine synthase (GS) and glutaminase (GLS), suggesting that baicalin modulates the expression of these enzymes. Beyond its anti-apoptotic role, baicalin also exhibits anti-inflammatory effects, improves motor function in the lower limbs, mitigates the severity of SCI, and helps restore serum metabolic homeostasis in SCI rat models [104]. Baicalin also exhibits significant anti-inflammatory properties relevant to SCI. It has been shown to mitigate the severity of SCI, improve motor function in the lower limbs, and help restore serum metabolic homeostasis [104].

In the context of neuropathic pain, a common sequela of SCI, baicalin has demonstrated potential by downregulating histone deacetylase 1 (HDAC1) expression and inhibiting histone H3 acetylation in the dorsal horn of the spinal cord, suggesting a role in modulating gene expression related to pain signaling [97].

While not explicitly detailed in the provided excerpts as a direct mechanism for SCI, baicalin's ability to modulate glial cell phenotypes (as seen in other contexts) and its role in promoting axonal regeneration and preserving oligodendrocyte numbers indirectly suggest a potential benefit in combating the glial scar, a major impediment to functional recovery after SCI [64,75].

Moving beyond conventional administration, a biomimetic nanoplatform has been developed to enable targeted baicalin delivery in SCI models. A biomimetic nanoplatform (Ba@Se-MSN&BV2) was engineered by loading baicalin into diselenide-bridged mesoporous silica nanoparticles (MSNs) and cloaking them with BV2 microglial membranes, enabling lesion-targeted accumulation and ROS-triggered, on-demand release in ROS-rich lesions. In glutamate-injured HT22 cells and primary hippocampal neurons, Ba@Se-MSN&BV2 reduced ROS, partially restored mitochondrial membrane potential, suppressed apoptosis, and enhanced neurite outgrowth, with protection exceeding that of free baicalin. In LPS-stimulated BV2 microglia, the nanoplatform lowered IL-1β and TNF-α, increased Arg1 and IL-10, and shifted polarization toward an anti-inflammatory, reparative phenotype. In a mouse contusion SCI model, Ba@Se-MSN&BV2 preferentially accumulated at the lesion, mitigated oxidative burden, attenuated glial scarring, and preserved axons and neurons, accompanied by sustained improvements in locomotor recovery. Proteomics highlighted CHCHD2 as a mitochondria-associated candidate that was downregulated in glutamate-injured neuronal cells and restored by Ba@Se-MSN&BV2. Knockdown/rescue assays supported a contributory role of CHCHD2 in the neuroprotective profile of the nanoplatform [105]. These findings reveal that biomimetic nanocarriers can substantially enhance baicalin's therapeutic performance, with the observed benefits being attributable to the synergistic action of the compound and the delivery system rather than to baicalin alone.

7.5. Parkinson's disease

PD is a progressive and long-lasting neurodegenerative condition characterized by the gradual loss of dopaminergic (DA) neurons in the substantia nigra (SN). This disorder is also associated with the buildup of intracellular Lewy bodies (LBs), which are predominantly formed from aggregated α-synuclein (α-Syn). [106]. In early 1924, researchers found that iron increased noticeably in the globus pallidus and SN of the PD patients' brains [107,108]. Elevated iron activity promotes oxidative stress, leading to a large number of ROS, resulting in cell death [[109], [110], [111], [112]]. Currently, the existing medications for PD primarily focus on alleviating the symptoms rather than halting the progression of the disease or preventing the degeneration of DA neurons. Baicalin has different therapeutic functions; however, the pivotal underlying mechanisms by which baicalin applies its preventive effects on the PD pathogenesis remain unclear [106].

Evidence for baicalin in PD is moderate, with several in vitro and in vivo studies reporting protection against dopaminergic neuron loss, reduction of oxidative stress, and inhibition of α-synuclein aggregation in toxin-induced models (e.g., MPTP, 6-OHDA). While these findings are promising, they are derived from a limited number of experimental paradigms, and the mechanisms underlying baicalin's neuroprotective effects, particularly its regulation of C/EBPβ and Nrf2 pathways, require further validation in additional models before they can be considered well-established.

In an experimental study, baicalin protected DA neurons against ROS and reduced the expression of C/EBPβ and α-synuclein in pLVX-Tet3G-α-synuclein SH-SY5Y cells. Therefore, baicalin blocked C/EBPβ by redox homeostasis, which may be an effective potential therapy for PD [106]. Lei and co-workers further elucidated baicalin's protective effects in PD using SH-SY5Y cells treated with 6-hydroxydopamine (6-OHDA) and an MPTP-induced mouse model. Baicalin (50 μM in vitro; 50 mg/kg in vivo) reduced ROS levels, protected dopaminergic neurons, and mitigated motor deficits. It inhibited C/EBPβ activation, a transcription factor linked to oxidative stress, and restored mitochondrial function. Behavioral tests (rotarod, pole test) confirmed improved motor coordination, highlighting baicalin's role in PD through C/EBPβ inhibition and mitochondrial protection [106]. Baicalin possesses a notable protective impact on 6-OHDA-mediated PD rats, via its antioxidant potentials, and through promoting the release of neurotransmitters and modulating the metabolism of N-acetyl aspartate and glutamate [113]. Thus, baicalin can prevent neurodegeneration in 6-OHDA-mediated PD rats via modulation of monoamine neurotransmitter release, antioxidant activities, suppression of dopaminergic neurons apoptosis in SN, and [113].

In α-syn/MPP⁺-treated BV2 cells and MPTP-induced C57BL/6 mice, baicalin mitigated oxidative stress, microglial activation, and inflammatory responses, protecting against dopaminergic neuron loss and relieving motor deficits. Baicalin significantly up-regulated Nrf2 and its downstream antioxidant enzymes while suppressing NLRP3 inflammasome activation. Notably, the beneficial effects of baicalin were blocked by Nrf2 knockdown, indicating that its neuroprotective actions depend on Nrf2-mediated antioxidative responses [114].

7.6. Alzheimer's disease

AD, the most common form of dementia, is a multifactorial, age-associated neurodegenerative disorder. Clinically, it is primarily characterized by memory impairment, progressive cognitive decline, and eventual loss of intellectual function. Currently, an estimated 47.5 million individuals are affected by AD worldwide, with projections indicating this number may rise to 82 million by 2030 and exceed 152 million by 2050 [115]. Although its precise etiology remains unclear, the hallmark symptom, cognitive deterioration, imposes a substantial burden on patients, caregivers, and healthcare systems [116]. The disease is commonly related to the presence of intracellular neurofibrillary tangles and extracellular amyloid plaques; however, the exact cellular processes leading to these pathological changes are not fully understood [117]. Amyloid-beta (Aβ) accumulation in the brain is widely regarded as a fundamental event in AD pathogenesis [77], where cleavage of amyloid precursor protein (APP) by the active component of γ-secretase generates Aβ peptides [118]. The AD pathogenesis may be caused by some cellular events and processes, including abnormal β-amyloid protein deposition, tau protein hyperphosphorylation, neurotransmitter response, inflammatory response, autophagy, oxidative stress, and the cholinergic hypothesis [119]. Some natural compounds have been revealed to protect against neurodegeneration and ameliorate cognitive function and brain memory through modulating a wide range of pathways [120,121]. As mentioned earlier, anti-neurodegenerative potentials of baicalin are associated with its important potentials, including antioxidant, anti-apoptotic, and anti-inflammatory effects, and expression promotion of neuroprotective factors [26,28,122].

Of note, the neuroprotective effects of baicalin in AD are supported by a relatively large body of preclinical evidence, with consistent findings across multiple transgenic mouse models and Aβ-induced injury models. These studies have collectively demonstrated improvements in cognitive function, reduction of Aβ plaque burden, and attenuation of tau hyperphosphorylation. However, despite the robustness of these preclinical data, no targeted clinical trials have been conducted to date, and the translational relevance of these findings to human AD pathology remains to be established.

Baicalin suppresses the neuroinflammation triggered by LPS in BV-2 microglia through inhibiting the TLR4-induced signal transduction by the mitogen-activated protein kinase (MAPK) and TLR4/myeloid differentiation protein 88 (MyD88)/nuclear factor κB (NF-κB) pathways and blocking the expression of microRNA-155 (which promotes neurodegeneration) [88].

