Repurposing Imeglimin for Chemotherapy-Induced Cognitive Impairment: Targeting Mitochondrial Dysfunction and Neuroinflammation

Abstract

Chemotherapy-induced cognitive impairment, known as chemo brain, is a severe side effect of cancer treatment that may cause severe memory, attention, executive skills, and cognitive learning damage. There are several underpinning factors of CICI comprising several pathways, such as oxidative stress, impaired mitochondrial function, neural inflammation, insulin resistance, and decreased neurogenesis. Due to its remarkable neuroprotective properties, imeglimin-a new class of antidiabetic medication – looks potentially promising as a treatment method for chemo brain-associated cognitive disorders. Imeglimin affects mitochondrial bioenergetics, playing a role in enhanced mitochondrial O2 uptake, increased membrane potentials and diminished oxidative stress. This is exceptionally important in the chemo brain context, as the chemotherapeutic agents such as cisplatin and doxorubicin commonly cause mitochondrial damage and oxidative stress in neurons of the brain. Also, by functioning as an antioxidant, imeglimin enhances redox homeostasis, thereby protecting against neuronal apoptosis and regular synaptic activity. Neuroinflammation, another significant activity in CICI, is fueled by microglial activation and cytokine production. The anti-inflammatory activity of imeglimin is associated with its ability to suppress NF-κB signaling and reduce the levels of pro-inflammatory cytokine TNF-α and IL-6. Such outcomes suggest that imeglimin might ameliorate the neuroinflammatory responses associated with chemotherapy. In addition, imeglimin enhances insulin sensitivity and modulates brain glucose metabolism, which associates it with the modern concept of chemo brain as “type 3 diabetes”. Enhancing insulin signaling is one of the mechanisms by which imeglimin may increase synaptic plasticity and improve cognitive resilience. Moreover, Imeglimin exhibits multiple mitochondrial and anti-inflammatory actions that may hold potential for mitigating chemobrain-related pathology. However, its therapeutic application in this context remains hypothetical and warrants dedicated preclinical and clinical evaluation. This review discusses these possible mechanisms and emphasises the need for more preclinical and clinical trials to support its role in reducing the cognitive effects of chemotherapy. Unlike prior descriptive chemobrain reviews, this article applies a hypothesis-driven translational framework to critically assess Imeglimin’s mechanistic plausibility, pharmacological constraints, and unmet validation gaps in chemotherapy-induced cognitive impairment.

Graphical Abstract

Employing this graphical abstract, here it is shown that Imeglimin mitigatescognitive deficits caused by chemotherapy as it targets oxidative stress,neuroinflammation and mitochondrial dysfunction, positively affectingcognitive functions and neuroprotection

Introduction

Chemotherapy-induced cognitive impairment (CICI), commonly known as ‘chemo brain,’ is a well-recognised neurocognitive complication of cancer therapy (Kerkmann et al. 2025). A myriad of people, who are being treated with chemotherapy, report a variety of cognitive symptoms, which include troubles with multitasking, distraction, executive impairments and the loss of memory (Miyashita 2024). These symptoms may persist for long periods after the administration of chemotherapy, thus significantly decreasing the quality of life that is enjoyed by those who have been diagnosed with this ailment (Papadopoulou et al. 2022). Although advances in cancer therapy have improved survival rates, researchers in neuropharmacology and oncology have increasingly recognized the clinical significance of chemo brain (Davies et al. 2024). The complex processes of chemo brain involve mitochondrial damage, oxidative stress, neuroinflammation, and alterations of neurotransmitter signalling mechanisms (Was et al. 2022a). These drugs, which act to target proliferating cancer cells, have unfortunately targeted healthy cells in the central nervous system (CNS). Mitochondrial impairment seems to be a significant factor in the development of chemo brain with chemotherapy increasing neuroinflammatory responses that compromise neuronal health and cause cognitive decline (Sahu et al. 2021). Greater insights into these pathways can help to open the door for better targeted therapies.

Chemotherapy-induced cognitive impairment (CICI) represents a pressing, unmet clinical challenge in modern oncology survivorship. Estimates suggest that 30–70% of patients receiving chemotherapy experience cognitive deficits that can persist for months or even years following treatment significantly impairing daily functioning, employment capacity and psychosocial well-being (Semendric et al. 2025). Despite its high prevalence, no pharmacological therapy is currently approved to prevent or reverse CICI leaving patients reliant on supportive or behavioral interventions with limited efficacy (Kotb et al. 2019). Therefore, identifying neuroprotective agents capable of targeting the underlying mitochondrial and neuroinflammatory disturbances is a timely and clinically relevant endeavor. Within this context, repurposing Imeglimin, a drug with proven safety and mitochondrial-targeting activity offers a promising translational approach (Haywood et al. 2023).

