Clinical insights into catechin-based nanomedicine: a review of therapeutic potential in neurodegenerative diseases

Abstract

Neurodegenerative diseases (NDs) such as Alzheimer's, Parkinson's, and Huntington's diseases are characterized by progressive neuronal loss, oxidative stress, neuroinflammation, and cognitive decline. The most prevalent and bioactive catechin in green tea, epigallocatechin-3-gallate (EGCG), has shown promise as a neuroprotective agent because of its many biological properties. The review discusses the potential of EGCG in combating neurodegeneration and cognitive impairments through antioxidant benefits and signaling pathways. Recent advancements in structural analogs, liposomal encapsulation, and nanoformulations have shown potential in improving pharmacokinetics. High dosage safety issues and inter-individual response variability remain significant challenges in the field of medicine. The review emphasizes the importance of structured clinical trials, formulation uniformity, biomarker-guided monitoring, and customized therapy approaches to fully realize EGCG's potential as a neuroprotective drug. EGCG improves autophagic clearance, reduces tau hyperphosphorylation, and inhibits amyloid-beta aggregation, aiding in neuroprotective properties. Early clinical trials suggest it can be used as an adjuvant therapy, and recent advancements in formulation and delivery techniques are promising.

Introduction

Millions of people worldwide are impacted by neurodegenerative diseases (NDs), which are among the most common health issues (Goncalves et al. 2021). NDs are an increasingly prevalent cause of death and morbidity globally (Erkkinen et al. 2018), with an expected 152 million individuals affected by 2060 (Dugger and Dickson 2017), with Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and prion disorders (Kovacs 2019). Among the many forms of dementia, AD has the highest prevalence at 62%, followed by PD at 73% (Radi et al. 2014). The global burden of NDs is rising as a result of an older population, higher life expectancy, and changing environmental conditions. The World Health Organization (WHO) estimates that NDs cause 13% of fatalities in developed nations, 16.8% of deaths in poor nations, and 12% of all deaths worldwide. NDs such as PD, AD, and dementias are expected to account for 38% of global disability by 2030, resulting in significant life loss (Feigin et al. 2020). The WHO reported in 2015 that dementia costs the world approximately 1.1% of GDP (Feigin et al. 2019). AD, PD, ALS, HD, multiple sclerosis (MS), and other NDs are influenced by various genetic, molecular, and environmental factors. The main causes of NDs are age, inflammation, increased reactive oxygen species (ROS), and epigenetic instability. NDs are influenced by various molecular factors, including protein dynamics, oxidative stress (OS), mitochondrial dysfunction, and exposure to metal toxicity and pesticides (Sheikh et al. 2013). Neuronal degeneration, a severe disease, worsens with age, and current treatments only alleviate symptoms, highlighting the need for more effective treatment options (Gribkoff and Kaczmarek 2017). The development of new medications for NDs faces major obstacles due to a lack of knowledge about biology, the blood–brain barrier (BBB), and therapeutically appropriate animal models (Danon et al. 2019). Researchers have focused on reducing the misfolded protein load in NDs, despite their pathological definition of disease-specific misfolded protein aggregation and altered cellular stress response (Mallucci et al. 2020; Cummings et al. 2020). Most NDs are asymptomatic and develop late, leading to treatment starting later in the disease's progression and limited patient benefits. Early therapies may be able to stop or significantly decrease the progression of the disease. These treatments may restore neuronal function by reducing or eliminating the main stressor (Solanki et al. 2015). Psychiatric disorders and NDs, characterized by abnormal thoughts, emotions, actions, and social communication, are increasing in prevalence worldwide. Neuroinflammation, a condition characterized by inflammation of the central and peripheral nervous systems, is believed to be a significant contributor to these diseases. Numerous studies have linked inflammatory dysfunctions to neurodegeneration and mental diseases in both human and animal models (Onore et al. 2012; Theoharides et al. 2013; Theoharides and Zhang 2011). Neuroinflammation, triggered by elevated inflammatory responses, damages healthy neurons and disrupts brain activity. Active microglia are essential in neuroinflammatory processes, which can lead to mental diseases and neurodegeneration (Hong et al. 2016). Bifidobacterium species significantly contribute to the essential microorganisms in the fecal microbiota of breastfed newborns (Mastromarino et al. 2014). Bifidobacterium species, particularly Bifidobacterium longum and Bifidobacterium breve, have psychobiotic effects, potentially reducing stress, anxiety, and other depressive behaviors (Savignac et al. 2014; Andreo-Martínez and Martínez-González 2022). The genus Bifidobacterium, which colonizes newborns' intestines, can be affected by an imbalance in this species, potentially impacting infant neurodevelopment (Andreo-Martínez and Martínez-González 2022). Dementia is caused by NDs that cause progressive functional modifications of neural systems. AD is characterized by the accumulation of neurofibrillary tangles and amyloid plaques. Polyphenolic compounds have been found to have neuroprotective properties, including the ability to reduce neuroinflammation, protect neurons from neurotoxic damage, and potentially enhance memory, learning, and cognitive processes (Spagnuolo et al. 2016).

Green tea, derived from Camellia sinesis, is known for its anti-inflammatory and anticancer properties. Catechins, the primary antioxidants, are influenced by hydroxyl groups and structural groups. Unfermented green tea is a top source of catechins, which neutralize reactive oxygen and nitrogen species (Musial et al. 2020). Catechins, or flavan-3-ols, make up 70–80% of tea polyphenols found in the buds and leaves of young tea plants (Graham 1992; Liu et al. 2015). Green tea exhibits higher antioxidant activity in vitro, while dark tea often has higher in vivo antioxidant activity due to bioavailable polyphenol biodegradation products (Zhao et al. 2019; Cao et al. 2020). EGCG is the primary tea catechin responsible for green tea extracts' biological activity, including anti-inflammatory, antiapoptotic, antioxidant, and neuroprotective properties against NDs (Khalatbary and Khademi 2020). EGCG effectively mitigates any impairments in Barnes maze performance and nest construction (Walker et al. 2015). Additionally, EGCG enhances central memory impairment in tests of novel item identification and water mazes (Ettcheto et al. 2020). Moreover, EGCG protects against most of the motor impairments caused by rotenone in the open-field test, beam-crossing task, rota rod, and grip strength measurement (Tseng et al. 2020). EGCG-loaded nanoparticles show promising application potential due to their biocompatibility and degradability (Liu et al. 2019). Furthermore, EGCG-loaded nanoparticles significantly improved neurobehavioral impairments in open-field, Morris water maze, and novel object recognition tests (Singh et al. 2018). EGCG-enriched diets increase Bifidobacterium spp. abundance, suggesting that EGCG administration improves gut microbiota (Unno et al. 2014). Catechins have limited bioavailability, but can be absorbed through the gastrointestinal tract through three metabolic routes: methylation, glucuronidation, and sulfonation (Feng 2006). This review highlights that EGCG combats neurodegeneration and cognitive impairments by enhancing antioxidant benefits, modifying signaling pathways, improving autophagic clearance, reducing tau hyperphosphorylation, and inhibiting amyloid-beta (Aβ) aggregation.

Green tea catechins

The growing global interest in tea's health benefits and medicinal properties has sparked a surge in research on its medicinal properties (Cooper et al. 2005). Green tea, a health-promoting plant, is rich in phenolic compounds, including catechins, which are crucial for its growth and development. These compounds have strong antioxidant, iron-chelating, and anti-inflammatory properties (Mandel et al. 2012). Additionally, green tea is rich in lipids, sterols, vitamins B2, B3, C, vitamin E, and trace levels of vitamin K, with Gyokuro and Sencha having the highest concentrations. Only matcha tea contains vitamin A. Green tea is a highly abundant source of macroelements such as phosphorus, iodine, and fluorine. Green tea is known for its unique characteristic of the presence of the diphenylpropanoid skeleton (Graham 1992; Komatsu et al. 1993; Ahmad and Mukhtar 1999). EGCG, comprising 50–80% of green tea's catechin content, is the primary catechin isolated from the polyphenolic fraction (Bode and Dong 2009). Polyphenol, besides its antioxidant properties, has various biological effects through its interaction with proteins, cell surface membrane receptors, transcription and signaling pathways, mitochondrial function (Hoensch and Oertel 2015; Charo and Ransohoff 2006), DNA methylation, and autophagy (Kim et al. 2014a). In mice, in vivo investigations have demonstrated that EGCG suppresses Aβ-induced cognitive impairment by altering secretase activity (Rezai-Zadeh et al. 2005; Lee et al. 2009), reducing cerebral amyloidosis, modulating amyloid precursor cleavage, and reducing Aβ production (Shaham-Niv et al. 2018). Polyphenol, found in autoimmune encephalomyelitis, an animal model of MS, promotes neuroprotection and T-cell NF-κB inhibition (Aktas et al. 2004). Polito et al. found that tea consumption reduces the risk of AD due to its anti-amyloid properties (Polito et al. 2018). Epidemiological research indicates a correlation between EGCG consumption and a reduced risk of PD (Mandel et al. 2012). The trial assessed the safety and efficacy of green tea catechins in de novo PD patients, with 400 patients showing significant improvement after 6 months (Chan et al. 2009). In addition, Reglodi et al. emphasized that no negative health effects were observed in any groups that consumed green tea polyphenols. A year after a placebo group's gains decreased, green tea polyphenols alleviated symptoms in early de novo PD but did not significantly modify the disease. The use of EGCG in human treatments requires careful consideration of its quantity and frequency (Reglodi et al. 2017). Furthermore, Mandel et al. demonstrated that anti-inflammatory medications, antioxidants, and plant flavonoids may reverse disease progression. Recent animal and human research suggests that tea intake may lower the risk of dementia, AD, and PD. EGCG has shown neuroprotective properties in NDs (Mandel et al. 2008).

Physical and chemical properties

Despite being colorless, catechins have astringent and bitter tastes (Balentine et al. 2019). Catechins can be separated for food use by precipitating them with protein or caffeine. Catechins have a significant iron-binding capacity due to their galloyl group structure, which binds to iron in food and prevents the body from absorbing it (Zijp et al. 2000). Tea catechins become highly reactive and unstable when exposed to heat, oxidizing enzymes, and alkaline environments. The presence of peroxidase (POD) and polyphenol oxidase (PPO) enzymes results in the oxidation of catechins, resulting in the production of theaflavins (Zhao et al. 2022). POD and PPO activity are at their best at 40 °C and pH 5.5 (Subramanian et al. 1999). Therefore, the activities of both these enzymes can be slowed down by altering the pH and temperature (Gulati et al. 2003). Adjusting the temperature of epistructured catechins is crucial, as they can transition to non-epistructured catechins at temperatures exceeding 95 °C. Catechins are stable in acidic solutions, lose stability as pH rises from 4 to 8, and become highly unstable in alkaline solutions above pH 8. These characteristics can stabilize catechins when added to food. Catechins' hydroxyl groups provide strong antioxidative properties, scavenging ROS like superoxide radicals, nitric acid, and nitrogen dioxide, which are essential in cancer development (Yeasmen and Orsat 2024). Moreover, catechins can absorb peroxyl radicals, which prevents lipid peroxidation and free radical chain reactions (Terao et al. 1994).