Accumulating preclinical evidence indicates that baicalin can alleviate Aβ-associated cognitive impairment while reducing glial reactivity and downstream neurotoxic signaling. In rat models, baicalin improved Aβ1–42–mediated cognitive dysfunction and attenuated Aβ1–42–induced glial activation, supporting a consistent anti-neuroinflammatory phenotype across related experimental setups. At the cellular level, baicalin enhanced survival-related measures in Aβ-challenged SH-SY5Y cells (increased viability/proliferation and reduced apoptosis) and mitigated Aβ1–42–associated cell-cycle arrest at the S phase [123]. At the cellular level, baicalin enhanced survival-related measures in Aβ-challenged SH-SY5Y cells (increased viability/proliferation and reduced apoptosis) and mitigated Aβ1–42–associated cell-cycle arrest at the S phase. These findings collectively point to a reasonably well-supported protective effect on neuronal survival under Aβ stress [124]. Baicalin has been indicated to increase cell viability, stimulate proliferation, and reduce apoptosis in SH-SY5Y neuroblastoma cells following exposure to Aβ_1-42. Additionally, it mitigates Aβ_1-42-mediated cell cycle arrest at the S phase and influences apoptotic processes. Baicalin also downregulates the expression of cyclin D1, phosphorylated ERK (p-ERK), and Ras proteins upregulated by Aβ exposure, and this suppression is counteracted by a MEK pathway activator. These findings recommend that, via suppressing the Ras–ERK signaling, baicalin may modulate neuronal cell cycle apoptosis and progression in Aβ1–42-treated SH-SY5Y cells [124]. Wang et al. investigated baicalin's effects on AD using APP/PS1 transgenic mice and Aβ-treated primary neurons. Baicalin (50 mg/kg) decreased Aβ plaque burden and ameliorated spatial memory through the upregulation of the Wnt/β-catenin signaling, which promotes neurogenesis and synaptic plasticity. It also decreased tau hyperphosphorylation and neuroinflammation (lower IL-1β, TNF-α). In vitro, baicalin (10–20 μM) protected neurons from Aβ-induced toxicity, strengthening the evidence for Wnt/β-catenin as a novel mechanism in baicalin's anti-AD effects [125]. In a rat model of AD, baicalin improved spatial learning and memory (reduced escape latency, increased cross-platform time), increased hippocampal neuron survival, and decreased neuronal apoptosis. Mechanistically, baicalin downregulated NPTX-1 and CRP expression while upregulating NPTX-2 expression in brain tissue [126].

In a model of AD comorbid with type 2 diabetes (AD-T2DM), baicalin remarkably improved cognitive performance, ameliorated glucose and lipid metabolism, and suppressed neuroinflammation. Metabolomics revealed disruptions in energy, amino acid, and purine metabolism pathways. Network pharmacology identified ALDH2, NOS2, GOT1, GPT, and XDH as key targets. Baicalin directly bound to and regulated ALDH2 and NOS2 gene expression, modulating arginine and proline metabolism and key metabolites such as GABA and l-arginine, thereby improving neuronal function and insulin sensitivity [127].

In an aged mouse model (18 months old), oral baicalin was administered at 50 mg/kg daily for 8 weeks to assess its effects on age-related cognitive decline and cerebrovascular health. Behavioural evaluations including the novel object recognition and Morris water maze showed remarkable ameliorations in recognition and spatial memory compared with untreated aged controls. Histological analyses showed that baicalin mitigated neuronal loss in the hippocampal CA1 region, enhanced synaptic density (elevated PSD-95 and synaptophysin expression), and reduced microglial activation and inflammatory cytokines (TNF-α, IL-1β). Baicalin also preserves BBB integrity in AD models, similar to its effects observed in ischemic stroke. Mechanistically, baicalin boosted antioxidant defenses (elevated SOD, decreased MDA) and upregulated brain-derived neurotrophic factor (BDNF)–TrkB signaling. Limitations included the use of only one baicalin dose, male-only subjects, absence of long-term follow-up, and lack of translational measures such as pharmacokinetics and safety in humans [69].

In the context of AD, nanotechnology-based strategies have also been explored to overcome baicalin's bioavailability limitations and enhance its therapeutic efficacy. Baicalin-myricetin-coated selenium nanoparticles (BMSe@BSA) were developed for targeted brain delivery in AD. These nanoparticles, with an average size of 90.57 nm and entrapment efficiency of ∼90%, effectively inhibited amyloid fibril formation, downregulated pro-inflammatory cytokine expression (IL-1β, TNF-α), preserved neuronal integrity, and significantly enhanced cognitive performance in Aβ1-42-induced AD mouse models, demonstrating a promising nanotherapeutic approach for multi-pathway intervention in AD [128].

7.7. Traumatic brain injury

Traumatic brain injury (TBI) is a major global health burden, causing extensive cerebral tissue damage and increasing long-term risk of neurodegeneration and disability [[129], [130], [131]]. Although TBI is often followed by persistent neurological sequelae—including vascular dementia, Alzheimer's disease, motor deficits, and behavioral/personality changes—the therapeutic landscape remains limited, with a lack of treatments that robustly and specifically target post-traumatic secondary injury processes [132,133]. Mechanistically, TBI pathology is commonly conceptualized as comprising an immediate primary injury (largely irreversible) and a subsequent secondary injury phase, during which inflammatory signaling, oxidative stress, apoptosis, and calcium dysregulation progressively exacerbate neuronal loss and circuit dysfunction [134,135]. Within this secondary phase, intervention is considered potentially modifiable. Although noninvasive neuromodulation approaches such as repetitive transcranial magnetic stimulation and transcranial direct current stimulation have been explored, their clinical impact is constrained by insufficient spatial targeting precision, and no current therapy has consistently demonstrated sufficient efficacy to meaningfully improve outcomes across TBI patients [[136], [137], [138]]. Accordingly, identifying agents that interfere with convergent secondary injury pathways remains a key translational goal.

Baicalin has attracted attention for its ability to mitigate several TBI-related endpoints, particularly brain edema, oxidative stress, mitochondrial dysfunction, apoptosis, and neurobehavioral impairments. Across the studies summarized here, protective outcomes (e.g., reduced edema and improved functional performance) appear consistent, although the mechanistic depth and causal support vary by pathway and model. A central mechanistic theme involves cell stress–response regulation, including proposed roles in autophagy and mitochondrial apoptosis. Baicalin has been reported to promote autophagy and to ameliorate mitochondrial apoptotic injury in experimental TBI models [139]. In a separate study, baicalin reduced brain edema, apoptosis, and oxidative stress while activating the Akt/Nrf2 axis and improving neurological function [140]. While these findings converge on reduced cell-death and oxidative injury, the current evidence should be interpreted with care: statements about autophagy involvement are biologically plausible given autophagy's established participation in apoptosis regulation across CNS disorders, but, in the TBI context presented here, the mechanistic linkage between autophagy modulation and baicalin's functional benefit remains model- and study-dependent unless accompanied by direct causal testing (e.g., autophagy inhibition or rescue experiments) [[141], [142], [143]]. With respect to PI3K/Akt–Nrf2 signaling, the directionality of the proposed pathway is reasonably consistent: Akt/Nrf2 activation is repeatedly associated with antioxidant enzyme induction and reduced oxidative damage in TBI models treated with baicalin [144,145]. Baicalin also activates the Akt/Nrf2 antioxidant axis in TBI models, consistent with its effects observed in ischemic stroke [146].