One of the major obstacles to the management of chemo brain is the dearth of proven pharmacological therapy. Current procedures mainly focus on the cognitive rehabilitation strategies, symptomatic management, and lifestyle modification, which typically deliver only minimal benefits (Tomaszewski Farias et al. 2023; Parameswaran et al. 2021). Traditional neuroprotective agents such as anti-inflammatory drugs and antioxidants have shown some promise but fail to address the underlying mitochondrial dysfunction that plays a vital role in chemo-brain pathology (Madireddy and Madireddy 2023). This emphasizes the need for novel therapeutic approaches that precisely target mitochondrial health and energy metabolism in the brain (Liao et al. 2025). Imeglimin HCl, a novel mitochondrial-targeting drug developed initially for the treatment of type 2 diabetes has recently garnered interest for its neuroprotective capabilities (Li et al., 2024). A tetrahydro-triazine-based compound, this drug increases cellular bioenergetics, decreases oxidative stress and regulates glucose metabolism all key factors in maintaining cognitive function (Gupta et al. 2023). Considering the similarities between mitochondrial impairment observed in chemo brain and metabolic dysregulation in diabetes, it exhibits as an emerging therapeutic candidate for alleviating CICI (Fleming et al. 2023; Alhowail and Aldubayan 2021). Imeglimin’s notable mechanism of action includes increasing mitochondrial oxidative phosphorylation while decreasing overly reactive oxygen species (ROS) production, thus protecting neuronal integrity (Zhang et al. 2024a). Moreover, its regulatory effects on glucose metabolism may help neutralize the metabolic deficiencies in chemo brain, which are often linked with reduced cerebral glucose utilization (Lin et al. 2019). Following its metabolic benefits, imeglimin has also been reported to regulate neuroinflammation, additionally supporting its pivotal role in protecting against cognitive decline (Kato et al. 2024).The convergence of these neuroprotective mechanisms positions Imeglimin as a promising therapeutic candidate for addressing the underlying pathology of chemo brain, making it a subject of rising interest in translational neuroscience and oncology (De Luca 2022). Although imeglimin has demonstrated efficacy in preclinical models of diabetic neuropathy and ischemic stroke, it is important to acknowledge that its effects have not yet been studied in validated preclinical models of chemotherapy-induced cognitive impairment (CICI) (Kaku et al. 2025). The pathophysiological basis of CICI differs from these models, while ischemic injury induces acute mitochondrial collapse due to energy failure, calcium overload, and reperfusion injury, CICI arises more gradually from DNA damage, oxidative stress, defective mitophagy, and persistent neuroinflammatory signaling (Uto et al. 2024). Moreover, chemotherapeutic agents such as cisplatin, doxorubicin, and paclitaxel induce CICI through distinct mechanisms of DNA damage, topoisomerase II inhibition, and microtubule disruption, suggesting that mitochondrial targeting alone may not fully reverse all drug-specific neurotoxic pathways. Hence, the translational relevance of imeglimin’s neuroprotective effects from stroke and diabetic models to CICI should be interpreted cautiously (Galizzi and Di Carlo 2022). While preclinical studies have displayed imeglimin’s efficacy in increasing mitochondrial function and decreasing neuroinflammation, its application in chemo brain remains an unexplored area (Konkwo and Perry 2021). Examining its effects in clinical settings requires a multidisciplinary approach that incorporates pharmacology, neurology, and oncology (Barbaro et al. 2021). The ability of imeglimin to be repurposed for chemo brain treatment also coincides with the broader trend of identifying existing drugs with novel implementations, therefore accelerating the translational pipeline for treatments (Abdullaeva et al. 2025). Although Imeglimin shows great promise, several barriers must be overcome before it can be considered a viable treatment for chemo brain, including determining optimal neuroprotective doses, evaluating long-term safety, and investigating its responses in diverse patient populations (Mitusova et al. 2022). Moreover, it is essential to watch very closely the interactions of imeglimin with the existing chemotherapy schemes to avoid possible side effects and preserve treatment efficacy and patient safety. This article explores the therapeutic potential of imeglimin for controlling the chemo brain by assessing its mitochondrial targeting properties, translational merit, and neuroprotective actions (Hallakou-Bozec et al. 2021). Other investigations should attempt to specify the specific effect of imeglimin in chemo brain through a thorough pre-clinical and clinical investigation, opening the way to its use in the neurorehabilitation programs and oncology treatment (Doupis et al. 2021).

Unlike existing reviews that broadly discuss oxidative stress or mitochondrial dysfunction in chemotherapy-induced cognitive impairment (CICI), the present article provides a targeted, mechanistic exploration of how Imeglimin’s unique pharmacodynamic profile, integrating mitochondrial bioenergetic restoration, redox regulation, and metabolic modulation, could be strategically repurposed to address the neuropathological hallmarks of CICI (Wang et al. 2025). Imeglimin, a first-in-class tetrahydrotriazine derivative approved initially for type 2 diabetes, possesses distinctive mitochondrial-modulating, antioxidant, and anti-inflammatory properties that may hold relevance for neuroprotection. However, its potential application in CICI remains unexplored, mainly, making this review among the first to evaluate its mechanistic plausibility for this indication critically (Bagnall-Moreau et al. 2019). By synthesizing evidence from diabetic, ischemic, and neurodegenerative models, this paper distinguishes itself from generic chemobrain reviews through a hypothesis-driven translational framework. It aims to bridge metabolic and neurological insights to propose Imeglimin as a novel repurposed candidate for mitigating chemotherapy-related neurotoxicity and promoting cognitive resilience in cancer survivors (Yatsuga et al. 2015).

The majority of current literature about Chemotherapy-Induced Cognitive Impairment (CICI) tends to cover a wide net, with little specificity; discussing numerous classes of chemotherapy, varying clinical symptoms, and outlining general pathogenetic mechanisms, e.g., oxidative damage, neuroinflammation, and disturbances in neurotransmitter levels. Although foundational description overviews are useful, trying to bridge concepts to the translational value of only a single therapeutic candidate is a rarity (Chen and Johnston 2025; Mounier et al. 2020b). This is especially true for those reviews discussing drug repurposing in CICI, characterized by the shallow notion of cognitive enhancers or peripheral antioxidants, without a critical envelope of the more complex issues of mitochondrial bioenergetics, blood-brain barrier (BBB) issues, basic pharmacokinetics, and drug-drug interactions with the present review is filling these gaps with a hypothesis-driven translational framework focusing on Imeglimin as a single mechanistically unique candidate. Instead of merely listing pathways out of context, this review pulls together disparate evidence from models of metabolism, ischemia, and neurodegeneration to ascertain whether Imeglimin’s actions on mitochondria, redox control, and metabolism map onto the pathophysiology of CICI. Further, the review is not purely descriptive but tells a focused story while own barriers to translational research including poor blood-brain barrier permeation, a lack of CICI-specific efficacy data, and possible complexing with chemotherapeutic agents.

Scope and Structure of the Review

This review is organized to provide a comprehensive and logically structured understanding of Imeglimin’s potential role in CICI. Section "Imeglimin: A Novel Mitochondria-Targeting Drug" introduces Imeglimin’s pharmacological profile and mitochondrial targeting properties. Sections "Integrated Pathophysiological Mechanisms of CICI" and "Neuroprotective Mechanisms of Imeglimin" describe the pathophysiological mechanisms underlying CICI, emphasizing mitochondrial dysfunction, oxidative stress, and neuroinflammation, followed by the mechanistic actions of Imeglimin in modulating these pathways. Section "Imeglimin and Neurotransmitter Regulation in Chemo brain" explores its influence on neurotransmitter regulation and cognitive resilience, whereas Sect. "Potential Therapeutic Application of Imeglimin in Chemo brain" and the concluding sections discuss translational implications, pharmacological considerations and future research directions. This structured approach enables an integrated perspective linking pathophysiology to potential therapeutic repurposing.

Literature Search Methodology

This narrative review was prepared by performing a comprehensive search of relevant literature published between 2010 and 2025. Databases including PubMed, Scopus, Web of Science and Google Scholar were systematically searched using combinations of the following keywords: chemotherapy-induced cognitive impairment, chemo brain, Imeglimin, mitochondrial dysfunction, oxidative stress, neuroinflammation, and drug repurposing.