Bioavailability

The remarkable health-promoting effects of EGCG have been thoroughly studied, with an emphasis on its neuroprotective properties. Despite its benefits, EGCG's low absorption makes it challenging to use clinically for treating NDs. EGCG, taken orally, has a half-life of 1.9–4.6 h, a peak plasma concentration of 1.3–2.2 h, and is nearly completely digested within 24 h (Mehmood et al. 2022). Pharmacokinetic studies indicate that merely 0.1% of the eaten EGCG dosage in healthy individuals attains measurable levels in the circulation at peak concentration time (Gan et al. 2018; Zhang et al. 2024). EGCG is primarily absorbed in the small intestine through passive diffusion, with the remaining EGCG being broken down by intestinal microbial enzymes in the colon (Mehmood et al. 2022; Bakun et al. 2023; Ouyang et al. 2020). After consumption, EGCG is metabolized in phase II by hepatocytes and enterocytes (Gan et al. 2018; Na and Surh 2008). EGCG's poor bioavailability is due to its polyphenolic hydroxyl structure, which facilitates binding processes like methylation, glucuronidation, sulfation, and cysteine binding (Lambert and Yang 2003). Additionally, EGCG enters the colon, causing colonic bacteria to hydrolyze conjugate groups such as glucuronides and sulfates, delivering glycosides, and catabolizing them to produce phenolic acids and ring cleavage products (Mehmood et al. 2022; Miyazawa 2000). The disposition of EGCG peaks at 90 min and is almost undetectable 24 h after oral ingestion, depending on ADME (Lee et al. 2002). EGCG enters the stomach after being taken orally. The stomach's acidic environment promotes structural stability (Zeng et al. 2017). After that, the small intestine absorbs the EGCG component. EGCG concentration in peripheral blood is minimal due to high transfer from the small intestine to the large intestine, transformation via enterocytes, and generation of 11 catechin ring fission products. Both conjugated and unbound forms of these ringed fission products can be found in plasma. EGCG forms may penetrate the BBB and reach the brain parenchyma, promoting neuritogenesis and reducing neurodegeneration (Pervin et al. 2019). Urine is a byproduct of liver cell metabolism of remaining EGCG, containing sulfated intermediates, glucuronide, and methylated intermediates. (Lu et al. 2003). The stability of polyphenols is maintained by several factors (Lee et al. 2002; Scholl et al. 2018). High temperatures and an alkaline environment can negatively impact the structural integrity of EGCG, leading to its chemical breakdown (Li et al. 2011). EGCG's oral bioavailability in humans is limited and declines with eating (Naumovski et al. 2015). Studies show EGCG selectively interacts with vitamins and minerals, with minerals like chromium and selenium enhancing bioavailability and antioxidant activity, while vitamins and fish oil decrease EGCG oxidation (Shirai and Suzuki 2008; Peters et al. 2010; Giunta et al. 2010). The plasma concentration of EGCG reaches its maximum after consuming Teavigo after an overnight fast. Additionally, EGCG enhances internal stability when taken in conjunction with meal supplements (Andreu-Fernández, et al. 2020).

The brain's parenchyma is accessed through the BBB, regulating neuronal cell proliferation and neurogenesis (Unno and Nakamura 2021). There are two opinions on the impact of EGCG bioavailability on neuroprotection: limited bloodstream entry and gut accumulation (50%), with less than 0.01% found in liver, blood, and brain (Shimizu et al. 2014). Lambert et al. compared oral and intravenous administration of EGCG in mice, finding that most ingested EGCG enters the bloodstream as the glucuronidated form, with the colon and small intestine accumulating significant amounts (Lambert et al. 2003). EGCG, when intravenously administered, was rapidly disseminated in an uncoupled condition in other tissues such as the brain, liver, and lung (Zeng et al. 2022; Chen et al. 1997). EGCG may impact signaling and functional abnormalities in intestinal neuroimmune communication via the brain–gut axis, which houses a large immune cell and neural network population (Chen et al. 2024; Luo et al. 2022; Wang et al. 2024). Microbial signaling pathways are essential for neuroprotection, and the gut–brain axis is key in brain injury, neuroinflammation, and associated disorders (Chiu et al. 2020; Jiang 2024). Gut microorganisms can break down EGCG into fission products that are easier to cross the BBB and more accessible, potentially providing neuroprotective benefits (Pervin et al. 2019). Additionally, EGCG's neuroprotective effects include increased intestinal permeability, increased 5-hydroxytryptamine levels in the hippocampus, lower serotonin levels in the colon, and increased dopamine neuron activity in the gut (Ng et al. 2017; Li et al. 2020; El-Missiry et al. 2018). By changing the gut microbiota, EGCG reduces intestinal inflammation and restores the intestinal barrier. The gut microbiome's modification, through influencing physiological processes like immune cell growth, amyloid deposition, BDNF, and NMDA signaling, ultimately reduces neuroinflammation and NDs (He et al. 2022; Bergstrom et al. 2015; Wang et al. 2011). EGCG impacts tryptophan-related metabolites, short-chain fatty acids, and secondary bile acids in the gut microorganisms' metabolome (Zuo et al. 2024; Naito et al. 2020).

Neurodegeneration

Vascular plants contain flavonoids, low molecular weight secondary metabolites categorized into anthocyanins, flavan-3-ols, flavones, flavanones, flavonols, and isoflavones. All phenolic compounds with a 15-carbon skeleton have a three-ring structure consisting of two six-carbon benzene rings and a heterocyclic pyran or pyrone ring (Fraga et al. 2019). EGCG, comprising over 60% of green tea's catechins, is composed of a galloyl group, benzenediol ring, pyrogallol ring, and tetrahydropyran moiety (Reygaert 2018). The number and location of hydroxyl groups affect the molecule's interface with the biological matrix (Botten et al. 2015). Additionally, EGCG has two structures that allow for the chelation and neutralization of the metal ions: the ortho-3′,4′-dihydroxy moiety and the 4-keto,3-hydroxyl or 4-keto,5-hydroxyl moiety (Acker et al. 1996). NDs have common characteristics, including degeneration of different neuronal subtypes and pathological changes within specific brain regions, despite their distinct pathological and clinical manifestations. Neurodegenerative processes are significantly influenced by pro-apoptotic protein dysregulation, OS, immune-mediated inflammation, mitochondrial dysfunction, and decreased trophic factor expression (Farkhondeh et al. 2019; Fahn and Cohen 1992; Berg et al. 2001). A study focused on the interaction between EGCG's anti-neuroinflammation and anti-OS properties and NDs. OS and neuroinflammation are linked because ROS aggravate inflammation, and inflammation increases ROS production (Taylor et al. 2013). The NF-κB transcription factor pathway can be directly activated by ROS, which promotes the production of inflammatory cytokines (Manoharan et al. 2024).

Oxidative stress and inflammation

OS and inflammation are linked to an imbalance between ROS and antioxidant molecules. OS and inflammation are linked to NDs, diabetes, and cardiovascular diseases (Zhang et al. 2015a). Catechins, due to their chemical composition and the total number of phenolic hydroxyl groups in polyphenols, exhibit both direct and indirect antioxidant effects (Fraga et al. 2010). Free radicals can be reduced by phenolic hydroxyl groups reacting with reactive nitrogen species and ROS (Bors et al. 1990; Rice-evans et al. 1995). These enzymes regulate the production of proteins like NADPH, GSH, CAT, and SOD, which are crucial for maintaining the redox balance (Bernatoniene and Kopustinskiene 2018; Khan et al. 1992). Catechins indirectly act as antioxidants, controlling signaling pathways and protein activity, triggering phase II metabolizing enzymes, blocking pro-oxidant enzymes, and triggering antioxidant enzymes based on concentrations (Fraga et al. 2010; Fraga and Oteiza 2011). EGCG and its derivatives are prominent bioactive substances with potent antioxidant properties (Khan and Mukhtar 2018). These can regulate NADPH oxidase (NOXs), caspases, and cell survival molecules, thereby reducing superoxide production and NF-κB transcription factor activity (Fraga et al. 2010; Fraga and Oteiza 2011; Han et al. 2018). A catechol group is necessary for antioxidant capacity to be synergistic with GSH (Pereira et al. 2013). Enzymatic antioxidants and other low molecular weight antioxidants will be increased as part of the defensive mechanisms in response to OS. Piperine, when combined with EGCG, can enhance the bioavailability of EGCG and have a beneficial antioxidative effect on certain antioxidant enzymes (Brückner et al. 2012). Recent research aims to enhance the efficacy of antioxidants. EGCG enzymatic glucosylation and lipophilic EGCG products have been shown to enhance antioxidant activity in numerous cellular models (Nadim et al. 2014; Feng et al. 2013). The positive health effects can be attributed to EGCG–protein interactions and ROS-related pathways (Saeki et al. 2018). Catechins have the potential to function as a therapeutic agent by inhibiting numerous OS-related pathways that cause inflammation (Liu et al. 2014; Fan et al. 2017) and by modifying activator protein-1 (AP-1) and NF-κB activity (Braicu et al. 2013). Catechins have anti-inflammatory properties via preventing oxidative damage and inflammation through the interaction of the NF-κB and MAPK pathways (Ohishi et al. 2016). Inflammation and OS can also be inhibited by Nrf2 activation (Khan and Mukhtar 2018). EGCG may also reduce the NF-κB pathway, which in turn may prevent the release of inflammatory cytokines (Brückner et al. 2012). The digestive system can absorb catechins through three metabolic processes: sulfonation, glucuronidation, and methylation (Feng 2006). EGCG is the only flavonol form that is found in a considerable percentage of plasma (Rothwell et al. 2018), with the other forms being identified as glucuronidated or sulfated (Feng 2006).