These results support a pathway-level association linking baicalin to oxidative stress mitigation via Akt/Nrf2. However, as currently described, the mechanistic claims would be strengthened by additional evidence demonstrating causality (e.g., pathway inhibition demonstrating loss of baicalin protection, or genetic/target-specific validation across more than one TBI paradigm). Therefore, Akt/Nrf2 should be presented as a prominent and plausible mechanism, but not uniformly established as causal across all studies. In addition to single-agent effects, combination approaches suggest that baicalin may synergize with other neuromodulatory/therapeutic strategies to enhance neuroprotection. Peng and colleagues reported that combined treatment (baicalin plus low-intensity transcranial ultrasound) produced greater protection against brain damage than baicalin or ultrasound alone. This supports the broader therapeutic potential of baicalin as part of multi-modal interventions; nevertheless, generalization to other TBI settings requires further comparative evaluation. Overall, the most consistent therapeutic theme across the cited TBI studies is attenuation of secondary injury, reflected by reduced edema, oxidative stress, and apoptosis, alongside improved neurobehavioral outcomes. Proposed mechanistic explanations—particularly Akt/Nrf2-mediated antioxidant defense and downstream reductions in mitochondrial/apoptotic injury and inflammatory reactivity—are supported by experimental correlates and pathway activation patterns in TBI models [140,147]. Still, several mechanistic elements (notably autophagy as a causal mediator) should be framed as hypotheses based on current model evidence, rather than as established consensus mechanisms, until stronger causal intervention data and replication across additional paradigms are available. The evidence summarized here is derived from preclinical TBI models and focuses on relatively short-term functional and molecular endpoints. Broader translational interpretation will require more standardized dosing schedules, inclusion of both sexes, longer follow-up, and pharmacokinetic/safety characterization—particularly because TBI severity and secondary injury trajectories vary substantially across clinical presentations [[136], [137], [138]]. Table 1 summarizes current evidence on the beneficial properties of baicalin against neurological diseases.

Table 1.

The therapeutic effects of baicalin against neurological diseases.

Disease	dose	Targets/pathways	effects	Model	Cell line/Animal	Ref
Cerebral IRI	100- 200 mg/kg	AMPK signaling pathway, NLRP3	Activation of the AMPK signaling pathway, decrease the activity of the NLRP3 inflammasome; suppress cerebral ischemia-reperfusion injury.	In vivo	SD rats	[67]
	-	TLR4 pathways, B(p-NF-κB)	Inhibit inflammatory response, decrease the expression of TLR4 and p-NF-κB, protective effect on HBMECs.	In vitro	HBMECs	[68]
	25 mg/kg(BO-BA-LP) intravenously	-	Improve cerebral I/R, brain infarction volume, and neurological deficits.	In vivo	Rats	[75]
	18 mg/kg(BA and BA-LP)	-	Alleviate pathological injuries of I/R.	In vivo	Rats	[76]
	50-100 mg/Kg	TMA, TMAO, IL-1β, IL-6, and TNFα,	Suppress neuro-inflammation; improve hippocampal neuronal plasticity, memory and cognition.	In vivo	Mice	[69]
	1 μmol/L, 10 μmol/L 50 mg/kg	SDH activation, ROS, GS	Decrease oxidative stress; promote GS stability, prevention of neuronal injury.	In vitro, in vivo	Astrocytes SD rats	[70]
Ischemic stroke	Refined Qingkailing (RQKL) 15, 30, and 60 mg/kg	Bcl2, IL-1β, IL-6, IL-10, TNF, AKT/PI3K signaling pathway	Inhibit inflammatory response and cell apoptose, prevent blood-brain-barrier damage.	In vivo	SD rats	[90]
	Exo-BA(containing 1.6 mg of BA)	ROS, Nrf2/HO-1 pathway	Suppress ROS generation, up-regulate Nrf2/HO-1 pathway, anti-oxidative effects, and improve cerebral ischemic injury.	In vivo	SD rats	[84]
	combinationof BA and JA 2 mL/kg (BA (5 mg/mL), JA (25 mg/mL))	CD27, IL-6, IL-10, NF-κB, TLR	Synergistic effects between BA and jasminoidin(JA), reduce infarct volume.	In vivo	male mice	[89]
	50, 100, 150 mg/kg combination therapy with t-PA	MMP-9	Attenuate t-PA-induced HT, reduce mortality rate treatment.	In vivo	SD rats	[85]
Spinal cord injury	50-200 mg/Kg 40 μM	Bax, Bcl-2, Caspase-3 NF-κB, PI3K/Akt signaling pathway	Decrease neuronal apoptosis and pathological spinal cord injury; increase the Basso, Beattie, Bresnahan Locomotor Rating Scale score.	In vivo	Female SD rats SH-SY5Y cells	[103]
	50-100 mg/Kg	IL-1β, IL-6, TNFα, NF-κB,	Anti‐inflammatory effect, protective effects on ameliorating Spinal cord injury.	In vivo	Male SD rats	[104]
Parkinson	20- 40 mg/kg 25-50 μM	ROS, C/EBPβ	Anti‐inflammatory effect, ameliorate the Parkinson's disease behavior performance, decrease neuron loss in the substantia nigra.	In vivo, in vitro	Male mice SH-SY5Y cells	[106]
	50, 100, 150 mg/kg	SOD, CAT, GSH-Px activity, MDA content	Anti-oxidant effect, modulate release of monoamine neurotransmitter, decrease dopaminergic neuron loss in the substantia nigra.	In vivo	SD rats	[113]
Alzheimer disease	0.8-67.5 μM	TLR4/MyD88/NF-κB and MAPK pathways, MAPK family	Suppress neuro-inflammation.	In vitro	BV-2 microglia	[88]
	30, 50,100 mg/kg	TNF-α, IL-6	Suppress neuro-inflammation; improve amyloid β1–42 protein-related pathology and memory deficits.	In vivo	Male mice	[123]
	5 μM, 10 μM, 20 μM	Ras-ERK signaling pathway.	Suppress apoptosis.	In vitro	SH-SY5Y cells	[124]
TBI	100 mg/Kg	mitochondrial apoptotic pathway	Reverse TBI-induced apoptosis; improve disruption of the BBB, decrease cerebral edema, neuroprotective effects.	In vivo	Mice	[139]
	50, 100,150 mg/kg	Akt/Nrf2 pathway	Neuroprotective effect, ameliorate neurobehavioral function.	In vivo	Male mice	[140]
	20 mg/kg, combined with LITUS	-	Synergistic neuroprotective effects.	In vivo	SD rats	[145]

8. Baicalin and psychological diseases

8.1. Depression

Major depressive disorder (MDD) is a debilitating condition marked by persistent depressed mood, reduced interest in activities, cognitive impairments, and vegetative symptoms, including disrupted appetite or sleep [148]. Although therapeutic methods have considerably expanded in recent years, between one and two-thirds of affected subjects will not respond to the first antidepressant medications, and 15-33% will not respond to various interventions [149,150]. Therefore, a remarkable proportion of depression patients have persistent or residual manifestations despite adequate antidepressant treatment. Failure to achieve remission with antidepressants can cause elevated recurrence or relapse risk, impaired vocational and social function, and a poor prognosis [151]. Thus, finding novel therapeutics is an ongoing struggle in depression therapy.

The antidepressant effects of baicalin are supported by a relatively substantial body of preclinical evidence, with consistent findings across multiple behavioral paradigms including chronic unpredictable mild stress (CUMS), corticosterone-induced, and olfactory bulbectomy models. These studies have identified several converging mechanisms, including suppression of neuroinflammation, reduction of oxidative stress, and promotion of hippocampal neurogenesis. However, the evidence remains entirely preclinical, and no controlled clinical trials have evaluated baicalin for major depressive disorder.

Adult hippocampal neurogenesis is essential for modulating emotional resilience, extinguishing panic-related memories, and enhancing psychiatric adaptability, particularly in the context of depressive disorders. Experimental behavioral assays have shown that baicalin alleviates symptoms like depression-like behaviors, mechanical allodynia, and thermal hyperalgesia. Notably, inhibition of the Akt signaling pathway significantly diminishes the therapeutic benefits of baicalin in reducing these inflammation-induced behavioral symptoms. Collectively, it is hypothesized that baicalin exerts analgesic effects by promoting adult hippocampal neurogenesis through Akt-dependent mechanisms [152].