Only peer-reviewed English-language publications such as original research articles, reviews and translational studies were included. References were selected based on their relevance to the mechanisms of chemotherapy-induced neurotoxicity, mitochondrial dysfunction, and Imeglimin’s pharmacological properties. Studies focusing purely on metabolic outcomes unrelated to neuroprotection were excluded.

Additional sources were identified from the reference lists of key papers to ensure literature completeness. No formal quality assessment or meta-analysis was conducted since this work is a narrative, hypothesis-generating review aiming to explore potential mechanistic intersections between Imeglimin and chemotherapy-induced cognitive impairment.

Imeglimin: A Novel Mitochondria-Targeting Drug

Imeglimin represents an innovative class of oral antidiabetic agents that distinctively targets mitochondrial insufficiency, a vital contributor to neurodegenerative and metabolic disorders (Chen et al. 2022; Li et al. 2024; Konkwo and Perry 2021). In contrast to traditional hypoglycemic agents, this drug increases cellular energy production, boosts insulin sensitivity, and decreases Cellular oxidative burden, making it a promising candidate for conditions other than diabetes, involving CICI also known as chemo brain (Chen et al. 2022). Its mechanism of action is focused on regulating mitochondrial efficiency, where it increases oxidative phosphorylation proficiency, stabilizes the electron transport chain, and alleviates Reactive oxygen species production (Napolitano et al. 2021). By enhancing mitochondrial ATP production and decreasing cellular stress, Imeglimin HCl assists synaptic integrity and neuronal survival, crucial factors in cognitive preservation (Toczyska 2022). In relation to pharmacokinetics, Imeglimin (marketed as Twymeeg) demonstrates outstanding oral bioavailability and a beneficial safety profile with prompt absorption and a peak plasma concentration attained within hours (Sessions 2022). It passes through minimal hepatic metabolism, mainly excreted unchanged via the kidneys, decreasing the risk of drug-drug interactions (Benet et al. 2019). However, imeglimin’s physicochemical characteristics raise a significant pharmacological limitation. With a log P of approximately − 0.9, imeglimin is hydrophilic and therefore likely exhibits poor passive diffusion across the blood-brain barrier (BBB) (Asha Spandana et al. 2020). This raises concerns about its ability to achieve therapeutic concentrations within the central nervous system under normal physiological conditions (Teleanu et al. 2019). Although conditions such as diabetes and chemotherapy can transiently increase BBB permeability, imeglimin’s CNS availability may only occur in these pathological contexts, potentially limiting its use as a prophylactic agent for CICI. Therefore, future studies should evaluate its BBB transport mechanisms and explore nanoparticle or carrier-mediated delivery systems to improve CNS penetration (Luo et al. 2025).

Pharmacodynamically, it gives dual action by enhancing insulin secretion in response to glucose levels while at the same time increasing peripheral glucose uptake, mechanisms that also contribute to neuroprotection (Pramanik et al. 2024). These characteristics position imeglimin as a viable therapeutic option for alleviating mitochondrial dysfunction and neurocognitive decline in chemo brain, meriting further examination in neuro-oncology research.

Another clinically important aspect relates to imeglimin’s potential for pharmacokinetic interactions. Imeglimin is reported to inhibit organic cation transporters 1 and 2 (OCT1/2) and multidrug and toxin extrusion transporter 1 (MATE1), which are key in the renal and hepatic clearance of chemotherapeutic agents such as cisplatin and doxorubicin (Clémence et al. 2020). Inhibition of these transporters may alter drug disposition, potentially increasing systemic exposure or toxicity (Chen et al. 2024). Therefore, any proposed co-administration of imeglimin with chemotherapy regimens should be preceded by rigorous pharmacokinetic and safety assessments to avoid detrimental drug–drug interactions (Chevalier et al. 2023).

Integrated Pathophysiological Mechanisms of CICI

Altered mitochondrial function plays a critical role in the pathogenesis of CICI (chemo brain), as neurons intensely rely on mitochondrial ATP production for synaptic transmission, plasticity, and overall neurocognitive function (Taber 2020). Chemotherapeutic agents such as methotrexate, doxorubicin and cisplatin interrupt mitochondrial homeostasis by disrupting electron transport chain (ETC) activity, resulting in decline in ATP synthesis and rise in Reactive oxygen species (ROS) accumulation (Taber 2020; Murphy et al. 2019). These interruptions impair mitochondrial membrane integrity, triggering the release of cytochrome c and initiating apoptotic pathways, which take part in/contributes to neuronal loss in vital cognitive regions like prefrontal cortex and hippocampus (Verma et al. 2023; Akbar et al. 2016). Moreover, chemotherapy enhances mitochondrial DNA (mtDNA) damage, disrupting mitochondrial formation and decreasing the expression of vital metabolic modulators, involving TFAM, NRF1 and NRF2 (Mohamed Yusoff et al. 2025). The subsequent metabolic stress interrupts calcium homeostasis, resulting in disrupted synaptic activity and excitotoxicity, further aggravating cognitive disturbances (Verma et al. 2022). Considering the critical role of mitochondria in neuronal energy metabolism and redox balance, focusing mitochondrial dysregulation represents a potential therapeutic avenue for alleviating chemo brain (Clemente-Suárez et al. 2023b).

Mitochondrial Dysfunction and Oxidative Stress

Oxidative stress, powered by increased ROS production, is a primary factor in mitochondrial dysfunction in the chemo brain (Rummel et al. 2021). Chemotherapeutic drugs interrupt mitochondrial redox homeostasis by disrupting complexes I and III of the ETC, resulting in ROS overproduction and electron leakage (Rummel et al. 2021). The increased oxidative burden damages mtDNA, proteins, an.d lipids, resulting in mitochondrial swelling, permeability transition pore (mPTP) opening, and subsequent mitochondrial fragmentation (Morciano et al. 2021). Moreover, the oxidative damage activates glial cells, stimulating neuroinflammation through the release of pro-inflammatory cytokines like TNF-α, IL-1β, and IL-6, which further disrupts mitochondrial efficiency (Lin et al. 2022). Antioxidant defense mechanism, involving catalase, superoxide dismutase (SOD), and glutathione peroxidase (GPx), becomes impaired, leading to persistent oxidative injury and neuronal apoptosis (Rana and Gautam 2022; Ryan et al. 2025). Furthermore, chemotherapy-induced redox imbalance disrupts mitochondrial fission-fusion dynamics by interrupting the balance between Drp1-mediated fission and Mfn2/Opa1-mediated fusion, resulting in faulty mitochondrial networks and disrupted energy metabolism (Wu et al. 2024). This sequence of mitochondrial destruction takes part in neurocognitive impairment seen in chemo brain, showcasing the need for targeted redox agents and mitochondrial-stabilizing interventions.