Etiopathology of neurodegenerative diseases

ND, such as AD and PD, are primarily linked to family types, with their frequency increasing with age. Environmental and genetic factors contribute to the most prevalent, sporadic types. Heavy metals, such as lead and mercury, disrupt intracellular targets, leading to pathogenic processes like brain inflammation, OS, mitochondrial dysfunction, and protein turnover. Exposure to heavy metals early in development may increase the risk of NDs later in life. Antioxidants and nonsteroidal anti-inflammatory medications can reduce the risk of AD by suppressing early pathogenic processes. Heavy metal accumulation in fetal rat telencephalon brain cells suggests lead and mercury may contribute to NDs, emphasizing the need for preventative action (Monnet-Tschudi et al. 2006). NDs involve the loss of susceptible neurons due to OS, apoptosis, and neuroinflammation. Dementia, AD, PD, spinocerebellar degenerations, extrapyramidal diseases, frontotemporal degenerations, tauopathies, α-synucleinopathies, amyloidoses, and TDP-43 proteinopathies are various diseases characterized by clinical characteristics and protein abnormalities (Sahoo et al. 2022; Singh et al. 2024). Additionally, NDs are progressive nervous system diseases characterized by the loss or destruction of neurons in the brain and/or spinal cord at any stage of life. Neurodegeneration in AD, PD, HD, and ALS is a multifactorial process involving toxic responses leading to neuronal death (Ritchie and Lovestone 2002; Kuriyama et al. 2006a). OS is characterized by antioxidant depletion, decreased trophic factor expression, inflammation, glutamatergic excitotoxicity, proapoptotic protein expression, increased iron and nitric oxide, and impaired protein handling and aggregation (Fahn and Cohen 1992; Riederer et al. 1989; Berg et al. 2002). A study on the cause, order, and ultimate pathway of predisposed neuronal cell death in the brain is still ongoing. New therapeutic neuroprotective strategies suggest that modulating multiple targets in the CNS can improve therapeutic efficiency due to the multi-etiological nature of disorders (Mandel et al. 2007; Schyf et al. 2006). Because of their wide range of biological and pharmacological activities, such as cardiovascular, anti-inflammatory, and anti-carcinogenesis effects (Higdon and Frei 2003; Khan and Mukhtar 2007; Kuriyama et al. 2006b), as well as their more recently identified antidiabetic (Kuriyama et al. 2006b; Li et al. 2006; Anderson and Polansky 2002), antiobesity (Wolfram et al. 2006), and neuroprotective/neurorestorative qualities (Mandel et al. 2005), it is therefore not surprising that green tea catechins have garnered growing interest as therapeutic cytoprotective agents for the treatment of NDs. NDs are caused by various psychological and environmental stressors, leading to a decline in immunologic resistance. Stressors increase tissue susceptibility to viruses, leading to a cycle of autoantibodies and tissue autoantigens (Pierpaoli 2005).

Catechin (EGCG) use in neurodegenerative diseases

Alzheimer’s disease

A variety of brain disorders, including AD, are referred to be NDs because they cause brain shrinkage and cell destruction, which in turn impair cognitive or physical functioning. Tea drinking was linked to a low prevalence of AD and severe cognitive impairment, but diabetes and stroke in the elderly were linked to dementia (Yang et al. 2016; Abubakar et al. 2025). Amyloid precursor protein (APP) forms amyloid proteins, with 1–40 and 1–42 being most prevalent, leading to cognitive decline and brain atrophy due to Aβ oligomerization and accumulation (Villemagne et al. 2013), and soluble Aβ oligomers can have neurotoxic effects (Haass and Selkoe 2007). In AD, abnormal protein aggregation caused by hyperphosphorylation of Tau, a protein involved in microtubule structure and function, disrupts axonal transport (Jouanne et al. 2017). The two primary neurotransmitter types implicated in AD are cholinergic and glutamatergic; soluble Aβ oligomers can raise glutamate (Paula-Lima et al. 2013). Phosphorylated tau protein is responsible for Aβ plaques, neurofibrillary tangles, inflammation, microglia-induced inflammation, neurotransmission alterations, glutamate receptor over-activation, calcium homeostasis, ROS production, mitochondrial dysfunction, and synaptic dysfunction (Reddy and Beal 2008; Domenico et al. 2009; Birch et al. 2014; Elfawy and Das 2019). Neuroprotection may be possible by focusing on these processes. Daily tea drinking has been linked to a reduction in cognitive decline (Ma et al. 2016). Catechins' antioxidant properties may prevent neurodegeneration, as late-onset NDs are linked to increased OS (Bennett et al. 2008; Kim et al. 2015). AD patients exhibit elevated levels of oxidized DNA, proteins, and peroxidized lipids (Pratico 2008). A study found that administering green tea catechins to mice for 26 weeks effectively prevented cognitive decline caused by amyloid-induced changes. Lipid peroxidation and ROS levels were 20% lower in the hippocampus and plasma than in the control group (Haque et al. 2008). Catechins' capacity to scavenge radicals and chelate iron may be the cause of these antioxidative increases (Sang et al. 2003; Seeram et al. 2006; Mandel and Youdim 2004). In addition, catechins can chelate metal ions like copper and iron in AD patients by preventing the Fenton reaction (Weinreb et al. 2009; Ward et al. 2014). Morales et al. indicated that catechins can mitigate cognitive loss-related behavioral changes and mitigate OS in the brain and peripheral organs. Damaged and injured neurons release pro-inflammatory substances such as cytokines and cytotoxic chemicals, which may cause cell death (Morales et al. 2014). EGCG pretreatment, administered at a dosage of 1.5/3 mg/kg for 3 weeks, effectively inhibits the production of inflammatory proteins, cytokines, and cognitive loss induced by LPS (Lee et al. 2013).

Additionally, EGCG decreased BV-2 microglia's reactions linked to LPS-induced inflammation (Wu et al. 2012). The PKC-related pathways that are important in cell survival and the synthesis of soluble, non-toxic amyloid β are impacted by catechins in AD (Berra et al. 1997; Alkon et al. 2007). Levites et al. (2003) found that low EGCG concentrations enhance sAPP production in human neuroblastoma and PC12 cells, and that dietary EGCG for 2 weeks increases PKC α and ε in mice. Moreover, Kaur et al. (2008) found that aged Wistar rats treated with green tea extract (0.5%) for 8 weeks showed significant improvement in memory and learning abilities. The AchE activity in the cerebrum appeared to be lower in older rats than in younger ones. According to Kim et al. (2004), scopolamine-induced amnesia can be reversed with a diet containing 0.2% tea polyphenol. Tea polyphenols not only alter behavior, but also reduce AchE activity. The tea polyphenol and acetylcholine esterase enzymes have undergone extensive in silico, in vitro, and in vivo studies (Ali et al. 2016; Srividhya et al. 2012). Proapoptotic mediators like Bcl-2 and caspase-9, as well as inflammatory mediators like TNF-α, COX-2, and the NF-κβ pathway, are activated when ROS is produced in neuronal cells (Kimura-Ohba and Yang 2016). By increasing antioxidant enzymes and scavenging ROS, catechins may prevent NDs by lowering OS, which in turn may lessen direct or indirect brain damage (Shay et al. 2015).

In mice given lipopolysaccharide injections, pre-administration of EGCG raised levels of inflammatory proteins and decreased cytokines, preventing memory damage (Lee et al. 2013). The administration of 10 mg/kg/day of EGCG for a month led to a reversal of cognitive deficits in a rat model of streptozotocin-induced dementia (Biasibetti et al. 2013). Microglial activity in AD is associated with inflammation, which EGCG can prevent (Mérillon and Ramawat 2019). EGCG can activate cell survival pathways such as PI3K/Akt, ERK, and PKC by activating anti-apoptotic and pro-survival genes and suppressing pro-apoptotic proteins (Levites et al. 2002). Rats' neural deficits caused by restraint stress can be ameliorated by EGCG, which also partially restores normal levels of dopamine, serotonin, and plasma glucocorticoids (Zhao et al. 2017). Chronic EGCG administration ameliorated learning and memory impairments in rats subjected to moderate stress and decreased Aβ1–42 concentrations in the hippocampus CA1 area, and attenuated neuronal damage (Gu et al. 2014). In older mice with accelerated senescence, green tea catechins can also prevent memory loss and brain morphologic and functional deterioration (Unno et al. 2007). Therefore, by triggering cell survival signaling pathways, EGCG can inhibit cognitive impairment and potentially protect neurons (Rossi et al. 2008). Green tea catechins, when consumed orally, were found to prevent spatial learning and memory impairments in SAMP8 mice (Li et al. 2009).

Additionally, green tea drinking has been shown to have positive effects in AD mouse models in numerous studies (Xicota et al. 2017). Neuronal damage and a decrease in Aβ were demonstrated in the hippocampus after 4 weeks of EGCG treatment at doses of 2 mg/kg/day or 6 mg/kg/day (He et al. 2012). After receiving EGCG for 4 months, APP/PS1 animals displayed decreased hippocampal microglia activity and Aβ plaques, along with decreased IL-1β and increased levels of the anti-inflammatory cytokines (Bao et al. 2020). Phosphorylated tau isoforms were reported to be suppressed following intraperitoneal injection of 20 mg/kg EGCG for 60 days and oral treatment with 50 mg/kg EGCG for 6 months, using the Swedish mutant APP (APPSw) transgenic AD mouse model (Rezai-Zadeh et al. 2008). In mice, EGCG reduces cerebral amyloidosis by blocking the cleavage of amyloid precursor proteins and the production of β-amyloid (Lee et al. 2009). α-Secretase inhibits Aβ production by cleaving APP, producing sAPP-α. Combining EGCG and fish oil increases bioavailability, increases sAPP-α production, and inhibits cerebral Aβ deposits in Tg2657 mice (Giunta et al. 2010) (Fig. 1).

Fig. 1.

The figure highlights the neuroprotective effects of EGCG on AD pathology. EGCG combats OS, tau phosphorylation, neuroinflammation, and neurogenesis. It enhances antioxidant enzyme activity and reduces ROS/RSN levels, maintaining neuronal health. It also inhibits tau phosphorylation, mitigates neuroinflammation, and promotes neurogenesis. These combined effects preserve neuronal integrity, prevent cognitive decline, and may delay AD progression

Parkinson’s disease

PD is a slow-progressing ND affecting the motor system, typically affecting individuals over 50. But those under 50 may also be impacted. α-synuclein, a 140 amino acid protein, is primarily found in the presynaptic cleft of nerve cells in the brain. It is essential for regulating dopamine synthesis, promoting neuronal development, and preventing neuronal death. Under typical physiological conditions, α-synuclein is unable to form a fibrillary structure due to the equilibrium between its monomeric and oligomeric forms. The excess α-synuclein produced is eliminated through lysosomal autophagic pathways and ubiquitin–proteasome machinery (Ghiglieri et al. 2018). α-Synuclein increases levels, degrading mitochondrial function and disrupting membranes. This non-toxic structure aggregates, interfering with neural mechanisms, leading to neuron death (Burré et al. 2015; Parker et al. 1989). OS and neuroinflammation contribute to PD by causing damage and altering the signaling pathways. Antioxidant and anti-inflammatory medications are suggested as supplemental treatments (Renaud et al. 2015). Sergi investigated the potential of EGCG, a nutraceutical, in preventing and treating PD, while also considering environmental factors such as diet and drug use (Sergi 2022). Stopping aggregation formation is a crucial step in preventing the pathophysiology of PD. In vitro PCl2 cells, EGCG reduces α-synuclein toxicity and aggregation. The substance forms an unstructured oligomer with unfolded synuclein polypeptide chains, inhibiting synuclein production, monomeric synuclein, and fibrillary intermediates (Ehrnhoefer et al. 2008). Dopaminergic neurons in the brain's Substantia Nigra pars compacta (SNpc) area is impacted by PD (Ni and Ernst 2022). PD is believed to cause a decrease in brain dopamine levels due to the death of approximately 80% of dopaminergic neurons (Barber et al. 2017). Motor control loss and abnormal nerve firing are the results of dopamine deprivation (Magrinelli et al. 2016). MPTP, a neurotoxin found in the substantia nigra, is a key tool in understanding the underlying molecular processes of PD (Salari and Bagheri 2019). Catechin-rich polyphenol extracts improved motor deficit, restored dopamine and tyrosine hydroxylase levels, and decreased α-synuclein oligomers and their aggregation in cynomolgus monkeys treated with MPTP (Chen et al. 2015a). EGCG pretreatments significantly altered striatal antioxidants in male C57/BL mice, reducing dopamine loss. They prevent the enzyme TH reduction in the dopamine biosynthesis pathway, which catalyzes the synthesis of L-DOPA from tyrosine (Levites et al. 2001).