Inflammation has crucial roles in the pathogenesis of depression. Regarding the anti-inflammatory potentials of baicalin, several investigations have underscored the anti-depressive activities of baicalin, hence making it a compelling potential agent in depression treatment. Recent investigations have shown that the baicalin's anti-inflammatory impacts are linked to TLR4, which takes part in pathological alterations of CNS diseases such as depression. In this context, Li et al. demonstrated that, in a CUMS mouse model of depression, administration of baicalin at doses of 25 and 50 mg/kg notably alleviated depressive-like behaviors. Furthermore, baicalin markedly decreased the levels of pro-inflammatory mediators, such as TNF-α, IL-6, and IL-1β, in serum, hippocampal tissue, and cell culture supernatants. It was also revealed that baicalin suppressed the expression of key inflammatory mediators such as HMGB1, phosphorylated NF-κB p65, and TLR4 in both in vivo and in vitro models. [153]. Another research carried out by Guo et al. on neuroinflammation-mediated depressive-like behaviors of CUMS mouse model revealed beneficial effects of baicalin (60 mg/kg); this outcome was probably via the TLR4 expression suppression through the PI3K/AKT/FoxO1 axis [154]. Similarly, Zhang and colleagues indicated that baicalin contributed to neuronal survival and their differentiation through the Akt/FOXG1 signaling, resulting in antidepressant impacts [155].

According to the results of a recent study performed by Yu and co-workers, baicalin (20 and 40 mg/kg) reverses depression‐like symptoms, including the elevation in corticosterone concentrations as well as hypothalamic and hippocampal inflammation inhibition. Moreover, baicalin concurrently reverses the expression of NF‐kB p65 and SIRT1 in the olfactory bulbectomized rat model and BV‐2 cells. This research illustrated that the antidepressant‐like effect of baicalin is probably applied via modulating inflammation and increase of the SIRT1‐NF‐kB signaling pathway [156].

The peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) is a transcriptional coactivator that constrains inflammation by NF-κB pathway regulation. Baicalin enhances the PGC-1α expression and alleviates the depression-like behaviors. Moreover, baicalin alleviates neuroinflammation in the hippocampus of mice through modulating the NF-κB; however, PGC-1α knockdown reverses the baicalin effects on neuroinflammation as well as the NF-κB signaling [157]. In addition to the anti-inflammatory potentials of baicalin in the reduction of depression-like behaviors, it has been shown that baicalin exerts its beneficial impacts via suppression of oxidative stress, promotion of hippocampal neurogenesis, and regulation of BDNF/ERK/CREB, Wnt/β-catenin, and NMDAR/NR2B-ERK1/2-related pathway [[158], [159], [160]]. Baicalin also alleviates chronic corticosterone-mediated depressive-like behaviors by promoting the adult-born hippocampal granule cells' maturation and providing a considerable protection on the morphology of hippocampal neurons [160]. Proteomic and systems biology research has revealed that baicalin influences molecular pathways by restoring the nuclear translocation of glucocorticoid receptors (GR) through the modulation of GR phosphorylation within the hypothalamus [161]. Furthermore, one of the mechanisms through which baicalin exerts its antidepressant effects is by modulating the expression of BDNF and its receptor TrkB, while also enhancing synaptic plasticity via the activation of the Rac1-cofilin signaling [162].

Previous investigations have identified the adaptor protein APPL2 (phosphotyrosine interacting with PH domain and leucine zipper 2) as a regulator of GR activity and responsiveness. Disruption of this pathway impairs hippocampal neurogenesis, contributing to depressive phenotypes [163]. In a study, baicalin administration suppressed the APPL2/GR signaling, promoting neurogenesis in brain regions including the subventricular zone, olfactory bulb, and hippocampus in both APPL2 transgenic mice and models of chronic corticosterone-mediated depression. Behavioral assessments demonstrated that baicalin mitigated anxiety- and depressive-like behaviors and improved olfactory function in these models [164].

Apoptotic mechanisms are known to be implicated in the pathology of depression and other neurological diseases [165]. Baicalin has been demonstrated to modulate oxidative stress markers such as glutathione peroxidase, superoxide dismutase, and malondialdehyde, while downregulating apoptotic protease-activating factor-1 (Apaf-1), thereby reducing activation of caspase-dependent apoptotic pathways in olfactory bulbectomy-mediated depression models. Furthermore, baicalin decreases apoptosis and neuroinflammation in the hippocampus of CUMS rats by suppressing the IL-1β and caspase-1 expression. This neuroprotective effect is linked to inhibition of the GSK3β/NF-κB/NLRP3 signaling, a critical mediator of inflammation-induced neuronal injury [166].

Aberrant activation of the NLRP3 inflammasome has been involved in CNS inflammation and hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis, both of which contribute to depressive pathology [167].

CUMS not only reduces sucrose preference and elevates corticosterone levels, but also enhances the expression and activity of cyclooxygenase-2 (COX-2) and increases levels of prostaglandin E2 (PGE2) in the brain. Baicalin (10, 20, 40 mg/kg) effectively mitigates these stress-induced biochemical changes, suggesting that its antidepressant actions are partially mediated through suppression of the COX-2/PGE2 axis [168].

Thawkar et al. demonstrated that baicalin produces antidepressant effects in CUMS-exposed rats by increasing key neurotransmitter levels while lowering IL-1β, P2X7 receptor, NOX2, and ROS expression, effectively counteracting depressive alterations at both behavioral and molecular levels [169].

Teng and colleagues showed that oral baicalin produced antidepressant-like effects in chronic restraint stress (CRS) mice by restoring impaired hippocampal long-term potentiation (LTP) through BDNF-TrkB signaling. Intra-dorsal hippocampal microinjection of the TrkB antagonist ANA-12 abolished baicalin's antidepressant effects. Baicalin also reduced ROS/H₂O₂ production in a BDNF-associated manner, and molecular docking suggested that baicalin binds more effectively to TrkB than ANA-12 [170].

Ren et al. demonstrated that baicalin improved depressive behavior in atherosclerotic mice by modulating intestinal microbiota and brain lipid metabolism. Baicalin inhibited Erastin-induced ferroptosis in HT-22 hippocampal neurons by promoting SLC7A11, GSH, and GPX4 expression, inhibiting ACSL4, and decreasing ROS. Metagenomic and lipidomic analyses revealed that baicalin improved gut dysbiosis (Helicobacter_typhlonius, Escherichia_coli) and lipid metabolism disorders (PE) associated with ferroptosis [171].

Lu and colleagues discovered a novel antidepressant mechanism of baicalin: enhancing KIF5A-mediated axoplasmic transport and vesicular trafficking in glutamatergic neurons. Baicalin significantly alleviated CUMS-induced depressive behaviors, improved hippocampal neuronal damage, increased dendritic spine density, and promoted presynaptic vesicle accumulation. Transcriptomic analysis revealed upregulation of vGLUT2, GluN2B, GluA1, and PSD95. Notably, baicalin upregulated KIF5A expression, enhancing vesicle movement along axons and increasing VAMP2 enrichment in synaptosomes [172].

Moreover, baicalin has been found to upregulate AMPA receptor expression and inhibit neuronal apoptosis in CUMS-exposed rats, further supporting its role as a neuroprotective antidepressant (25).

Baicalin also improves mitochondrial integrity in the hippocampus of CUMS mice. It increases the expression of NIX (a key regulator of cell death), activates AMPK, and restores mitophagy and mitochondrial function in hippocampal HT22 cells, which may underlie its antidepressant effects [173].

Finally, the Na⁺/H⁺ exchanger 1 (NHE1), which regulates intracellular and extracellular pH, plays a vital role in neural physiology and pathology. Baicalin's inhibition of Rho-associated kinase 2 (ROCK2) alleviates depression-like behaviors in CUMS mice. This effect is associated with reduced activation of NHE1 and calpain1, as well as decreased neuronal apoptosis [174].

Totally, the antidepressant effects of baicalin are mediated through multiple interconnected mechanisms, including suppression of neuroinflammation, reduction of oxidative stress, promotion of neurogenesis, inhibition of apoptosis, and restoration of neurotransmitter balance. These diverse mechanisms highlight baicalin as a promising multitargeted candidate for depression, although clinical validation remains lacking.