Neuroinflammation and Synaptic Impairment

Effective mitochondrial bioenergetics is essential for maintaining neuronal activity, cognitive resilience and synaptic plasticity (Trigo et al. 2022). Nonetheless, chemotherapy prompt a metabolic shift, decreasing oxidative phosphorylation proficiency and enhancing reliance on glycolysis, resulting in energy deficiencies in the brain (Zhao and Li 2021; Liu et al. 2025b). Weakened ATP production restricts synaptic vesicle cycling, dendritic spine formation, and neurotransmitter release, eventually interrupting memory and learning processes (Li and Sheng 2022). Moreover, chemotherapy-induced variation in AMPK and mTOR signalling interrupts mitochondrial biogenesis and autophagic turnover, additionally degrading cellular energy homeostasis (Langer et al. 2024). Imbalance of mitochondrial calcium buffering aggravates excitotoxicity by dysregulating calcium-sensitive enzymes included in synaptic plasticity, such as CaMKII and CREB, critical for long-term potentiation (LTP) (Hasan et al. 2024). Furthermore, mitochondrial impairment increases astrocytic and microglial reactivity, resulting in chronic cognitive inflammation, which enhances neuronal energy deficiencies and quickens neuronal decline(Verma et al. 2023; Sharma and Aran 2025). Addressing these mitochondrial bioenergetic disruptions presents a promising strategy to mitigate neurotoxicity associated with chemotherapy. (Rao et al. 2022; Alhowail and Aldubayan 2021).

Collectively, mitochondrial dysfunction, oxidative stress and neuroinflammation constitute an interconnected triad in CICI pathology (Picca et al. 2020). Chemotherapy-induced mitochondrial injury enhances ROS production which activates glial cells and inflammatory cytokines further impairing neuronal energy metabolism and synaptic integrity (Picca et al. 2020). Therefore, therapeutic agents that simultaneously stabilize mitochondrial bioenergetics, suppress redox imbalance, and attenuate inflammation could offer the most comprehensive neuroprotective benefit (Gao et al. 2024).

Neuroprotective Mechanisms of Imeglimin

It is important to emphasize that the neuroprotective mechanisms attributed to Imeglimin in this review are primarily derived from metabolic, ischemic, and neurodegenerative disease models (Hou et al. 2025). While these pathways overlap conceptually with the known pathophysiology of chemotherapy-induced cognitive impairment, their applicability to CICI remains inferential. Accordingly, all mechanistic links discussed below should be interpreted as hypothesis-generating rather than definitive evidence of efficacy in the context of chemotherapy-induced neurotoxicity (Zemgulyte et al. 2022).

Imeglimin exhibits potent neuroprotective effects by targeting mitochondrial malfunction, neuroinflammation, free radical damage, and metabolic disturbance, each of which contributes to CICI (chemo brain). Its distinct mechanism includes increasing Mitochondrial cellular energy while simultaneously regulating redox balance and neuroimmunology responses, maintaining neuronal integrity in susceptible brain regions, as shown in Fig. 1 (Trigo et al. 2022; Lee et al. 2021).

Fig. 1.

Mechanism of Chemotherapy-Induced ROS Production and Neuroinflammation

Mechanistic Basis of Imeglimin’s Neuroprotection in CICI

Imeglimin alleviates redox imbalance by directly decreasing overwhelming Reactive oxygen species (ROS) generation at the mitochondrial level and increasing endogenous antioxidant preservation (Li et al. 2024a; Swain et al. 2024). It balances the electron transport chain (ETC), attenuating electron leakage from complexes I and III, which are the main sources of superoxide radicals (Fujii et al. 2022). By stimulating nuclear factor erythroid 2-related factor 2 (Nrf2), this drug boosts the transcription of key antioxidant enzymes, including superoxide dismutase (SOD), glutathione peroxidase (GPx), and heme oxygenase-1 (HO-1), restoring redox homeostasis (Tripathi et al. 2024). Moreover, imeglimin may attenuate the initiation of nuclear factor kappa B (NF-κB), a vital modulator of neuroinflammation, thereby decreasing the production of pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6 (Li et al. 2024; Caldarelli et al. 2024). This repression of neuroinflammatory signaling prevents astrocytic activity and microglial overactivation, protecting synaptic function and neuronal sustainability (Zhang et al. 2024b; Kwon and Koh 2020). By focusing on both inflammatory and oxidative pathways, this compound forms a neuroprotective environment that neutralizes chemotherapy-induced neuronal damage (Gupta et al. 2022; Cauli 2021). Particularly, these mechanisms have not yet been directly validated in chemotherapy-induced cognitive impairment models and therefore remain speculative pending CICI-specific experimental confirmation.

Modulation of Mitochondrial Function

Imeglimin enhances mitochondrial performance by increasing oxidative phosphorylation productivity and inhibiting mitochondrial fragmentation, critical for sustaining neuronal energy requirement (Li et al., 2024; Galizzi and Di Carlo 2022). It increases ATP generation by regenerating mitochondrial membrane capability and stabilizing Calcium homeostasis within mitochondria, inhibiting excitatory neurotoxicity-induced bioenergetic collapse (Cham et al. 2024). Additionally, this compound modulates mitochondrial quality control by regulating organelle unification dynamics through balancing of dynamin-related protein 1 (Drp1) and mitofusin 2 (Mfn2), inhibiting excessive mitochondrial fission seen in chemotherapy-induced neurotoxicity (Sharma et al. 2021). It also enhances mitochondrial formation via generation of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α), which elevates transcription factors like NRF1 and TFAM, important for mitochondrial functional integrity and energy homeostasis (Kumar and Tanwar 2024). Imeglimin inhibits synaptic energy insufficiency and aids neuronal survival in the chemo brain (Qian et al. 2024). The mechanistic evidence for imeglimin’s modulation of mitochondrial pathways such as Nrf2, PGC-1α/TFAM, and Drp1/Mfn2 remains largely derived from diabetic or ischemic models (Satheesan et al. 2025a). Direct experimental validation of these effects in the context of chemotherapy-induced mitochondrial injury is still lacking (Li et al. 2024b). For instance, imeglimin’s role in PGC-1α activation and mitochondrial biogenesis has not yet been confirmed in neural tissues exposed to chemotherapeutic stress. Thus, while these pathways provide a plausible mechanistic rationale, further molecular and preclinical studies are essential to substantiate these claims specifically in CICI models (Hushmandi et al. 2024). Especially, these mechanisms have not yet been directly validated in chemotherapy-induced cognitive impairment models and therefore remain speculative pending CICI-specific experimental confirmation.