Additionally, EGCG administration in MPTP C57/BL mice reduces neuronal death and α-synuclein expression, while increasing striatal protein kinase C-α (PKC-α) offers neuroprotection (Mandel et al. 2004). EGCG promotes PKC expression in human NB SH-SY5Y cells, which leads to poor degradation (Kalfon et al. 2007). By activating ERK and JNK, activated PKC enhances neuronal survival (Maher 2001). EGCG prevents MPP + absorption and transmission to presynaptic dopaminergic neurons (Pan et al. 2003). COMT inhibitors are used in medicine to treat PD by preventing the conversion of L-DOPA to 3-O-methyl dopa. EGCG enhances the effectiveness of other brain medications by inhibiting COMT in both vivo and in vitro, thereby preventing further methylation of L-DOPA (Kang et al. 2010). EGCG, found to inhibit MAO-B and upregulate dopamine conversion in aged rat brains, has a multi-potential role in PD prophylaxis (Lin et al. 2010). PD is a pathogenic characteristic due to iron accumulation in the substantia nigra. Iron accumulation in the brain is caused by a compromised BBB and malfunctioning iron transport and storage systems, leading to OS, α-synuclein aggregation, neuroinflammation, and cell death (Batista-Nascimento et al. 2012). Protein aggregation, a common characteristic of PD, may be caused by alpha-synuclein aggregation. Three techniques were used to investigate EGCG's effects on SNCA aggregation. The study suggests that EGCG might be a powerful SNCA aggregate remodeling agent and a possible disease-modifying medication for PD and other α-synucleinopathies (Xu et al. 2016). EGCG has shown promise in treating PD. Experimental studies have shown its effectiveness in PD models, affecting apoptosis, OS, inflammation, ferroptosis, dopamine production regulation, and α-synuclein aggregation (Wang et al. 2022).

Moreover, EGCG, an antioxidant and iron-chelating compound, demonstrated neurorescue effects against MPTP-induced PD in C57 male black mice, preventing neurotoxicity, inhibiting OS, controlling ferroportin, and preventing functional and neurochemical impairments (Xu et al. 2017). Sanchez-Giraldo et al. investigated the potential of EGCG as an antioxidant to reduce OS damage in PD. A new core–shell nanoparticles system was developed, preserving EGCG's stability and bioactivity while allowing regulated distribution. The nanoparticles were tested on nerve-like cells and in vivo in an OS model of PD. Results showed EGCG's effectiveness in reducing OS, inhibiting parkin knockdown, and preventing lipid peroxidation, life span reduction, and locomotor impairment (Sánchez-Giraldo et al. 2020). In a study using a PD rat model, EGCG improved motor function, reduced tyrosine hydroxylase expression, suppressed OS, and reduced inflammation in the substantia nigra of PD rats (Wang et al. 2025). Additionally, Zhou et al. explored the use of EGCG in PD treatment, revealing that it prevents MPTP toxicity, restores movement, boosts T cell ratio, and reduces inflammatory factors. EGCG may have neuroprotective benefits by modifying the peripheral immune response (Zhou et al. 2018). Additionally, a study found the protective effect of EGCG in PD rats, divided into control, model, and EGCG therapy groups. EGCG significantly reduced rotation speed, increased left forelimb utilization, decreased neuron apoptosis, decreased α-synuclein expression, and decreased mTOR, AKT, and GSK-3β protein expression (Zhou et al. 2019). Rotenone (ROT) neurotoxicity is a common animal model of PD. EGCG has anti-oxidative, anti-inflammatory, and neuroprotective properties. A study found that EGCG treatment could prevent motor deficits caused by ROT therapy, reduce lipid peroxidation and nitric oxide production, and protect against mitochondrial dysfunction and neurochemical deficiencies. This is the first report of EGCG's neuroprotective impact against ROT-induced motor deficits, suggesting it may have therapeutic potential in treating or postponing PD in humans (Tseng et al. 2020) (Fig. 2).

Fig. 2.

Green tea catechins play a crucial role in preventing PD, a condition characterized by dopamine deficiency. They inhibit MAO-B activity, promote dopamine reabsorption, and inhibit plaque formation. The presence of catechins helps preserve dopamine, which is crucial for nerve cell signaling and resorption

Multiple sclerosis

MS, a chronic autoimmune disease, significantly impacts the CNS. This condition involves the growth of astrocytes, neuronal damage, and T-cell infiltration, leading to inflammation and demyelination. Relapsing–remitting MS (RRMS) is the most common type, characterized by partial or complete remission and relapses with new symptoms. Secondary progressive MS (SPMS) and primary progressive MS (PPMS) have continuous disability progression (Lublin 2014). MS has no cure, but disease-modifying treatments (DMTs) may reduce MRI activity and relapses in the disease (Rae-Grant et al. 2018). EAE animal models are widely utilized for studying the molecular and clinical aspects of MS. EGCG appears to mitigate EAE and alleviate symptom severity by decreasing immune cell infiltration, modifying T-cell equilibrium (Wang et al. 2012a; Sun et al. 2013), and lowering inflammatory cytokines (Wang et al. 2012a; Sun et al. 2013). A study on EAE treatment, involving EGCG, GA, and DMT, showed significant disease onset delay and decreased inflammatory infiltrates (Herges et al. 2011). The effects of EGCG were tested on MS mice using a model produced by cuprizone. EGCG significantly increased oligodendrocyte transcription factor 1 and proteolipid protein in the cerebral cortex (Semnani et al. 2016, 2017). Bellmann-Strobl et al. (2021) evaluated catechins' effects on human populations, with less than 80% of 122 RRMS patients in the safety and effectiveness evaluation completed. The emergence of new hyperintense lesions on T2-weighted brain MRIs served as their effectiveness end point. The 18-month course of adding oral EGCG to GA did not improve MRI results.

A clinical study revealed that EGCG treatment improves the degree of OS (Mossakowski et al. 2015). Furthermore, another study found no significant differences in brain shrinkage between groups. Researchers probed whether the study's poor results could be due to the small sample size and over 30% dropout rate (Rust, et al. 2021). Lovera et al. (2015) evaluated the efficacy of Polyphenon E, a 50% EGCG, in treating MS patients. The study was inhibited due to abnormal liver function tests in five out of seven Polyphenon E patients, suggesting an increased risk of hepatotoxicity. EGCG treatment has been proven safe in various studies, with comparable adverse effects in both treatment and placebo groups (Bellmann-Strobl, et al. 2021; Rust, et al. 2021). A systematic review found the safety and effectiveness of EGCG as a dietary supplement in managing MS. Results show that EGCG administration improves metabolic health markers and functional skills, especially when paired with coconut oil. However, it has little effect on primary outcomes like disease progression. EGCG administration appears to provide clinical and functional benefits, particularly in physical and metabolic health, but does not seem to significantly impact disease progression indicators (Schuldesz et al. 2024). A study found the impact of EGCG and coconut oil on IL-6 levels, anxiety, and functional impairment in MS patients, dividing them into an intervention and control group. Results showed that IL-6 levels dropped in both groups, but state anxiety and functional ability decreased in the intervention group. The Mediterranean diet's antioxidant potential may also contribute to this reduction (Platero et al. 2020). Mahler et al. investigating EGCG in enhancing energy metabolism and substrate usage in MS patients found that women who received EGCG had higher adipose tissue perfusion, glucose supply, and postprandial energy expenditure than men who received a placebo. Postprandial energy expenditure was lower after EGCG than a placebo during exercise, suggesting males were more productive. EGCG also increased muscle metabolism during moderate activity more in men than in women, possibly to sex-specific effects on endocrine and autonomic regulation (Mähler et al. 2015). Additionally, Cuerda- Ballester et al. found that nutritional intervention with coconut oil and EGCG improved gait and balance in MS patients (Cuerda-Ballester et al. 2023). Furthermore, a study involving 45 MS patients found that the administration of coconut oil and EGCG improved their lipid profiles, fat intake, and functional impairment. The study found that the decrease in TG levels in the intervention group (IG) was associated with an improvement in functional disability, while the decrease in body fat was negatively linked to HDL levels and positively correlated with CRP and TG levels. This suggests that the functional gains may be due to the reduction of blood TG levels (Rubia Ortí, et al. 2023).

Another study found the impact of EGCG treatment on retinal thickness analysis in animal models of MS (Table 1). The study found no discernible changes in longitudinal retinal thickness after two years between the EGCG-treated and placebo arms. EGCG does not have any neuroprotective effects, and the investigation was likely underpowered to identify an effect, which is consistent with the main SUPREMES trial's findings (Klumbies et al. 2021). Platero et al. found the effect of EGCG and coconut oil on cortisol activity in MS patients, dividing them into an intervention and control group. The intervention group consumed coconut oil and EGCG daily for 4 months, while the control group received a placebo. Blood samples showed increased blood albumin levels in the intervention group. Abdominal obesity and depression levels also decreased. Mixing EGCG and coconut oil increased albumin content, reducing despair in MS patients (Platero et al. 2021). Moreover, another study involving 51 MS patients found that the intervention group showed increased levels of BuChE, βHB, PON1, albumin, and functional capability, while decreasing IL-6 and fat percentage. The intervention group's triglycerides, fat percentage, and PON1 activity showed favorable relationships with BuChE (Rubia Ortí, et al. 2021).

Table 1.