8.2. Dementia

Dementia refers to a syndrome marked by a substantial decline in cognitive abilities compared to a person's prior functioning, leading to disruptions in daily work, home life, or social interactions. Rather than being a single disease, dementia is better understood as an acquired condition with multiple underlying causes [175]. In older adults, neurodegenerative disorders are the predominant cause of dementia. These include dementia with Lewy bodies [176], AD [177], vascular dementia [178], frontotemporal lobar degeneration [179], and PD [180]. Non-neurodegenerative causes of cognitive impairment, which may present at various ages, encompass a wide range of circumstances such as vitamin B12 or thiamine deficiencies [181], hypothyroidism [182], normal pressure hydrocephalus [183], chronic alcohol abuse [184], chemotherapy-related cognitive dysfunction [185], infections like HIV [186], space-occupying brain lesions such as subdural hematomas or tumors [187], traumatic brain injury [188], and severe psychiatric illnesses such as major depression or anxiety disorders [189]. Currently, an estimated 48 million people around the world are living with dementia, and this number is expected to reach approximately 131 million by 2050 [190]. The global burden of dementia is largely attributed to the disability it causes, rather than mortality, similar to other age-associated conditions. Therefore, treatment strategies primarily aim to ease the impact of cognitive and behavioral symptoms and to delay further cognitive deterioration. Despite these goals, treatment options remain limited, with only a few approved medications offering modest clinical benefits.

Recent studies have underscored baicalin's potential neuroprotective effects in dementia models. For instance, Zhao et al. reported that the administration of baicalin enhanced the differentiation and proliferation of endogenous neural stem cells in a rat model of dementia induced by Aβ_1-40 injection [191]. Another study showed that a compound treatment containing cholic acid, jasminoidin, and baicalin ameliorated memory deficits in a rat model of dementia triggered by ibotenic acid [192]. Additionally, Sohn and co-workers evaluated the effects of Hwangryunhaedok-tang (HRT), a traditional herbal preparation containing baicalin, geniposide, and berberine, on a rat model of vascular dementia induced by bilateral common carotid artery occlusion (BCCAO). HRT treatment improved cognitive performance and memory in behavioral assessments, restored cholinergic function, and reduced neuronal damage in the hippocampus. Moreover, HRT suppressed microglial activation and downregulated the phosphorylation of p38 MAPK and JNK signaling pathways, which were elevated following BCCAO [193].

8.3. Attention deficit hyperactivity disorder

Attention deficit hyperactivity disorder (ADHD) is a prevalent neurodevelopmental situation that typically emerges during early childhood and remains one of the most prevalent psychiatric diagnoses in children and adolescents. The core symptoms of ADHD include impulsivity, hyperactivity, and attentional deficits. A notable characteristic of ADHD is its clinical variability; manifestations can differ significantly between individuals, often presenting with opposing behavioral traits. Additionally, the disorder frequently coexists with other psychiatric conditions and its symptoms may fluctuate depending on the surrounding environment, sometimes remaining hidden during clinical assessments [194,195]. Although the precise etiology of ADHD remains unclear, it is widely recognized that genetic predispositions play a substantial role in the development of the disorder. Altered dopaminergic signaling has been heavily implicated in ADHD pathophysiology and is believed to be a central mechanism contributing to the disorder's progression [196,197]. Pharmacologically, methylphenidate (MPH), commonly known by the brand name Ritalin, is the primary and most commonly prescribed treatment for both children and adults with ADHD. As a derivative of amphetamine, MPH has been used for over five decades and is effective in alleviating the hallmark symptoms of the disorder, including inattentiveness, impulsive behavior, and hyperactivity [198]. However, being a CNS stimulant, Ritalin is associated with several adverse effects, including enhanced risks of depression, anxiety, and obsessive-compulsive behaviors. These side effects can negatively impact the overall quality of life in children undergoing MPH therapy [199,200]. Hence, further search should be continued to find a suitable therapeutic agent to be added to standard treatments to decrease their side-effects and enhance their efficacy.

The therapeutic potential of baicalin in ADHD has been explored in a limited number of preclinical studies, all of which are derived from the spontaneously hypertensive rat (SHR) model. These studies have reported that baicalin restores dopamine homeostasis and improves behavioral symptoms, with efficacy comparable to methylphenidate in some parameters.

As a neurotherapeutic and psychotherapeutic agent, multiple investigations have stated that baicalin has anticonvulsant [201], anxiolytic [202], and anti-psychotic [203] potentials, indicating an indirect evidence that baicalin can pass through the BBB [204]. Baicalin has demonstrated therapeutic potential in ADHD by restoring dopamine homeostasis. In SHRs, a well-established ADHD model, baicalin activated the Nrf2/Keap-1/HO-1 pathway, reducing high oxidative stress and inflammation. This led to restoration of the DAT-VMAT2 transport balance and enhancement of dopamine homeostasis. The study revealed that high oxidative stress disrupted DAT-VMAT2 balance, leading to DA deficits, and baicalin effectively ameliorated these imbalances [205].

In addition to studies on baicalin alone, its effects have also been compared with those of MPH, the standard pharmacological treatment for ADHD. MPH and baicalin regulate the memory and learning abilities as well as motor ability of SHR rats with ADHD and hence handle the core symptoms of ADHD, including inattention, impulsive behavior, and hyperactivity [206]. Regarding the effect of baicalin against ADHD, Zhou et al. reported that baicalin and MPH hydrochloride can ameliorate LDH and synaptosomal ATPase activities in ADHD rats. Of note, baicalin applies its therapeutic effect dose-dependently, and high-dose baicalin exerts considerably greater effects compared to methylphenidate hydrochloride. Baicalin displays its therapeutic effects possibly through upregulation of the adenylate cyclase (AC)/cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling [207]. In another research, Zhou et al. indicated that both baicalin and MPH at doses of 100 and 150 mg/kg remarkably reduced the hyperactivity and ameliorated the spatial learning memory deficit in the SHR rats and enhanced the synaptosomal mRNA and protein levels of synaptosomal-associated protein of molecular mass 25kD, tyrosine hydroxylase, synataxin 1a and vesicular monoamine transporter 2 compared to saline treatment. Also, MPH markedly elevated DA levels in both the striatum and prefrontal cortex, while baicalin caused a significant elevation in DA levels only in the striatum [208]. It has been shown that medium and high doses of MPH and baicalin considerably enhanced the relative expression of Ca MKⅡand ERK1/2 mRNA in synaptosomes of SHR rats [209].

In summary, baicalin has demonstrated therapeutic potential in ADHD by restoring dopamine homeostasis through activation of the Nrf2/Keap-1/HO-1 pathway and restoration of the DAT-VMAT2 transport balance. It also modulates the AC/cAMP/PKA signaling pathway and enhances synaptosomal protein expression in the striatum and prefrontal cortex, with efficacy comparable to methylphenidate in preclinical models. However, all evidence to date is derived from rodent models, and human studies are completely lacking. Therefore, while baicalin holds promise for ADHD, its clinical applicability remains entirely speculative at this stage.