Regulation of Glucose Metabolism in the Brain

Imeglimin repairs carbohydrate metabolism in the brain by increasing insulin sensitivity and regulating glucose uptake in neurons, vital for synaptic transmission and neural processing (Qian et al. 2024). It stimulates AMP-activated protein kinase (AMPK), a crucial metabolic sensor, which increases glucose transport through upregulation of GLUT3 and GLUT4 transporters in neurons and astrocytes (Muraleedharan and Dasgupta 2022). This assures a constant supply of glucose for ATP generation, decreasing dependence on glycolysis and inhibiting metabolic stress-induced neuronal dysfunction (Zhang et al. 2021). Moreover, Imeglimin modulates insulin signaling by increasing Akt phosphorylation and preventing glycogen synthase kinase-3β (GSK-3β), inhibiting tau hyperphosphorylation and synaptic degradation, both of which are associated with CICI. By balancing neuronal glucose homeostasis and inhibiting insulin resistance, imeglimin sustains cognitive function and neural plasticity, making it a promising therapeutic strategy for chemo brain (de la Monte 2024). Particularly, these mechanisms have not yet been directly validated in chemotherapy-induced cognitive impairment models and therefore remain speculative pending CICI-specific experimental confirmation.

Critical Perspective on Mechanistic Overlap

While the neuroprotective mechanisms summarized above, antioxidant activity, mitochondrial regulation, and anti-inflammatory modulation are well supported in metabolic and ischemic disease models, it is important to recognize that their direct applicability to CICI remains largely theoretical (Bilski et al. 2025). The present synthesis draws mechanistic parallels between Imeglimin’s established mitochondrial effects in diabetes and the known mitochondrial disturbances observed in CICI. However, the pathogenesis of CICI involves a unique combination of chemotherapy-induced DNA damage, disrupted mitophagy, and chronic neuroinflammation, which differ from the acute oxidative and metabolic stress seen in diabetic models (Teleanu et al. 2022). Therefore, these proposed overlaps should be interpreted as hypothesis-generating connections rather than definitive mechanistic evidence. Future studies employing CICI-specific models are needed to validate whether Imeglimin’s metabolic and mitochondrial effects can translate into meaningful neuroprotection in this context (Yu et al. 2025).

This diagram illustrates how chemotherapy induces excessive reactive oxygen species (ROS) via mitochondrial damage, NADPH oxidase activation, and lipid/DNA injury, culminating in microglial activation, neuroinflammation, and cognitive dysfunction associated with chemo brain.

Type 3 Diabetes as a Heuristic Framework: Relevance and Limitations for CICI

The expression ‘type 3 diabetes’ was introduced in the field of literature discussing Alzheimer’s disease (AD) to refer to a state of the brain where there is resistance to insulin and the inability to utilize insulin/IGF and to utilize glucose in a disrupted manner (Kciuk et al. 2024b). Significantly, this is an off-the-cuff, non-diagnostic notion and its boundaries and cause-effect relationships are the subject of controversy, with a number of authors construing it as a mechanistic perspective for AD-like neurodegeneration rather than as an independent clinical entity (Michailidis et al. 2022).

In the current review, we have used the ‘type 3 diabetes’ analogy carefully and heuristically to address overlapping biology relevant to CICI, and not to equate CICI with AD. A number of findings indicate that metabolic vulnerability may overlap with the CICI pathophysiology: systemic chemotherapy has been linked to decreases in in vivo brain glucose metabolism, while the insulin/IGF-axis has been suggested to be a mechanistic contributor to the cognition changes that accompany chemotherapy (Atabi et al. 2025).Due to CICI’s complex features (such as neuroinflammation, oxidative stress, vascular effects, other BBB effects, and glial changes), CICI is still not characterized as a brain insulin-resistant disorder, as is the case with AD, and so any CICI conceptualized as “type 3 diabetes” is still an hypothesis-generating argument that deserves testing, although these measurements are to be estimations that CICI models provide (Kciuk et al. 2024a).

Imeglimin and Neurotransmitter Regulation in Chemo Brain

Preclinical findings suggest that this drug may play a vital role in conserving neurotransmitter balance in the brain, which is severely impaired in CICI (chemo brain), (Rao et al. 2022; Sabry et al. 2023). Chemotherapy-induced mitochondrial abnormality and redox imbalance result in synaptic deterioration, neural deficits, and neurotransmitter imbalance (Murillo et al. 2023; Babu and Urulangodi 2023). By focusing on mitochondrial bioenergetics, metabolic dysfunction, and excess ROS activity, imeglimin increases neurotransmitter homeostasis, preserving vital pathways included in executive function, memory, and learning (Swain et al. 2024; Galizzi and Di Carlo 2022).

Impact on Dopaminergic and Cholinergic Systems

Imeglimin regulates dopaminergic and cholinergic signaling, two neurotransmitter systems heavily impacted by chemotherapy-induced neurotoxicity. In the dopaminergic system, defective mitochondrial processes hinder dopamine production by preventing tyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine biosynthesis (Segura-Aguilar and Paris 2022). Imeglimin repairs mitochondrial ATP generation and decreases redox imbalance, therefore retaining TH activity and balancing dopamine levels in the striatum and prefrontal cortex, regions critical for Cognitive adaptability and motivation (Swain et al. 2024; Lisco et al. 2023). Moreover, this compound protects dopamine transporter (DAT) dysfunction, assuring optimized dopamine reuptake and decreasing synaptic dopamine depletion (Ang et al. 2024). In the cholinergic system chemotherapy-induced disturbed redox homeostasis and Immune response impair acetylcholine generation by attenuating choline acetyltransferase (ChAT) and promoting acetylcholinesterase (AChE) overactivity, leading to cholinergic deficits (Emmett et al. 2019). Twymeeg balances this by regulating mitochondrial bioenergetics and decreasing inflammatory mediators that suppress ChAT activity (Wan and Garg 2021). This increases acetylcholine accessibility, supporting hippocampal-dependent memory functions (Huang et al. 2022). By protecting both dopaminergic and cholinergic transmission, Imeglimin counteracts neurotransmitter dysregulation and alleviates cognitive decline in the chemo brain (Li et al. 2024; de la Monte 2024).