Catechin (epigallocatechin-3-gallate) is used to prevent and treat NDs

Disease name	Study model	Dose/conc	Findings	Refs
Alzheimer’s disease	Adult male Sprague–Dawley rats	100 mg/(kg d), 250 mg/(kg d), and 625 mg/(kg d)	Improved the antioxidant system, learning, and memory function of AD-infected rats by reducing Tau protein hyperphosphorylation	Nan et al. 2021
	Male Wistar rats	10 mg/kg	Protected against Aβ-induced memory and coordination impairment in rats	Rasoulijazi et al. 2007
	APPsw mice	50 mg/kg	Altered tau pathology in Alzheimer's transgenic mice, thereby reducing Aβ-mediated cognitive impairment	Rezai-Zadeh et al. 2008
Parkinson’s disease	C57BL/6 J mice	25 mg/kg and 50 mg/kg	Restored movement behavior, protected tyrosine hydroxylase-positive cells, increased T lymphocyte ratio, and reduced inflammatory factors in the substantia nigra pars compacta region	Zhou et al. 2018
	Adult Sprague–Dawley male rats	50 mg/kg	Effect on apoptosis and mTOR/AKT/GSK-3β pathway in substantia nigra neurons in 6-dopamine-induced Parkinson rats	Zhou et al. 2019
	C57BL/6 J female mice	10 mg/kg	Reduced anxiety-like behavior and motor impairments, ameliorated PFF-induced degeneration of TH-immunopositive neurons, and increased the release of anti-inflammatory cytokines	Shen et al. 2024
Multiple sclerosis	C57BL/6 mice	50 mg/kg	Increased in PLP and Olig1 expression, suggesting it may alleviate symptoms and pathological conditions linked to autoimmune inflammatory diseases	Semnani et al. 2017
Huntington’s disease	Male Wistar rats	10, 20, and 40 mg/kg	Improved memory and restored glutathione system functioning	Kumar and Kumar 2009
Down syndrome	Ts65Dn mice	200 mg/kg	Improved neurobehavioral and skeletal phenotypes in the Ts65Dn DS mouse model	Goodlett et al. 2020
	Ts65Dn mice	50 mg/kg	Showed minimal improvement in cognitive phenotypes, unfavorable bone phenotypes	Stringer et al. 2017
Fetal alcohol spectrum disorders	C57BL/6 J mice	30 mg/kg	Ameliorated these effects, attenuated alcohol-induced changes in placental angiogenic factors, and partially rescued neuronal nuclear antigen, DCX, and GFAP levels	Almeida-Toledano et al. 2021
	Pregnant female mice	400 mg/kg	Reduced embryonic injuries in mice, resulting in similar embryo sizes and neural marker gene expression	Long, et al. 2010
Amyotrophic lateral sclerosis	SOD1-G93A transgenic mice and wild-type mice	10 mg/kg	Increased motor neurons, reduced microglial activation, reduced NF-κB and cleaved caspase-3 reactions, and reduced protein levels of iNOS and NF-κB in the spinal cords	Xu et al. 2006
	Transgenic mice	1.5, 2.9, and 5.8 μg/g	Prolonged symptom onset and lifespan, preserved survival signals, and attenuated death signals	Koh et al. 2006
Cerebral ischemia and Brain injury	Male Sprague–Dawley rats	50 mg/kg	Prevented neurological impairment, decreased infarct volume, and attenuated inflammation-related molecules in rats	Zhang et al. 2015b
	Male Sprague–Dawley rats	20 mg/kg	Decreased neurological function score, protected nerve cells, inhibited neuronal apoptosis, and reduced OS injury and brain injury markers	Nan et al. 2018
	Adult male rats	50 mg/kg	Improved neurological deficits, reduced infarct volume, alleviated histopathological changes, and decreased TUNEL-positive cells in the cerebral cortex	Park et al. 2020
	Male Sprague–Dawley rats	100 mg/kg	Reduced brain water content and vascular permeability, inhibited TBI-induced IL-1β and TNF-α mRNA expression, and decreased microglia activation	Zhang et al. 2015c

Huntington's disease

Huntington's disease (HD) is a progressive ND characterized by mental symptoms, cognitive decline, and motor dysfunction. Motor symptoms are linked to cortical and striatal function, while cognitive abnormalities are linked to cortical and hippocampal function. The study found medicinal substances that can prevent neuronal death and restore synaptic plasticity. It demonstrated two new therapeutic targets for HD's cognitive and motor symptoms, PAC1 receptor and FASN enzyme, and characterized PACAP and EGCG as potential drugs (Cabezas Llobet 2019). The first exon of the IT-15 gene, responsible for the 350 kDa huntingtin protein, contains an unstable polyQ repeat enlargement, causing HD (Harjes and Wanker 2003). The enlargement must exceed 35 repeat units, causing HTT fibril aggregates to form neuronal inclusions, causing a gradual decline in cortical and striatal neurons (Rosenblatt 2007). Chorea, a common HD sign, can be effectively treated with tetrabenazine (TBZ), an antipsychotic medication that blocks VMAT-2 in the CNS (Savani and Login 2007). Cholinesterase inhibitors like rivastigmine improve cognitive function in patients with progressive HD-related dementia (Wyant et al. 2017). Recent research has primarily focused on compounds that could prevent mutant HTT from aggregating. EGCG and other constituents are potent inhibitors of HTT exon 1 aggregation. Green tea polyphenols can inhibit the initial stages of polyQ growth, thus preventing the formation of amyloid fibrils in HD models. EGCG and its byproducts, such as free radical elimination, ROS reduction, and metal ion chelation, may mitigate toxic effects and htt accumulation in in vivo HD models (Ehrnhoefer et al. 2006). EGCG inhibits polyQ aggregation and may protect neurons that express a modified HTT protein from its harmful effects. The alteration in the lipid composition of cellular and subcellular membranes results in the accumulation of amyloid-producing proteins. Modified htt showed increased affinity for phospholipids, altering the stability of the phospholipid double layer compared to non-mutated htt. The study investigated whether lipid vesicles altered EGCG's or curcumin's ability to alter aggregated HTT and influence HTT and lipid linkage. EGCG effectively inhibited amyloid formation by preventing the formation of HTT fibrils in the presence of lipid vesicles, regardless of its interaction with the membrane environment (Beasley et al. 2019). Furthermore, EGCG ameliorates neurodegeneration brought on by mutant HTT in Drosophila models (Varga et al. 2020). A clinical investigation assesses cognitive performance changes in HD patients by administering a maximum daily dose of 1200 mg of EGCG (Priller 2022).

Down syndrome

Down syndrome (DS) is the most common genetic disorder linked to intellectual disability. The presence of a third copy of chromosome 21 leads to facial traits such as a flattened face, epicanthus, up-slanted eyes, and hypotonia (Dierssen 2012). Cognitive abnormalities in DS can vary in severity due to an imbalance between high cerebral cortex activation and enhanced hippocampus synapse suppression (Dierssen 2012). A study found synaptic dysfunction, which is a condition characterized by changes in synaptic proteins like glutamate, GABA, or other neuromodulator receptors, leading to reduced synaptic function (Cué and Dierssen 2020). DS's reduced flexibility and synaptic changes may hinder its adaptability to environmental changes, affecting brain processing and storage, and affecting spatial memory (Lott and Dierssen 2010). There have been suggestions for ways to help DS patients with dementia. DS patients are being treated with psychotropic medications, antipsychotics, and antidepressants due to unsatisfactory outcomes (Vicari et al. 2013). The effectiveness of acetylcholinesterase inhibitors in treating DS dementia is under investigation due to insufficient data (Vaughan et al. 2016; Hanney et al. 2012). Because of its pro-cognitive properties, EGCG therapy has been suggested for DS in recent years (Singh et al. 2011). EGCG may have positive benefits by inhibiting metalloproteinase 9 (MMP-9). DS disrupts the metabolic pathway of nerve growth factor (NGF), thereby affecting the regulation of proteolysis-related enzymes like MMP-9. EGCG may alter MMP-9's ability to degrade NGF (Wyganowska-Świątkowska et al. 2018). Recent research focuses on the mechanism of EGCG, specifically the suppression of DYRK1A, a serine/threonine kinase involved in cell proliferation, neuronal enhancement, and plasticity, in DS patients. Research on transgenic mice overexpressing DYRK1A reveals that EGCG effectively spreads throughout the brain without adverse effects due to its inhibitory and connectivity mechanisms (Gu et al. 2020; Souchet et al. 2015). DS therapy targets active DYRK1A concentration, potentially aiding in behavioral issues by affecting GABAergic and glutamatergic pathways (Souchet et al. 2015). Research indicates that environmental enrichment and EGCG treatment, at an average dosage of 30 mg/kg/day, can enhance learning and memory in Ts65Dn mouse models (Catuara-Solarz, et al. 2016; Catuara-Solarz, et al. 2015). EGCG treatment decreases mitochondrial bioenergetics and biogenesis in DS, boosts neuronal progenitor cell proliferation, and inhibits ROS production in Ts65Dn mice (Valenti, et al. 1832; Valenti, et al. 1862).

Additionally, EGCG medication may be more effective in modulating DS impairments during the neonatal phase (Stagni et al. 2016). Goodlett et al. found that daily EGCG gavage treatments for 3 weeks caused growth impairment in euploid and trisomic mice, while it did not improve conduct evaluation in Ts65Dn mice (Goodlett et al. 2020). Neither lower nor higher doses of EGCG during puberty improved cognitive impairment in DS animal models (Stringer et al. 2015; Stringer et al. 2017). Few clinical trials show that EGCG significantly improves visual memory, recall, response inhibition, and conduct performance in DS patients, compared to placebo alone or cognitive training (Torre et al. 2016; Torre et al. 2014). Improving immediate detection memory was the primary benefit of EGCG. EGCG may be beneficial when combined with cognitive training, which enhances plasticity by normalizing DYRK1A activity. Plasma homocysteine, a biomarker of hippocampus DYRK1A levels, is linked to human memory improvement, indicating a strong correlation between DYRK1A activity and intellectual advancement (Torre et al. 2014). A recent study found that EGCG, given at a dose-dependent rate (30 mg/kg/day) before three years old, can affect face development, but may have negative effects at higher doses (Starbuck et al. 2021). Moreover, Cieuta-Walti et al. found the safety, tolerability, and effectiveness of EGCG in pediatric DS children found that 86% experienced treatment-emergent adverse events (AEs) in the EGCG group, while 35% experienced AEs due to the medication. Despite EGCG being safe and well-tolerated, available data do not support its effectiveness in this population. EGCG enhances cognitive and functional performance and assesses the safety and tolerability of a dietary supplement containing EGCG (Cieuta-Walti et al. 2022). DS is a genetic disorder characterized by neurodevelopmental abnormalities and cognitive impairment. DYRK1A, a gene involved in brain changes, is believed to be a significant factor. EGCG, an inhibitor of DYRK1A, has been shown to improve cognitive function in Dyrk1A transgenic mice. However, EGCG has little effect on hippocampal-dependent memory. Periodic EGCG delivery may help prevent DS effects (Stagni et al. 2017). Green tea's positive effects on the brain are primarily mediated by EGCG, which inhibits DYRK1A, a gene in Down syndrome. Preclinical and clinical investigations suggest EGCG may be an appropriate therapy for DS. While some studies show no behavioral improvement, others show temporary improvements in hippocampal growth and cognitive function (Stagni et al. 2021).