8.4. Anxiety

Anxiety disorders are the most widespread psychiatric conditions globally, with an estimated prevalence of 7.3% (ranging from 4.8% to 10.9%). Among these, specific phobias are the most frequently diagnosed (10.3%), followed by panic disorder at 6.0%, social phobia at 2.7%, and generalized anxiety disorder (GAD) at 2.2% [210,211]. Epidemiological data show that women are approximately 1.5 to 2 times more likely to experience anxiety disorders compared to men. Anxiety, particularly GAD and panic disorder, often coexists with depressive disorders, complicating both diagnosis and treatment. Moreover, different types of anxiety disorders frequently overlap, which presents additional challenges for non-specialist clinicians. Consequently, anxiety disorders are frequently underdiagnosed and inadequately treated in primary healthcare settings [212]. Treatment approaches combining psychotherapy and pharmacological interventions have shown greater efficacy than placebo or waitlist controls for managing anxiety symptoms [213]. While traditional benzodiazepines are effective anxiolytics, their use is limited due to adverse effects such as drowsiness, muscle relaxation, dependence, and the development of tolerance, prompting the pursuit of safer alternatives [156]. Emerging evidence suggests that baicalin may possess anxiolytic properties, although current findings remain limited [214,215]. Mechanistic studies have revealed that baicalin's anxiolytic-like effects in vivo are mediated through specific GABA_A receptor subtypes, particularly those containing α2 and α3 subunits [216]. In a recent study, baicalin not only exhibited anxiolytic and antidepressant-like effects but also enhanced hippocampal neurogenesis in a neuroendocrine model of depression and anxiety in mice [217]. In a zebrafish model of acute and unpredictable chronic stress, researchers evaluated the anxiolytic properties of baicalein administered at behaviorally effective doses (not explicitly specified but guided by prior toxicity testing up to 1000 μg/mL in embryos and non-toxic in adults). Adult wild-type zebrafish were exposed to validated stress paradigms (acute net chasing, conspecific alarm substance, and 7-day chronic stress) and treated with baicalein, diazepam, or fluoxetine. Behavioral outcomes, quantified through novel tank and light/dark preference tests, demonstrated that baicalein reversed stress-induced anxiety-like behaviors, significantly increasing top-zone exploration and light-zone time, without impairing baseline locomotion. Molecular docking predicted strong affinity of baicalein for the GABA_A receptor benzodiazepine site, suggesting a GABAergic mechanism. Although brine-shrimp lethality assays and adult zebrafish toxicity observations indicated a favorable safety profile, limitations were noted in the absence of precise dosing details, concentration–response relationships, and measurements of neurochemical or receptor binding in vivo. Future work should address these gaps and evaluate efficacy in higher vertebrate models to substantiate translational potential [218]. Yang et al. demonstrated that baicalin (50 mg/kg) significantly reduced seizure severity in pentylenetetrazol (PTZ)-kindled epileptic rats while alleviating anxiety and depressive-like behaviors. Baicalin counteracted neuronal loss and damage in the hippocampus by enhancing BDNF expression and promoting neurogenesis, particularly in the dentate gyrus (DG) region. The co-localization of Iba-1 with NLRP3 indicated activation of NLRP3 inflammasome in microglia, and RT-PCR revealed that baicalin may alleviate anxiety and depressive-like behaviors by activating the P2RX7/NLRP3/IL-1β signaling pathway. Molecular docking confirmed good binding affinity of baicalin with P2RX7, NLRP3, and IL-1β proteins [219].

In summary, the anxiolytic effects of baicalin appear to be primarily mediated through positive modulation of GABA-A receptors, particularly those containing α2 and α3 subunits, along with promotion of hippocampal neurogenesis and reduction of neuroinflammation. Recent evidence also suggests involvement of the P2RX7/NLRP3/IL-1β signaling pathway in alleviating anxiety-like behaviors. Despite these promising preclinical findings, the evidence base for baicalin's anxiolytic properties remains limited compared to its antidepressant profile, and further studies, particularly in validated anxiety models, are needed to confirm its therapeutic potential.

The evidence for baicalin's anxiolytic effects is relatively limited compared to its antidepressant profile. Current findings are derived from a small number of preclinical studies, primarily in rodent models and recently in zebrafish, suggesting potential involvement of GABA-A receptor modulation and anti-neuroinflammatory mechanisms. These preliminary observations require confirmation in additional validated anxiety models before firm conclusions can be drawn.

A visual summary of the effects of baicalin on neurological and psychological diseases is presented in Fig. 2, Fig. 3, respectively. In addition, Table 2 summarizes recent studies on the therapeutic properties of baicalin specifically in psychological disorders. Furthermore, Table 3 provides an overall summary of the key mechanisms of action of baicalin across all CNS-related disorders discussed in this review.

Fig. 2.

Integrated signaling pathways underlying baicalin-mediated neuroprotection in neurological and psychological disorders. This schematic details the diverse molecular targets of baicalin across conditions such as cerebral ischemia, spinal cord injury, and neurodegenerative diseases. Key mechanisms include AMPK and NLRP3 modulation for redox balance, SDH/GS regulation for glutamate clearance, SIRT1 and Wnt/β-catenin pathways for neurogenesis, and BDNF/ERK/CREB signaling for synaptic plasticity, alongside disease-specific targets like HDAC1 and GABA_A receptors.

Fig. 3.

Pathological hallmarks of major CNS and psychological diseases targeted by baicalin. The diagram summarizes the shared and distinct pathological features of depression, anxiety, Alzheimer's disease, and Parkinson's disease. Baicalin addresses these conditions by mitigating neuroinflammation and oxidative stress, restoring monoamine levels, normalizing HPA axis hyperactivity, and inhibiting the progression of proteinopathies such as amyloid-β deposition, tau phosphorylation, and α-synuclein aggregation.

Table 2.

The effect of baicalin on psychological diseases as evidenced by recent studies.

Disease	Dose	Targets/pathways	effects	Model	Cell line/Animal	Ref
Depression	25,50 mg/kg 20, 40, 80 μM	IL-1β, IL-6, TNF-α HMGB1/TLR4/NF-κB pathways.	Antidepressant effect, Inhibition of HMGB1/TLR4/NF-κB pathways, anti‐inflammatory effect.	In vivo, in vitro	Mice PC12 cells	[153]
	60 mg/kg	TLR4, PI3K/AKT/FOXG1 pathway	Antidepressant effect, suppress neuro-inflammation.	In vivo	Mice	[154]
	60 mg/kg 100 μM	AKT/FOXG1 pathway	Antidepressant effect, regulate neurogenesis-associated pathway, Improve neuronal differentiation and survival.	In vivo, in vitro	Mice SH-SY5Y cells	[155]
	10, 40, 50 mg/kg	PI3K/AKT pathway	Promote hippocampal neurogenesis; decrease painful sensation and depressive symptoms.	In vivo	Male mice	[152]
	30, 60 mg/kg 10, 50, 100 μM	PGC-1α/NF-κB pathway	Suppress neuro-inflammation; ameliorate depression-like behaviors.	In vivo, in vitro	Male mice SH-SY5Y cells	[157]
	25, 50 mg/kg	NMDAR/NR2B-ERK1/2-related pathway	Antidepressant effects, anti‐inflammatory effect, inhibit oxidative stress.	In vivo	Male mice	[[158], [159], [160]]
	25, 50 mg/kg	BDNF/ERK/CREB signaling pathway	Antidepressant effect, ameliorate cognitive functions.	In vivo	Male mice	[[158], [159], [160]]
	30, 60 mg/kg 30 μM	PI3K/AKT/GSK3b/b-catenin pathway	Antidepressant effect, decrease serum corticosterone levels, Improve hippocampal cells survival and maturation.	In vivo, in vitro	Female mice HT-22 cells	[[158], [159], [160]]
	40, 80,160 mg/kg	GR, HPA axis	Antidepressant effect, normalize GR nuclear translocation, ameliorate negative feedback of HPA axis.	In vivo	Male mice	[161]
	25, 50,100 mg/kg	Rac/LIMK/cofilin pathway, SYP, TrkB PSD95, BDNF	Antidepressant effect, improve synaptic plasticity.	In vivo	Male mice	[162]
	3.35, 6.7 mg/kg	APPL2/GR pathway	Antidepressant effect, promote SVZ, OB and hippocampus neurogenesis, decrease emotional and olfactory dysfunctions.	In vivo	Male mice	[164]
	20, 40 mg/kg	Apaf-1, caspase-3, caspase-9	Antidepressant effect, suppress apoptosis.	In vivo	Male mice	[166]
	20, 40 mg/kg	IL-1β, IL-6, NLRP3 inflammasome	Antidepressant effects, anti‐inflammatory effects.	In vivo	Male rats	[220]
	10, 20, 40 mg/kg	COX-2	Antidepressant effect, decrease PGE2 levels in brain.	In vivo	Male rats	[168]
	20 mg/kg	LC3, P62, TOM20, AMPK, PGC-1α, NIX	Antidepressant effect, ameliorate mitochondrial function in HT22 cells.	In vivo, in vitro	Mice HT22 cells	[173]
	60 mg/kg 1, 10, 100 μM	NHE1, ROCK2	Antidepressant effect, decrease neuronal apoptosis.	In vivo, in vitro	Male mice PC12 cells	[174]
Dementia	10 mg/kg	Nestin, GFAP and NSE protein	Improve cognitive function; promote neural proliferation and differentiation, decrease pyramidal cell defects in hippocampus.	In vivo	Male SD rats	[191]
	CBJC 3 mL/kg 1.25 mg/mL baicalin))	CBR1,EGF, CRBP1 cyclinG1	Antioxidant effect, improve neuroprotection and neurogenesis.	In vivo	Male SD rats	[192]
	HRT 200, 400 mg/kg	p38, JNK	Improve cognitive function, neuropreventive effects, suppress neuro-inflammation.	In vivo	Male SD rats	[193]
ADHD	3.33, 6.67, 10 mg/mL	-	Ameliorate hyperactivity, impulsive behavior, and inattention.	In vivo	Rats	[206]
	3.33, 6.67, 10 mg/mL	AC/cAMP/PKA pathway	Upregulating the AC/cAMP/PKA signaling pathway.	In vivo	Rats	[207]
	3.33, 6.67, 10 mg/mL	Ca MKⅡand ERK1/2	Up-regulate expression of Ca MKⅡand ERK1/2 in mRNA and protein.	In vivo	Rats	[209]
Anxiety	3.3, 10, 30 mg/kg	a2 and a3 containing GABAA receptors	Anxiolytic-like effects.	In vivo	Male mice	[216]
	40, 80, 160 mg/kg,	GR	Ameliorate several anxiety like behaviors, regulate the expression of GR, promote hippocampus neurogenesis	In vivo	Male mice	[217]