Potential Role in Synaptic Plasticity and Memory Enhancement

Imeglimin increases synaptic reorganization and memory by steadying mitochondrial dynamics, aiding neurotransmitter homeostasis, and stimulating neurotrophic signaling (Li et al. 2024; de la Monte 2024). Chemotherapy interrupts long term potentiation (LTP), a vital mechanism of memory and learning, by damaging N-methyl-D-aspartate (NMDA) receptor function and reducing brain-derived neurotrophic factor (BDNF) levels (Was et al. 2022b). Imeglimin repairs LTP by enhancing ATP generation, which is crucial for synaptic vesicle recycling and neurochemical release. It also upregulates BDNF through triggering of AMP-activated protein kinase (AMPK) and cyclic AMP response element-binding protein (CREB), each of which are vital for neurogenesis and synaptic strengthening (Fan et al. 2025). Furthermore, imeglimin increases synaptic integrity and spine density by decreasing redox imbalance and inflammatory damage to the postsynaptic membrane. Via these mechanisms, imeglimin enhances mental function, synaptic resilience and memory formation, making it a promising therapeutic approach for alleviating chemo brain-induced cognitive deficits (Hallakou-Bozec et al. 2021).

Potential Therapeutic Application of Imeglimin in Chemo Brain

Imeglimin’s potential to increase cellular respiration, decrease oxidative stress, and regulate neurotransmitter stability positions it as an emerging therapeutic avenue for CICI (chemo brain) (Yanai et al. 2023; Bagnall-Moreau et al. 2019). Considering its dual action in neuronal protection and metabolic homeostasis, this drug reduces cognitive deficits by protecting neuronal energy homeostasis and synaptic plasticity (Clemente-Suárez et al. 2023a). Preclinical studies propose its ability to neutralize chemotherapy-induced mitochondrial impairment, neurotransmitter imbalance and inflammatory response, therefore enhancing cognitive performance (Was et al. 2022a). Nonetheless, translating these observations into clinical characteristics requires thorough examination through translational research, biological marker identification, and well-designed clinical trials to assess its efficacy and prolonged safety in cancer survivors (Perez-Gracia et al. 2017).

Compared with other mitochondrial modulators, Imeglimin demonstrates a distinct dual mechanism that integrates redox regulation with glucose metabolism. Metformin, another biguanide with mitochondrial activity provides neuroprotection mainly through AMPK activation but exhibits limited CNS penetration and carries a risk of lactic acidosis under oxidative stress (Satheesan et al. 2025b). Similarly, the mitochondria-targeted peptide SS-31 (elamipretide) directly stabilizes cardiolipin and mitigates reactive oxygen species (ROS) generation but lacks systemic metabolic benefits. In contrast, Imeglimin simultaneously enhances mitochondrial efficiency, redox homeostasis and metabolic balance offering a potentially broader neuroprotective profile (Kaji et al. 2024b).

However, despite these promising mechanistic attributes it must be emphasized that no direct preclinical or clinical studies have yet examined Imeglimin’s efficacy in chemotherapy-induced cognitive impairment (CICI). The connections proposed in this review are inferred from mechanistic parallels observed in diabetic neuropathy, ischemic injury and neurodegenerative disorders where mitochondrial dysfunction and oxidative stress play central roles (Shireen et al. 2025). While these similarities provide a solid conceptual foundation, extrapolation without experimental validation remains speculative. Therefore, the current discussion should be viewed as hypothesis-generating rather than confirmatory, underscoring the need for systematic in vivo validation, dose optimization, and safety assessments when considering Imeglimin for translational application in oncology-related neuroprotection (Ataei and Abdollahi 2022). A comparative summary of Imeglimin and other mitochondrial modulators is presented in Table 1.

Table 1.

Comparison of Imeglimin with other neuroprotective/mitochondrial modulators

Parameter	Imeglimin	Metformin	SS-31 (elamipretide)	Pioglitazone	Reference
Primary mechanism	Dual modulation of mitochondrial bioenergetics and glucose metabolism; reduces ROS and enhances oxidative phosphorylation	Activates AMPK pathway; improves insulin sensitivity and mitochondrial function	Targets cardiolipin in the inner mitochondrial membrane; reduces mitochondrial ROS generation	PPAR-γ agonist; enhances mitochondrial biogenesis and anti-inflammatory responses	(Ohguro et al. 2025)
Mitochondrial targeting	Directly improves ETC efficiency and membrane potential	Indirect via AMPK activation	Direct binding to mitochondrial membrane	Indirect via transcriptional control of PGC-1α	(Hozumi et al. 2023)
Antioxidant/anti-inflammatory effect	Inhibits NF-κB and activates Nrf2; reduces TNF-α, IL-1β, IL-6	Mild ROS suppression via AMPK	Potent ROS scavenger, limits lipid peroxidation	Reduces microglial activation and cytokine production	(Kaji et al. 2024a)
Metabolic regulation	Enhances insulin signaling and glucose uptake in neurons	Improves systemic glucose metabolism	No direct metabolic regulation	Improves lipid/glucose metabolism	(Chen et al. 2025)
Blood–brain barrier (BBB) penetration	Limited (hydrophilic; log P ≈ − 0.9); may need carrier systems	Moderate; crosses BBB under stress conditions	Efficient BBB penetration	Moderate	(Katila et al. 2022)
Preclinical/clinical evidence in neuroprotection	Preclinical data in diabetes and stroke; none in CICI yet	Evidence in diabetes-related cognitive decline	Preclinical models of ischemic brain injury	Evidence in Alzheimer’s and Parkinson’s models	(Li et al. 2024)
Safety profile	Favourable in diabetes; limited oncology data	Risk of lactic acidosis under oxidative stress	Generally safe in trials, mild local irritation	Weight gain, edema, and potential hepatotoxicity	(Agrawal et al. 2025)
Translational status for CICI	Hypothesis-generating; needs validation in chemo brain models	Partially explored	Preclinical stage	Not yet studied in CICI context	(Kuvirchenkova et al. 2025)

Comparative Translational Considerations Among Mitochondrial Modulators

The case of SS-31 (elamipretide) provides examples of efficient plasma-to-brain barrier transport and of direct stabilization of mitochondrial membranes (Zhao et al. 2019). However, they are translationally limited to controlling the redox state of mitochondria within the central nervous system. In comparison, imeglimin does not have a lesser CNS focus, since such a focus would not explain all the mechanisms and effects of imeglimin, particularly its unique systemic and metabolic effects (Tung et al. 2025). Imeglimin’s integrated effects on the cellular energetics of mitochondria, insulin action, and glucose utilization are increasingly relevant to the emerging conceptualization of the re- fuelling of chronically iatrogenically neurotoxic chemotherapeutics as having a greater role than previously thought (Sabbah et al. 2025). Such a disorder involves energetic and metabolic dysregulation, as well as localized neurotoxic inflammation, escalating the conceptualization of chemotherapeutic iatrogenesis. Furthermore, imeglimin is easier to reposition compared to investigational peptides like SS-31 due to its already established oral bioavailability, clinical safety history in metabolic diseases, and tolerability. SS-31, however, does have the clear advantage of crossing the BBB (Song et al. 2025). The current review, however, does not position imeglimin as a replacement to such agents. Instead, imeglimin is most likely to act as a complementary candidate that can control metabolic stressors which, as noted in the review, may indirectly aggravate CICI. Whether imeglimin can clinically contribute to the neuroprotection of CICI is a matter of resolving the CNS exposure limitations that have already been noted (Gyoutoku et al. 2025).