A study in Spain suggests that EGCG could enhance the benefits of non-pharmacological cognitive rehabilitation for young adults with DS. The study involved 84 participants with DS, aged 16–34 years, who were randomized to undergo cognitive training for a year along with either EGCG or a placebo. After 6 months, participants who received EGCG and cognitive training had significantly higher scores in inhibitory control and adaptive behavior. The study found that EGCG and cognitive training significantly outperformed placebo and cognitive training in terms of enhancing adaptive behavior, visual recognition memory, and inhibitory control. To validate the long-term effectiveness of EGCG and cognitive training, phase 3 trials with a broader group of people with DS will be required (Torre et al. 2016). In Ts65Dn mice, EGCG activates AMPK in neural hippocampal progenitor cells, which is associated with the recovery of hippocampal neurogenesis (Valenti, et al. 1862). By promoting the growth of brain progenitor cells both in vitro and in vivo, EGCG at 20 mg/kg enhanced neurogenesis in adult hippocampus euploid mice and improved spatial learning and memory function (Wang et al. 2012b). A study found that DYRK1A is linked to neurogenesis abnormalities, using iPSCs from twins with varying karyotypes. They show that when iPSCs are neurally induced into NPCs in the presence of EGCG, DYRK1A activity in these cells nearly returns to its regulatory level, restoring both the proliferative capacity and the apoptotic events, thus fostering neurogenesis. When DS-iPSCs with short hairpin RNA are used against DYRK1A, comparable effects are observed (Hibaoui et al. 2014). It has been shown that EGCG can pass the BBB in transgenic mice that overexpress Dyrk1A (Gu et al. 2020). Environmental enrichment and EGCG administration at an average dose of 30 mg/kg/day positively enhanced corticohippocampal-dependent learning and memory in Ts65Dn mice, preventing cognitive degeneration (Catuara-Solarz, et al. 2016; Catuara-Solarz, et al. 2015). Ts65Dn mice's hippocampal phosphoprotein deregulation was restored by EGCG at 42 mg/kg/day for a month, which also reversed the kinome deregulation process and restored the epigenetic profile. The treatment's positive impact on plasticity changes was greater if it began in the first few years of life (Toma et al. 2019, 2020).

Therefore, EGCG therapy has been suggested for DS because of its pro-cognitive properties. The craniofacial anomalies, another DS characteristic, have been the subject of another investigation. Humans with DS have been found to exhibit dysmorphic craniofacial phenotypes, which are anomalies that occur during fetal morphogenesis and growth. Pregnant Ts65Dn mice were given an oral gavage of EGCG at a dose of 200 mg/kg. The mice showed the same craniofacial dysmorphology as neonates with Down syndrome at E7 and E8. A lesser dose had no impact; however, certain craniofacial adjustments that lasted throughout maturity were observed (McElyea et al. 2016).

Furthermore, following 7 weeks of therapy with 20 mg/kg/day, only modest improvements in cortical measurements and no change in male Ts65Dn trabecular bone were noted (Jamal et al. 2022). GABAergic and glutamatergic pathways may be impacted by elevated DYRK1A, which could shift the balance of excitation and inhibition neurotransmissions in favor of inhibition and cause fine to delayed cognitive development. A DS mouse model with a YAC construct overexpressing Dyrk1A, along with additional genes, was utilized in the first investigation to illustrate the impact of DYRK1A inhibitors. Green tea polyphenols treatment improved cognitive impairment and brain morphology, and object recognition memory from pregnancy to maturity (Guedj et al. 2009). Moreover, another study found that therapy restored hippocampal BDNF levels in mice, a crucial neurotrophic protein responsible for transmission and plasticity at the adult brain synapse (Gu et al. 2020; Guedj et al. 2009).

Fetal alcohol spectrum disorders

FASD is a group of disorders resulting from pregnancy-induced ethanol exposure. Fetal alcohol syndrome (FAS), the most severe type, is characterized by growth deficiency, neurobehavioral dysfunction, and facial dysmorphology (Hoyme, et al. 2016). Alcohol consumption can lead to various pathological consequences, such as neuroimmune system dysregulation, neurotransmitter abnormalities, and epigenetic changes (Almeida et al. 2020). OS damage is the main cause of alcohol keratogenesis (Heaton et al. 2003). Alcohol-related changes are not treated, and FASD phenotypes persist for life. Early therapies, like behavioral interventions or developmental therapy, may prevent specific diseases and disabilities (Joya et al. 2015; Pei et al. 2017). Pharmacotherapy is being explored to address behavioral and cognitive traits prevalent in NDs. Exercise enhances brain function, and dietary therapies target OS, nutritional deficiencies (vitamins and minerals), and epigenetic changes brought on by maternal alcoholism (Murawski et al. 2015). Catechins are potential treatments for FASD due to their antioxidant properties and ability to penetrate multiple organs (Chu et al. 2007). Four preclinical investigations on EGCG treatment were identified, but none involved human subjects. EGCG improves antioxidant defense and lowers oxidative-nitrosative stress (Long et al. 2010; Tiwari et al. 2010; Almeida-Toledano et al. 2021). Studies using murine models in rat neonates showed that EGCG treatment at 50 or 100 mg/kg increased glutathione and superoxide dismutase levels (Tiwari et al. 2010). In pregnant mice, EGCG treatment at 400 mg/kg reduced the production of H₂O₂ and malondialdehyde (Long, et al. 2010). Nfr2 was reduced in response to EGCG therapy at 30 mg/kg and prenatal alcohol exposure (PAE). EGCG's antioxidant function is likely facilitated by other molecular pathways (Almeida-Toledano et al. 2021). By preserving sufficient placental vascularization, EGCG controls placental angiogenesis disorders and fetal growth restriction caused by PAE (Long, et al. 2010; Almeida-Toledano et al. 2021). Almeida-Toledano et al. demonstrated that continuous ethanol exposure can compensate for the decrease in the expression of VEGF-A and VEGF-R1 in a mouse model (Almeida-Toledano et al. 2021).

Furthermore, EGCG treatment has shown positive effects on prenatal brain development influenced by ethanol due to its ability to penetrate the BBB (Chu et al. 2007). Another study demonstrated reduced apoptosis in an in vitro model using rhombencephalic neurons from rat fetuses (Antonio and Druse 2008) and decreased caspase 3 and NF-κB in a rat model (Tiwari et al. 2010), demonstrating that EGCG prevents neuronal apoptosis caused by ethanol. A study suggests reducing acetylcholinesterase activity to maintain sufficient levels of acetylcholine, a glial cell proliferation activator and trophic factor that prevents neuronal apoptosis (Tiwari et al. 2010). EGCG can help prevent microcephaly and cognitive issues associated with PAE by reducing TNF-α and IL-1β levels (Tiwari et al. 2010). A mouse study suggests a daily EGCG dose of 30 mg/kg can prevent neuron loss and ethanol-induced delay, improve GFAP and BDNF expression, and address early astrocyte differentiation and neural plasticity disruptions (Almeida-Toledano et al. 2021). According to recent data from a study of 206 children's genome-wide DNA methylation patterns, PAE is linked to a variety of DNA methylation patterns (Portales-Casamar et al. 2016), including a decrease in the expression of DNA methyltransferase 1 (Dnmt1) (Tunc-Ozcan et al. 2018). EGCG therapy effectively addresses cognitive and behavioral issues caused by disruptions in fetal neurodevelopment (Tiwari et al. 2010). Moreover, EGCG modulates the expression of proteins and genes involved in neural differentiation and brain development, including Otx1 and Sox2 (Long, et al. 2010). EGCG inhibition of Dyrk1A protein in DS patients improves neuronal plasticity (Torre et al. 2016). Human testing is required for results from rodent models that resemble FASD. The neuro-SAF clinical experiment aimed to assess the impact of EGCG on cognitive function in 40 FAS children aged 7–14 (Sebastiani et al. 2021).

Amyotrophic lateral sclerosis and frontotemporal dementia

ALS is a rare ND characterized by the gradual loss of motor neurons, resulting in limb paralysis, speech, and swallowing difficulties. As the disease worsens, paralysis and respiratory failure are the outcomes (Longinetti et al. 2018). Frontotemporal dementia (FTD) is a condition marked by alterations to behavior, language, personality, and motor skills due to alterations in the temporal and frontal lobes (Greaves and Rohrer 2019; Couratier et al. 2017). EGCG can protect motor neuron cells in ALS from OS and mitochondrial damage (Koh et al. 2004). Oral EGCG supplements prolong life, enhance motor function, and dramatically delay the development of symptoms (Koh et al. 2006; Xu et al. 2006). EGCG increases neurofibrillary tangles and neuronal death mediated by GSK-3 activity (Koh et al. 2004). Koh et al. indicated that ALS mice show decreased death signals like cytosolic cytochrome c, cleaved PARP, and caspase-3, while increasing PI3K/Akt (Koh et al. 2006). Additionally, EGCG has anti-inflammatory and antioxidant effects on microglia and astrocytes. A study uses a transgenic mouse model of ALS to evaluate the neuroprotective benefits of EGCG. The mice's motor function was evaluated at age 70 days, and at 120 days, they showed decreased microglial activation, decreased NF-κB and cleaved caspase-3 reactivity, decreased protein levels of iNOS and NF-κB, and increased motor neurons. EGCG has various therapeutic benefits in ALS mice (Xu et al. 2006). Moreover, it has minimal impact on iron metabolism despite its alleged chelating capabilities (Che et al. 2017).