Table 3.

Summary of key neuroprotective mechanisms of baicalin in CNS disorders.

CNS Disorder	Key Mechanisms	Main Pathways/Targets
Cerebral ischemia-reperfusion injury	Anti-inflammatory, Antioxidant, Anti-apoptotic, BBB protection, Mitophagy regulation	AMPK/NLRP3, TLR4/NF-κB, Nrf2/HO-1, BDNF-TrkB, PI3K/Akt
Ischemic stroke	Anti-inflammatory, Antioxidant, Anti-pyroptotic, BBB stabilization, Astrocyte modulation	SIRT1/NF-κB, Nrf2/HO-1, NLRP3/Caspase-1/GSDMD, PI3K/Akt/mTOR
Spinal cord injury	Anti-apoptotic, Anti-inflammatory, BBB/BSCB protection, Mitochondrial stabilization	PI3K/Akt, TLR4/MD2/PI3K/AKT/NF-κB, CHCHD2
Parkinson's disease	Antioxidant, Anti-inflammatory, Dopaminergic neuron protection	Nrf2-NLRP3 axis, C/EBPβ inhibition
Alzheimer's disease	Anti-inflammatory, Anti-apoptotic, Synaptic plasticity, Metabolic regulation	Wnt/β-catenin, Ras-ERK, ALDH2/NOS2, BDNF-TrkB
Traumatic brain injury	Anti-apoptotic, Antioxidant, Autophagy modulation, Neurobehavioral recovery	Akt/Nrf2, Mitochondrial apoptotic pathway
Multiple sclerosis/Demyelination	Anti-inflammatory, Remyelination, OPC differentiation	TLR4/MD2/PI3K/AKT/NF-κB, PPARγ, Wnt/β-catenin
Depression	Anti-inflammatory, Neurogenesis, Synaptic plasticity, Antidepressant	TLR4/PI3K/AKT/FoxO1, BDNF/ERK/CREB, NLRP3, PGC-1α/NF-κB, KIF5A
Anxiety	Anxiolytic, Neurogenesis	GABA-A receptor, GR/HPA axis
ADHD	Dopamine homeostasis, Antioxidant	Nrf2/Keap-1/HO-1, DAT-VMAT2 balance

9. Limitations of the review

Several limitations of the present review should be acknowledged to ensure a balanced interpretation of the findings.

First, the vast majority of the included studies reported positive neuroprotective effects of baicalin, while studies with negative or inconclusive results are often under-represented in the published literature. This predominance of positive findings may be influenced by publication bias, as journals tend to favor studies with statistically significant or favorable outcomes. Moreover, selective reporting of favorable results cannot be excluded. Although we performed a comprehensive literature search across multiple databases without restricting by outcome direction, we cannot rule out the possibility that unpublished or null-finding studies would affect our overall conclusions.

Second, most of the evidence summarized in this review originates from in vitro and in vivo preclinical studies, with a limited number of well-controlled clinical trials. The translational potential of baicalin from animal models to human patients remains uncertain, and the positive results observed in preclinical settings may not necessarily be reproduced in clinical practice.

Third, considerable heterogeneity exists across the included studies in terms of baicalin dosage, route of administration, treatment duration, and animal models used. This variability makes it difficult to directly compare findings and draw definitive conclusions regarding the optimal therapeutic regimen.

Fourth, the pharmacokinetic limitations of baicalin, particularly its poor oral bioavailability and extensive first-pass metabolism, may limit its clinical applicability. Although several innovative delivery systems (e.g., nanoparticle-based formulations, exosome encapsulation) have been explored in preclinical studies, their safety and efficacy in humans have not yet been established.

Finally, the long-term safety of baicalin, especially at higher doses, has not been thoroughly investigated. While short-term studies have reported a favorable safety profile, potential hepatotoxic or nephrotoxic effects at prolonged administration require further evaluation.

Despite these limitations, the current evidence consistently supports the neuroprotective potential of baicalin and provides a strong rationale for future well-designed, blinded, and adequately powered preclinical and clinical studies. Fig. 4 shows detailed mechanistic actions of baicalin against CNS-related diseases with focus on underlying signaling pathways in.

Fig. 4.

Integrated molecular network of baicalin-mediated neuroprotection across CNS and psychological disorders. The schematic illustrates the convergence of shared molecular pathways—including TLR4/MyD88/NF-κB inhibition, PI3K/Akt/AMPK/MAPK modulation, Nrf2/HO-1 activation, NLRP3 inflammasome suppression, and BDNF/TrkB/Wnt/β-catenin signaling—that collectively mitigate neuroinflammation, oxidative stress, and apoptosis while promoting neurogenesis, synaptic plasticity, BBB integrity, and mitochondrial function. Disease-specific pathways reported in clinical and preclinical models, ranging from neurodegenerative conditions (e.g., AD, PD) to psychological disorders (e.g., depression, anxiety, ADHD), are highlighted on the right.

10. Conclusion

Baicalin, a bioactive flavonoid derived from Scutellaria baicalensis, has emerged as a promising multitargeted neuroprotective agent with therapeutic potential across a broad spectrum of CNS-related disorders. The present review comprehensively summarized the available preclinical evidence supporting the efficacy of baicalin in both neurological diseases, including cerebral ischemia-reperfusion injury, ischemic stroke, spinal cord injury, traumatic brain injury, PD, AD, and MS, as well as psychological disorders such as depression, anxiety, ADHD, and dementia.

The neuroprotective effects of baicalin are primarily mediated through multiple interconnected mechanisms, including suppression of neuroinflammation via inhibition of the NLRP3 inflammasome and TLR4/NF-κB signaling pathways, attenuation of oxidative stress through activation of the Nrf2/HO-1 antioxidant axis, inhibition of apoptotic pathways, and promotion of neurogenesis and synaptic plasticity through BDNF-TrkB and Wnt/β-catenin signaling. Furthermore, baicalin has been shown to modulate gut microbiota, protect the blood-brain barrier integrity, and facilitate remyelination, highlighting its pleiotropic nature. Its ability to cross the blood-brain barrier further enhances its therapeutic appeal for CNS applications.

The findings of this review should be interpreted in light of several limitations, which are discussed in detail in the limitations of the review section above.

10.1. Priority research questions

To bridge the gap between preclinical promise and clinical application, future investigations should address the following priority questions:

• 1.What is the optimal dosing regimen, route of administration, and treatment duration of baicalin for each specific CNS disorder?
• 2.Can innovative drug delivery systems (e.g., nanoparticles, exosomes, liposomes) significantly enhance the oral bioavailability and brain targeting of baicalin in large animal models and subsequently in humans?
• 3.What are the long-term safety and potential toxicological effects of baicalin, particularly at higher doses and with chronic administration?
• 4.How do the pleiotropic effects of baicalin—anti-inflammatory, antioxidant, anti-apoptotic, and neurogenic—interact and synergize to produce its overall neuroprotective profile?
• 5.Can baicalin be effectively combined with standard therapies (e.g., tissue plasminogen activator in stroke, levodopa in Parkinson's disease, or antidepressants) to achieve additive or synergistic therapeutic effects?
• 6.What are the precise molecular targets of baicalin in the CNS, and how do these targets differ across various neurological and psychological conditions?