The choice of imeglimin is, therefore, the central hypothesis of exploring a clinically established mitochondrial modulator that behaves as a systemically-acting agent and is, with justification, not positioned as a critique against neurotherapeutics with BBB penetration.

Despite its promising pharmacological profile, several translational barriers remain unaddressed. Table 2 summarizes the key knowledge gaps and the recommended directions for future investigation.

Table 2.

Knowledge gaps and future directions for Imeglimin in chemotherapy-induced cognitive impairment (CICI)

Area of concern	Current knowledge/limitation	Recommended future direction	References
Blood–brain barrier (BBB) penetration	Imeglimin is hydrophilic (log P ≈ = −0.9) and exhibits limited passive diffusion across the BBB. Its CNS availability under normal physiological conditions is uncertain.	Investigate carrier-mediated transport mechanisms (e.g., OCT, LAT systems) and design nanoparticle or lipophilic prodrug formulations to enhance CNS delivery.	(Chughtai et al. 2025)
Pharmacokinetic–pharmacodynamic (PK–PD) data	No data on plasma–brain concentration ratios, half-life in CNS, or optimal neuroprotective dosing.	Conduct PK–PD studies in rodent and non-rodent CICI models to determine brain exposure, dose–response, and safety thresholds.	(Mounier et al. 2020a)
Drug–drug interactions with chemotherapeutics	Imeglimin inhibits OCT1/2 and MATE1 transporters, potentially altering cisplatin and doxorubicin clearance.	Perform in vitro transporter assays and in vivo combination studies to evaluate safety and pharmacokinetic interactions.	(Ongnok et al. 2020)
Preclinical validation in CICI models	Evidence limited to diabetic and ischemic models; no published data in validated CICI paradigms.	Establish cisplatin, doxorubicin, and paclitaxel-based rodent CICI models to test neuroprotective efficacy, mitochondrial markers, and behavioral outcomes.	(Huang et al. 2020)
Mechanistic confirmation	Proposed pathways (Nrf2, PGC-1α/TFAM, NF-κB inhibition) are extrapolated from non-CICI contexts.	Use targeted molecular and transcriptomic analyses to confirm these pathways in chemotherapy-treated neural tissues.	(Yang et al. 2023)
Safety and tolerability in cancer patients	Safety data restricted to diabetic populations; potential metabolic or hepatic concerns in oncology remain unknown.	Conduct phase I safety assessments in cancer survivors or chemo-treated animals with comorbid conditions (cachexia, hepatic/renal stress).	(Saha et al. 2022)
Comparative effectiveness	No comparative studies versus other mitochondrial modulators or cognitive-enhancing agents.	Design head-to-head preclinical studies comparing Imeglimin, Metformin, SS-31, and Pioglitazone under identical chemobrain protocols.	(Chow et al. 2025)
Clinical translation strategy	Lack of regulatory pathway or biomarker-guided endpoints for CICI.	Develop translational frameworks using biomarkers (BDNF, mitochondrial DNA damage, cytokine panels) for early-phase clinical evaluation.	(Chew et al. 2024)

Translational Research and Future Directions

Translational research on Twymeeg in chemo brain should concentrate on interpreting its accurate molecular mechanism in improving its therapeutic ability and neuroprotection (Nguyen and Ehrlich 2020). Future studies should analyze its effect on mitochondrial dynamics, calcium homeostasis and neurotrophic factor signaling in chemotherapy-induced neurotoxicity (Chine et al. 2019). In preclinical studies examining CICI using paradigms where loss of hippocampal-dependent cognition occurs, PTSD and stress-related disorders, the chemotherapeutic agent was altered to clinically relevant chemotherapeutic agents, i.e., the preclinical model will use chemotherapeutic agents like cisplatin, doxorubicin, methotrexate, and or/paclitaxel, using a clinically relevant dosing and scheduling regimen capturing cumulative neurotoxicity rather than acute sickness behavior, a clinically relevant CICI model assessing cognitive impairment (John et al. 2021). Tasks implemented to assess the loss of hippocampal-dependent and prefrontal dependent (executive) cognition (and behavior) include the novel object recognition paradigm, the Morris water maze, the Y-maze and the attentional set-shifting paradigm, and others (Sekeres et al. 2021). Tasks implemented to assess loss of prefrontal-dependent (executive) cognitive impairment are complemented by endpoints such as measures of the neurobiological substrate, i.e., the neurobiological and molecular sequelae of neuroinflammation, and dysfunction and synaptic alterations, as well as neurobiological/behavioral outcomes (Ren et al. 2019). Collectively, these represent and comprise a validated experimental construct. This will be used to examine the mechanisms and the clinical tools/therapeutic CICI mechanisms.

Using advancing in vitro and in vivo models, in the form of patient-derived cerebral organoids and chemotherapy-treated rodents may give more insight into the neuroprotective effects of Imeglimin. Research is also needed to establish whether Imeglimin can be used in combination with available neuroprotective agents or cognitive-motivational drugs like neurotrophic regulators and anti-inflammatory substances to maximise success in treatment (Liu et al. 2025a). By employing innovative drug delivery strategies, such as ones that are dependent on nanoparticles, the penetration of Imeglimin into the blood-brain barrier may be enhanced, and in turn, the clinical usefulness of Imeglimin overall, can be increased (Zemgulyte et al. 2022).

From a translational and clinical safety standpoint, evaluation of transporter-mediated drug–drug interactions should be regarded as a mandatory early step. Without clear evidence that imeglimin does not adversely affect the pharmacokinetics or toxicity profile of concurrent chemotherapeutic agents, its use in oncology-related neuroprotection would be premature.