Cerebral ischemia and brain injury

A blood clot can lead to ischemic damage by reducing or stopping cerebral blood flow. Blocking the BBB decreases oxygen and glucose intake to brain tissue, leading to deterioration and potential accumulation of harmful substances (Farooqui 2010). Ischemia/reperfusion injury is influenced by neurochemical factors like glutamate release, glutamate receptor overstimulation, calcium overload, and calcium-dependent enzyme stimulation (Farooqui 2010). The rise in eicosanoids and the production of oxygen free radicals are leading to neuroinflammation and OS-induced brain damage (Hong et al. 2000). EGCG therapy effectively mitigates neuronal cell damage in the CA1 area of the hippocampus in gerbils, demonstrating its beneficial effects in ischemic/reperfusion injury (Lee et al. 2000). Another element of brain edema in ischemic damage is astrocyte swelling. This type of swelling in brain cell cultures is linked to glutamate release, calcium overload, OS, inflammation, and mitochondrial dysfunction. Research on C6 glial cell ischemia injury has shown that green tea extract has neuroprotective benefits, attenuating calcium influx and blocking edema. EGCG's beneficial effects on ischemia injury are due to its protective effects on mitochondria and inhibition of brain cell swelling (Panickar et al. 2009). TBI is characterized by two primary components. Neural cell membrane rupture causes intracellular contents to be released, breaking down the BBB and causing cerebral hemorrhage. TBI secondary component involves systemic and local neurochemical and pathophysiological changes, including systemic and local changes in signal transduction mechanisms, activation of microglial cells, and demyelination (Farooqui 2010; Raghupathi 2004). Acute neuroinflammation, a condition characterized by cell destruction and dysfunction linked to specific neurochemical processes, typically arises within hours or days after TBI. Prostaglandins, TNF, PAF, interleukin-1a, and interleukin-1b are essential neuroinflammatory factors in secondary brain injury (Farooqui 2010). Secondary TBI symptoms include excitotoxic damage, free radical production, increased mitochondrial membrane permeability, membrane loss, increased swelling, changes in Ca²⁺ homeostasis, and outer mitochondrial membrane rupture (Farooqui 2010; Raghupathi 2004). EGCG reduces parameters used to evaluate rat TBI in 6-week-old male rats, such as immunoreactivity, 8-hydroxy-20-deoxyguanosine, 4-hydroxy-2-nonenal, and malondialdehyde levels. EGCG administration before and after TBI may provide neuroprotection by absorbing free radicals and improving brain function by increasing the number of surviving neurons compared to water-treated rats (Itoh et al. 2011). EGCG significantly decreased infarct volume and iNOS activity in Wistar rats exposed to hypoxia–ischemia, compared to HI + saline controls. It markedly elevated the expression of NOS protein in the endothelium and neurons. EGCG's in vivo neuroprotective actions involve more intricate signal transduction pathways than just its antioxidant properties (Sutherland et al. 2005).

Machin et al. investigated EGCG on the MCAO model's ability to suppress apoptosis. Rattus norvegicus rats were treated for 7 days, and the results showed that green tea can prevent neuronal cell death by blocking the apoptotic pathway (Machin et al. 2021). Moreover, Zhang et al. found that EGCG, after tMCAO, reduced infarct volume, neurological function impairment, inflammation-related chemicals, and prevented cyclooxygenase 2 and NF-κB/p65 production in rats (Zhang et al. 2015b). EGCG protects against amyloidosis and neuronal injury in MCAO rats by reducing neurological function, protecting nerve cells, and preventing neuronal death, but it diminishes after PI3K inhibitors (Nan et al. 2018). Additionally, EGCG reduces brain damage caused by ischemia/reperfusion in a rat model. The rats were anesthetized and given EGCG or vehicle after reperfusion. The results showed that the 50 mg/kg EGCG dose significantly reduced infarction volume and neurological deficit total score, and reduced malondialdehyde and oxidized/total glutathione ratio levels. EGCG has antioxidant effects in a rat model of transient focal ischemia (Choi et al. 2004). EGCG treats inflammation, protects against regional myocardial ischemia/reperfusion damage by activating the RISK pathway and attenuating p38 and JNK. In rats, EGCG decreased infarct size compared to the control group, suggesting it may protect the heart by regulating PI3K-Akt. This suggests that patients at risk for myocardial I/R damage may benefit from EGCG's cardioprotective properties, especially in patients undergoing surgery (Kim et al. 2014b). A study on EGCG treatment for TBI revealed that it substantially reduced brain water content, vascular permeability, suppressed TNF-α and IL-1β mRNA production, and reduced TBI-induced OS (Zhang et al. 2015c).

Moreover, Park et al. found the neuroprotective properties of EGCG against cerebral ischemia in adult male rats. After MCAO injury, EGCG alleviated histological alterations, decreased TUNEL-positive cells, and repaired neurological abnormalities. It also decreased infarct volume. EGCG modulates the apoptotic signaling pathway, making it a strong neuroprotective drug (Park et al. 2020). EGCG can reduce free radical production, inhibit neuronal degeneration and apoptosis, and improve cognitive impairment in rats. EGCG treatment groups had significantly lower numbers of DNA-positive cells and malondialdehyde levels post-TBI compared to water groups. EGCG prevents apoptosis and neuronal degeneration caused by free radicals, and post-TBI and ongoing access to EGCG enhance brain function (Itoh et al. 2013). Moreover, EGCG has shown strong neuroprotective benefits in animal models of brain damage. In 102 mice, EGCG was administered immediately after a TBI injury, improving neurological damage, reducing oxidative damage, and increasing AMPK phosphorylation. EGCG may be a promising therapeutic intervention for cognitive and locomotor impairments after TBI (Wu and Cui 2020) (Fig. 3).

Fig. 3.

The protective role of EGCG against brain injury and cognitive dysfunction caused by hyperhomocysteinemia, a condition characterized by elevated homocysteine levels. EGCG counteracts hyperhomocysteinemia-induced damage by reducing OS, preventing DNA injury, inflammation, and apoptosis, and maintaining neurotransmitter balance. It promotes a healthy brain, improving cognitive and memory function and preventing brain injury and cognitive impairment

Challenges in the therapeutic application of catechins

After oral treatment, catechin plasma concentration typically reaches peak values in the sub-to-low µM range (Catterall et al. 2003). Catechins' low bioavailability is attributed to their volatility under neutral and alkaline conditions, which promotes auto-oxidation (Yoshino et al. 1999; Hong et al. 2002; Sang et al. 2005a). Additionally, they exhibit poor digestive recovery following passage through gastric and salivary fluids (Shim et al. 2012; Zhang et al. 2004; Zagury et al. 2019). Microbes can enzymatically consume or destroy catechins, and they have limited membrane permeability throughout the colon (Pervin et al. 2019; Krook and Hagerman 2012). Catechins, although effective in intravenous delivery, are susceptible to degradation, despite their potential to overcome the disadvantages of oral administration (Catterall et al. 2003). The therapeutic use of catechins is significantly hindered by the sensitivity of polyphenols to oxidants, light, and heat processing (Puligundla et al. 2017; Li et al. 2012). Furthermore, polyphenols might not be very specific. Negatively charged phenolates, produced when polyphenols' hydroxyl groups split, interact with positively charged amino acids like arginine and lysine, commonly found on protein surfaces (Wink 2015). Therapeutic use of catechins faces challenges, but understanding their interactions with amyloidogenic IDPs like Aβ peptide and harmful aggregates can help determine oligomer toxicity determinants and molecular mechanisms. A catechin library was utilized to identify hazardous surfaces within soluble Aβ assemblies, which is anticipated to aid in the formation of new anti-amyloid medications (Ahmed et al. 2017; Bieschke et al. 2010).

Toxicological studies

EGCG, despite its low oral bioavailability, can pose risks when taken in large doses or during fasting. Numerous studies have raised concerns about EGCG toxicity in treating various NDs and question its clinical therapeutic role. Multiple system atrophy (MSA) is a neurological condition marked by neuronal degeneration and gliosis in the striatum, olivocerebellum, and central autonomic regions (Poewe et al. 2022; Stefanova and Wenning 2023). A randomized clinical study found that 48 weeks of EGCG administration did not significantly impact the course of MSA or provide any clinical advantages. Two patients discontinued EGCG medication during the trial due to severe hepatotoxicity. The study found that hepatotoxicity would occur when therapeutic doses of transaminase exceed 1200 mg. The study confirms that EGCG is generally well-tolerated and suggests that targeting α-synuclein oligomers could be a useful treatment for NDs (Levin et al. 2019). Furthermore, EGCG has been shown to have negative effects on the liver and kidneys in several animal experiments (Molinari et al. 2006; Lambert et al. 2010). Ramachandran et al. investigated the relationship between the extent of hepatic injury induced by EGCG administration, its dosage, method of administration, and duration in mice. Elevated serum bilirubin, AST, ALT, and ALP levels after 108 mg/kg EGCG injection caused severe hepatic congestion, degeneration, hyperplasia, and calcification, leading to mortality by the eighth day. The study found that higher EGCG dosages led to increased liver damage in mice, despite less hepatotoxicity compared to subcutaneous injections (Ramachandran et al. 2016). Moreover, Wang et al. found that EGCG, administered subcutaneously to mice, caused severe hepatotoxicity and elevated serum levels, leading to 2-day mortality. Mice administered an injection of 55 mg/kg EGCG demonstrated hepatotoxic effects, but they lived through the entire research (Wang et al. 2015a). Additionally, the maximum tolerable dose of EGCG in mice is 45 mg/kg/day, and long-term administration does not affect oxidative defense. EGCG injections at doses of 55 or 75 mg/kg/day caused liver toxicity in murine models, affecting Nrf2 nuclear distribution and inhibiting hepatic antioxidant enzymes. Repeated injections of EGCG significantly decreased SOD, catalase, and GPX levels in mice, while higher concentrations led to significant hepatotoxicity and death correlated with dosage. Additionally, this therapy reduces antioxidant defense capacity and suppresses the expression of Nrf2 target genes (Wang et al. 2015b). Mice that received 750 mg/kg/day of EGCG via gavage for 7 days in a row showed a substantial rise in liver MT, MDA, ALT, and γH2AX levels as well as hepatocyte degeneration, which led to a 75% death rate. Mice that received a single gavage of 1,500 mg/kg of EGCG had an 85% death rate and ALT levels that increased by 108 times (Saleh et al. 2013). High-dose EGCG gavage resulted in urine containing EGCG-2′-cysteine and EGCG-2-cysteine metabolites. The study found that EGCG, when administered through diet rather than gavage, was well-tolerated and showed less hepatotoxicity in mice (Sang et al. 2005b). Studies indicate that fasting in beagles increases the risk of hepatotoxicity in comparison to animals fed before treatment with EGCG (Isbrucker et al. 2006). Additionally, studies on animals have demonstrated that alterations in several OS indicators are correlated with EGCG-induced hepatotoxicity (Lambert et al. 2010; Wang et al. 2015a). Lipid peroxidation produces MDA and 4-HNE, which are biochemical markers of OS (Lambert et al. 2010). OS, primarily responsible for hepatotoxicity caused by EGCG therapy, is linked to two molecular indicators: MT and γH2AX (Ouyang et al. 2020). An essential transcription factor in antioxidant defense is Nrf2. Keap1 sequesters Nrf2 under normal physiological conditions, but when OS occurs, Nrf2 separates from Keap1 and moves to the nucleus, where it binds to antioxidant response elements. The activation of the Nrf2-ARE signaling pathway upregulates numerous antioxidant genes (Wang et al. 2015b). The Nrf2-ARE signaling pathway is a crucial cellular defense mechanism against OS, stimulating and enhancing the production of antioxidant enzymes. This route is essential for reducing EGCG-induced hepatotoxicity, especially in the liver (Kweon et al. 2006).