10.2. Testable hypotheses

Based on the findings summarized in this review, the following testable hypotheses are proposed for future research:

• •Hypothesis 1: Baicalin exerts its neuroprotective effects in cerebral ischemia-reperfusion injury primarily through AMPK-mediated inhibition of the NLRP3 inflammasome and subsequent reduction of inflammatory cytokines.
• •Hypothesis 2: Baicalin promotes remyelination in demyelinating disorders such as multiple sclerosis through PPARγ-dependent differentiation of oligodendrocyte precursor cells into mature oligodendrocytes.
• •Hypothesis 3: The antidepressant effects of baicalin are mediated through suppression of the TLR4/PI3K/AKT/FoxO1 signaling axis, leading to reduced neuroinflammation and enhanced adult hippocampal neurogenesis.
• •Hypothesis 4: Baicalin protects against traumatic brain injury by activating the Akt/Nrf2/HO-1 pathway, thereby reducing oxidative stress, apoptosis, and blood-brain barrier disruption.
• •Hypothesis 5: Baicalin alleviates cognitive deficits in Alzheimer's disease models by activating Wnt/β-catenin signaling, which promotes synaptic plasticity and reduces Aβ plaque burden.
• •Hypothesis 6: The therapeutic efficacy of baicalin in attention deficit hyperactivity disorder is mediated through modulation of dopaminergic signaling in the striatum and prefrontal cortex, similar to methylphenidate but with a distinct mechanism of action.

10.3. Bridging the translational gap: which CNS conditions are most promising for clinical trials?

Despite the robust preclinical evidence supporting baicalin's neuroprotective effects, the translation of these findings into clinical practice faces substantial challenges. Several factors contribute to this translational gap, including the lack of standardized dosing regimens, limited data on long-term safety and pharmacokinetics in humans, and the inherent differences between animal models and human disease pathophysiology.

Nevertheless, based on the strength and consistency of preclinical data, certain CNS conditions appear more amenable to near-term clinical evaluation than others. We propose the following prioritization framework for future clinical trials:

• •Ischemic Stroke and cerebral IRI

The preclinical evidence for baicalin in ischemic stroke is among the most robust, with consistent neuroprotective effects demonstrated across multiple animal models (MCAO, tMCAO, OGD/R). Baicalin has been shown to reduce infarct volume, attenuate oxidative stress and neuroinflammation, and preserve blood-brain barrier integrity. Notably, baicalin's ability to mitigate hemorrhagic transformation associated with delayed t-PA therapy addresses an important unmet clinical need. Given the acute nature of stroke, relatively short treatment durations would be required, making clinical trial design more feasible.

• •AD and mild cognitive impairment

Baicalin has demonstrated consistent benefits in multiple AD models (APP/PS1 transgenic mice, Aβ-injected models), improving cognitive function, reducing Aβ plaque burden, and promoting neurogenesis through Wnt/β-catenin signaling. The availability of validated cognitive and biomarker endpoints (e.g., CSF Aβ, tau, neuroimaging) and the urgent need for disease-modifying therapies make AD a high-priority target for clinical investigation. However, the chronic nature of AD would require longer-term safety data, which currently remain limited.

• •Depression and anxiety disorders

Baicalin has shown antidepressant and anxiolytic effects across multiple preclinical models (CUMS, corticosterone-induced, olfactory bulbectomy). Its anti-inflammatory and neurogenic mechanisms, combined with its favorable safety profile in short-term human studies, make it an attractive candidate for clinical trials, particularly as an adjunctive therapy in treatment-resistant depression. The availability of well-validated clinical rating scales (e.g., HAM-D, HAM-A) and the relatively short duration of antidepressant trials further support its clinical feasibility.

• •ADHD

Baicalin has demonstrated efficacy in the spontaneously hypertensive rat model of ADHD by restoring dopamine homeostasis and improving behavioral symptoms, with effects comparable to methylphenidate in some parameters. Given the established safety profile of baicalin in human studies and the need for safer alternatives with fewer side effects, ADHD represents a promising but comparatively lower-priority target due to the availability of existing effective therapies.

• •PD and MS

Although preclinical evidence is promising (particularly for dopaminergic neuron protection and remyelination, respectively), these conditions present greater translational challenges. The chronic progressive nature of both diseases, the need for long-term safety data, and the complexity of clinical trial endpoints make them more suitable for later-stage investigations once safety and proof-of-concept have been established in other indications.

In conclusion, we propose that ischemic stroke and depression represent the most promising CNS conditions for near-term clinical trials, given the strength of preclinical evidence, feasibility of trial design, and availability of validated endpoints. AD would be an important subsequent target, contingent upon the availability of longer-term safety data. This prioritization framework aims to facilitate the rational and efficient translation of baicalin from bench to bedside.

10.4. Final remarks

While the current evidence strongly supports the neuroprotective potential of baicalin in preclinical models, it should be interpreted with appropriate caution. To date, no targeted clinical trials have evaluated baicalin specifically for CNS disorders, representing a major translational gap that must be addressed before any clinical recommendations can be made. Future research should prioritize the publication of all results, regardless of their direction, and should include rigorous, blinded, and well-powered preclinical studies with predefined primary outcomes to provide a more balanced and reliable evidence base for clinical translation. Well-designed randomized controlled trials are urgently needed to confirm the efficacy and safety of baicalin in human subjects. With continued investigation and targeted translational efforts addressing these specific hypotheses and research questions, and with the development of innovative delivery systems to overcome bioavailability challenges, baicalin may ultimately emerge as a valuable candidate for future multitargeted strategies against CNS disorders, but only after rigorous clinical validation. Until such data emerge, baicalin should be viewed as a promising experimental agent rather than a clinically proven therapy.

CRediT authorship contribution statement

Yasin Rashidi: Conceptualization, Writing – original draft, Writing – review & editing. Amir Hossein Barjasteh: Project administration, Writing – original draft, Writing – review & editing. Mehran Ilaghi: Conceptualization, Writing – original draft, Writing – review & editing. Ali Pozvei: Writing – original draft, Writing – review & editing. Mohamadreza Soltanpour: Visualization, Writing – original draft, Writing – review & editing. Sharareh Jahangiri: Writing – original draft, Writing – review & editing. Mehrsa Radmanesh: Writing – original draft, Writing – review & editing. Alireza Pourbafrani: Writing – original draft, Writing – review & editing. Seyed Hasan Hosseini Faegh: Writing – original draft, Writing – review & editing. Fatemeh Bagheri: Writing – original draft, Writing – review & editing. Shahrzad Zarifbargi: Investigation, Methodology, Writing – review & editing. Mohammad Hossein Pourhanifeh: Conceptualization, Supervision, Visualization, Writing – original draft, Writing – review & editing.

Consent for publication

Not applicable.

Ethics approval and consent to participate

Not applicable. This study is a review article and does not involve human participants, human data, or animal subjects. Therefore, ethical approval was not required.

Declaration of AI and AI-assisted technologies in scientific writing

During the preparation of this work, the authors used no generative AI or AI-assisted technologies for scientific writing, data analysis, or interpretation. Standard grammar and spelling checkers were used solely for language refinement. The authors reviewed and edited the content as needed and take full responsibility for the content of the published article.

Funding

No specific funding was received for this work.

Declaration of competing interests

The authors declare that there are no conflicts of interest regarding the publication of this review article. The research was conducted without any financial support or sponsorship from external sources that could potentially influence the outcomes or interpretations presented in this work. All authors have contributed equally to the preparation of this manuscript and have no financial or personal relationships that could inappropriately influence their work.

Appendix A. Supplementary data

The following is the Supplementary data to this article:

Data availability

No data was used for the research described in the article.