To determine Central Nervous System (CNS) pharmacokinetics and exposure-response relationships should be considered a prerequisite step prior to conducting mechanistic validation and/or efficacy testing in CICI models(Barbosa et al. 2025). A determination of whether imeglimin is capable of changing the redox balance, altering the mitochondrial function, and/or affecting the neural inflammatory cascade depends on whether the studies measuring brain concentrations, CNS drug half-lives and dose-response relationships have been conducted. Without this information, the extrapolation of mechanistic design and/or clinical relevance is illogical (Duraj et al. 2024).

BBB Penetration and CNS Exposure

A critical research question is whether imeglimin can achieve sufficient levels in the CNS needed to affect the relevant mitochondrial and neuroinflammatory targets needed to assess CICI. Although imeglimin is hydrophilic (log P ≈ − 0.9) and is likely to show poor passive diffusion across the blood–brain barrier (BBB), it is still not clear how much of it is available in the CNS under routine physiological conditions (Banks et al. 2024).

At the moment, it is not possible to reach any of these conclusions with certainty due to the absence of imeglimin data defining plasma–brain concentration ratios, CNS half-life, or brain PK–PD relationships. This absence of data suggests that it is not possible to achieve these clinically relevant concentrations in the brain to attain the neuroprotective effects (de Lange and Hammarlund Udenaes 2022).

Nonetheless, under certain circumstances, the claimed CNS consequences could be valid even if the changes in BBB permeability are due to systemic inflammation or vascular dysfunction caused by chemotherapy; however, that is extremely heterogenous and cannot be assumed to provide consistent exposure at the intended site (Lau et al. 2024).

For that reason, in the future, the potential to access the CNS should be the primary focus and should be justified by (i) the actual determination of the degree of exposure to the brain (e.g., measurement of brain tissue or microdialysis in appropriate experimental systems), (ii) investigation of the availability of potential pathways for carrier-mediated transport, and (iii) use of specific formulations designed to enhance the permeability of the CNS (e.g., nanoparticle systems, lipophilic prodrugs) (Archie et al. 2021; Hersh et al. 2022).

Until then, the proposed mechanistic links should be treated purely as academic in nature, rather than as evidence of actual engagement of the CNS targets of CICI.

Challenges and Translational Barriers

Despite its promising pharmacological profile several translational challenges limit the immediate application of Imeglimin in oncology-related neuroprotection. First, blood–brain barrier (BBB) penetration remains a major concern (Thangudu et al. 2020). With a log P value of approximately − 0.9, Imeglimin is hydrophilic and therefore exhibits low lipophilicity suggesting limited passive diffusion across the BBB (Mitusova et al. 2022). Although certain pathological states such as diabetes, inflammation or chemotherapy can transiently increase BBB permeability, this variability raises questions about achieving consistent therapeutic CNS concentrations (Thomas et al. 2025).

Second, pharmacokinetic and transporter-mediated interactions must be carefully evaluated. Imeglimin inhibits organic cation transporters (OCT1/2) and the multidrug and toxin extrusion transporter (MATE1) both of which are essential for the clearance of chemotherapeutic agents including cisplatin and doxorubicin (Zha 2018). Such interactions could modify systemic exposure, elevate toxicity or compromise treatment efficacy. Therefore, preclinical PK–PD studies assessing drug–drug interactions in cancer models are crucial before proposing combined therapy (Gebauer et al. 2021).

Third, potential adverse effects and metabolic considerations in cancer patients should not be overlooked. While Imeglimin is well tolerated in diabetic populations, its safety profile in individuals undergoing chemotherapy remains unexplored (Talib et al. 2021). Conditions such as cachexia, hepatic dysfunction and renal impairment may alter its pharmacokinetics (Olatunde et al. 2021). Finally, formulation advancements such as nanoparticle-based delivery systems or lipophilic prodrug design may help overcome current BBB and bioavailability limitations improving its translational feasibility in CICI management.

Potential clinical safety risks are be evaluated due to the reported actions of imeglimin on the inhibition of the organic cation integrators OCT1/2 and the MATE1 which are important to the renal and hepatic elimination of cancer drugs including cisplatin and doxorubicin. Inhibiting these transporters may lead to higher levels of systemic exposure to the drugs which may worsen toxicity or affect therapeutic response(Chevalier et al. 2020). Given that cancer patients are frequently treated with multidrug regimens, the pharmacokinetic bedrock of this drug interaction outlines a significant real-world risk. Therefore, extensive in vitro transporter assays as well as in vivo combination studies are necessary to evaluate these drugs related clinical safety risks before evaluating imeglimin in combination therapy with CICI (Hallakou-Bozec et al. 2021).

Now urgently needed for translational progress, are imeglimin’s central nervous system pharmacokinetic profile. Currently, there are no data describing plasma-to-brain concentration ratios, CNS half-life, exposure–response cycles, or potentially protective neuroactive doses in chemoregulatory cognitive impairment (CICI) models (de Lange 2013). Imeglimin’s capability to access and remain in some brain regions long enough to act on mitochondrial, redox or neuroinflammatory targets remains speculative. Therefore, all possible neuroprotective mechanisms described in this review are prospective, awaiting some manifestation for CNS bioavailability.

Conclusion

Mitochondrial dysfunction, oxidative stress, and neuroinflammation lead to cognitive disruption, a chronic problem in cancer survivors following chemotherapy. Imeglimin represents a mechanistically plausible but as yet unvalidated candidate for neuroprotection in chemobrain. All these properties of Imeglimin to enhance mitochondrial function, reduce reactive oxygen species, regulate glucose metabolism and neuroinflammation attribute it to be a potential chemo brain treatment option. In addition, the extent of its impact on neurotransmitter balance and synaptic plasticity has reinforced its eligibility as a neurotherapeutic option. Although, the preclinical evidence does seem promising, there needs to be extensive clinical studies to evaluate the safety and efficacy of this agent for patients with cancer. These findings could potentially inform future protocols aimed at improving cognitive outcomes in pediatric oncology survivors highlighting a prospective direction for clinical translation. Collectively, the mechanistic links discussed herein should be viewed as a conceptual framework to guide future CICI-specific investigations rather than as evidence of established therapeutic efficacy.

Author Contributions

HK, SB - Writing the manuscript, VG- Writing the manuscript, LK, AP- References, DK- Final Drafting.

Funding

Open access funding provided by Symbiosis International (Deemed University). No funding agency is acknowledged.

Data Availability

No datasets were generated or analysed during the current study.

Declarations

Competing Interests

The authors declare no competing interests.

Ethical Approval and Consent to Participate

No ethical approval required in this study.

Consent for Publication

I hereby give my consent for the publication of the entitled “Repurposing Imeglimin for Chemotherapy-Induced Cognitive Impairment: Targeting Mitochondrial Dysfunction and Neuroinflammation”.