Animal research shows that administering EGCG subcutaneously to mice at a dose of 45 mg/kg/day doesn't significantly weaken their liver's antioxidant defenses. EGCG injection at 75 mg/kg/day significantly boosts Nrf2 expression and target genes, while inhibiting vital liver antioxidant enzymes. The hepatic Nrf2 pathway is significantly suppressed by injection of 100 mg/kg/day of EGCG (Wang et al. 2015b). EGCG therapy in diabetic mice reduced kidney tolerance, increased NADPH oxidase levels, and caused kidney damage, leading to elevated serum levels of CYS-C and NGAL (Rasheed et al. 2017). A study identified the possible nephrotoxic effects of EGCG treatment, intensified by the increased risk of complications linked to diabetes and related comorbidities (Roghani and Baluchnejadmojarad 2010). Multiple studies have associated EGCG administration with GI damage, nephrotoxicity, and hepatotoxicity in animal models, including gavage or diet (Chengelis et al. 2008; Hsu et al. 2011). From minor vomiting and stomach erosion to severe ulceration, bleeding, and epithelial necrosis, the degree of GI side effects varied with dosage. The study indicated that animals getting EGCG through gavage or fasting experienced greater GI damage, but those supplied the compound via a meal, drink, or tablet exhibited fewer effects (Isbrucker et al. 2006; Kapetanovic et al. 2009). A study found the advantages and challenges of biomaterials as neuroprotective agents, focusing on their use in drug distribution and their potential to improve bioavailability, safety, efficacy, and toxicity in conditions like AD, PD, and ALS (Ramakrishna, et al. 2025; Prajapati, et al. 2025).

Safe dose studies

Establishing optimal EGCG dosage levels to enhance therapeutic efficacy while minimizing adverse effects is a critical issue. The challenge lies in extrapolating animal dosages to humans, as current clinical investigations regarding EGCG doses exhibit significant variability (Toolsee et al. 2013; Henning et al. 2015; Nguyen et al. 2012). Human studies reveal differing toxicity thresholds for EGCG ingested as a beverage vs capsules or tablets, demanding distinct evaluation of acceptable consumption amounts. Research indicates that doses of up to 676 mg of EGCG in pill or tablet form did not substantially adversely affect patients with various illnesses or healthy adults (Laurie et al. 2005). The ingestion of 800 mg or 1,200 mg of EGCG has been associated with hepatic damage (Levin et al. 2019; Ullmann 2004). EGCG demonstrates health benefits that are comparable to those of minerals. Patients can safely consume 338 mg of EGCG per day in the form of capsules or tablets (Hu et al. 2018). The maximum daily EGCG intake in drinks was recorded at 704 mg, without any noticeable negative effects exceeding the toxicity threshold (Toolsee et al. 2013).

Clinical trials

EGCG was authorized for a clinical trial in 2019 after its effectiveness in preclinical models of NDs. A randomized, double-blind, placebo-controlled study found that EGCG supplementation did not affect MSA progression. However, doses exceeding 1200 mg should be avoided (Levin et al. 2019). Antioxidant therapy for NDs is gaining attention due to its potential to delay or reduce OS-induced neurodegeneration. EGCG is among the antioxidants being researched, but pharmacokinetic and pharmacodynamic limitations hinder their clinical application, despite promising results in in vitro and in vivo testing (Silva et al. 2021). Researchers suggest that EGCG's poor bioavailability, including low absorption, poor pharmacokinetics, and low targeting efficacy, reduces its therapeutic potential. Its unstable physiological settings and susceptibility to quick degradation or metabolism also contribute to its partial degradation when administered intravenously (Cai et al. 2018). A study found that regular consumption of dietary flavonoids, such as epicatechin and proanthocyanidin dimers, can reduce the risk of PD in 49,281 men and 80,336 women, possibly due to their ability to phosphorylate cAMP-response element binding protein and inhibit NADPH oxidase activity (Gao et al. 2012). A linear link between tea and caffeine use and the risk of PD was found in a meta-analysis of eight studies with 344,895 individuals and seven studies with 492,724 people. Consuming two cups of coffee daily or 200 mg daily reduced the smoking-adjusted risk of PD by 26 and 17%, respectively (Qi and Li 2014). A case-controlled study found that daily tea consumption significantly reduced the probability of PD by 0.8 times, comparing 75 patients with idiopathic PD and 75 control patients (Hosseinitabatabaei et al. 2013). Epidemiological findings support the positive effects of tea consumption, although some lack convincing proof. A study involving 74,941 Shanghai women found that education increases the risk of PD, while tea drinking and secondhand tobacco smoke exposure are insignificant. The age-adjusted odds for those who consistently drank tea at least three times a week for 6 months or more were 0.8 (Chen et al. 2015b).

Tea consumption is linked to a lower prevalence of cognitive impairment in both a longitudinal study and a cross-sectional examination of Chinese adults aged 55 and older. The effects of low, medium, and high tea intake were more noticeable, with oolong and black teas having the most noticeable effects. Green tea consumption was not significantly different from black or oolong tea intake (Ng et al. 2008). A study of 681 Chinese nonagenarians and centenarians found that males with cognitive impairment had lower prevalence of tea consumption and exercise, but higher prevalence of smoking and alcohol consumption, but not in female patients (Huang et al. 2009). Another study of 716 Singaporean Chinese people found that increased tea consumption improved executive function, memory, global cognition, and information processing speed, not specific to any tea type (Feng et al. 2010). Furthermore, a study of Japanese citizens over 60 found that drinking green tea significantly reduced the risk of mild cognitive impairment (MCI) and dementia. Daily consumption of green tea was associated with a lower overall cognitive impairment incidence and a lower risk of dementia. Consumption of coffee or black tea was not linked to these risks (Noguchi-Shinohara et al. 2014). Moreover, another study conducted at Sado General Hospital in Niigata, Japan, found a 21.5% prevalence of cognitive impairment among 1143 patients aged 68.9. Cognitive impairment prevalence is linked to age, low BMI, myocardial infarction or stroke history, poor fruit consumption, and low green tea drinking (Kitamura et al. 2016).

Conclusion and future perspectives

EGCG exhibits significant neuroprotective properties against various NDs and cognitive impairments. It is a promising treatment for neuronal damage and cognitive function due to its various mechanisms, including antioxidant, anti-inflammatory, anti-apoptotic, and anti-amyloidogenic effects. EGCG, through its ability to alter key molecular pathways such as Nrf2, NF-κB, PI3K/Akt, and prevent protein misfolding and aggregation, provides therapeutic and preventive benefits for conditions like AD, PD, and HD. Despite promising in vitro and in vivo study outcomes, clinical translation of EGCG remains challenging due to its poor bioavailability, fast metabolism, and potential off-target effects. Recent advancements in drug delivery technologies, such as EGCG derivatives, liposomal carriers, and nanoformulations, have shown potential in enhancing medication stability and brain bioavailability. Extensive, precisely monitored clinical trials are needed to confirm the effectiveness, optimal dosage, long-term safety, and compatibility of EGCG with conventional treatments. Future studies should focus on overcoming pharmacokinetic constraints, investigating synergistic effects with additional neuroprotective drugs, and determining disease-specific treatments. Additionally, personalized medicine strategies that consider genetic, nutritional, and lifestyle aspects can enhance EGCG-based treatments for NDs. EGCG is a promising natural substance that could significantly aid in managing and preventing neurodegeneration and cognitive decline. EGCG has potential neuroprotective properties, but several research gaps limit its full clinical potential. These include insufficient clinical data, low bioavailability due to restricted BBB permeability, lack of standardized dosing regimens, incomplete understanding of intracellular signaling networks in human neurons, and potential side effects at excessive doses. These gaps inhibit the development of effective treatments for NDs, particularly in vulnerable or elderly populations. Future research should focus on developing advanced drug delivery methods, large-scale clinical trials, and combination therapy approaches to explore EGCG's neuroprotective properties. Researchers should also identify biomarkers to track therapeutic response and develop individualized treatment plans. Longitudinal and preventive studies should explore EGCG's potential for prevention. Systems biology and multi-omics methods can help decipher the intricate relationships between EGCG and neural networks, leading to novel treatment targets. Therapeutic use of EGCG is complicated by significant inter-individual variability due to genetics, gut microbiota composition, metabolism, and lifestyle. The effectiveness of EGCG may be enhanced through personalized medicine strategies that incorporate these elements. Furthermore, EGCG's approval and incorporation into standard neurotherapeutic regimens are complicated by regulatory obstacles related to determining its pharmacological classification, manufacturing consistency, and safety monitoring. Future approaches should prioritize large-scale, well-planned clinical trials focusing on dose optimization, long-term safety, and synergistic potential with current neuroprotective drugs. Understanding EGCG's mechanism of action can be improved by developing biomarkers for therapeutic monitoring, investigating preventive measures in at-risk groups, and utilizing systems biology and multi-omics methods.

Author contributions

Md. Al Amin: conceptualization; data curation; formal analysis; investigation; methodology; resources; software; supervision; visualization; roles/writing—original draft; writing—review and editing. Mehrukh Zehravi: data curation; investigation; methodology; resources; software; roles/writing—original draft; writing—review and editing; Supervision. Sherouk Hussein Sweilam: data curation; investigation; methodology; resources; software; roles/writing—original draft; writing—review and editing. Thukani Sathanantham Shanmugarajan: data curation; investigation; methodology; resources; software; roles/writing—original draft; writing—review and editing. Uppuluri Varuna Naga Venkata Arjun: formal analysis; investigation; validation; visualization; roles/writing—review and editing. Mogan Babu Nagaiyan: formal analysis; investigation; validation; visualization; roles/writing—review and editing. S. Mounika Reddy: formal analysis; investigation; validation; visualization; roles/writing—review and editing. Vijayakumar Subash: formal analysis; investigation; validation; visualization; roles/writing—review and editing. Kalam Mary swarnalatha: formal analysis; investigation; validation; visualization; roles/writing—review and editing. Arjun Pazhanikumar: formal analysis; investigation; validation; visualization; roles/writing—review and editing. Joel Mart: formal analysis; investigation; validation; visualization; roles/writing—review and editing. P. Dharani Prasad: formal analysis; investigation; validation; visualization; roles/writing—review and editing. Mohammad Idreesh Khan: formal analysis; investigation; validation; visualization; roles/writing—review and editing. Irfan Ahmad: formal analysis; investigation; validation; visualization; roles/writing—review and editing. Talha Bin Emran: conceptualization; formal analysis; funding acquisition; investigation; methodology; project administration; supervision; validation; visualization; writing—review and editing. All authors have read and agreed to the published version of the manuscript. The authors confirm that no paper mill and artificial intelligence was used.

Funding

This research received no external funding.

Data availability

All data supporting the findings of this study are available in the paper.

Declarations

Conflict of interest

The authors declare no conflict of interest.

Institutional review board statement

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Human ethics and consent to participate

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Informed consent

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