Epilepsy is a neurological disorder that shows strong genetic control on the timing and onset of symptoms and drug response variability. Some epilepsy syndromes have clear monogenic mutations but genes with control on the phenotype and severity of the disorder and drug sensitivity are present in the whole genetic profile. Genetic modifiers are not the cause of epilepsy but control significant networks such as synaptic plasticity and ion channels and neurodevelopment and neuroinflammation and therefore the reason why two individuals with the same primary mutations have different clinical courses. The review comprehensively examines the genetics of epilepsy to outline standard and minority genetic determinants and to distinguish between single-genetic and poly-genetic causes. It examines genetic modifiers and the mechanism by which they act and the control they exert on drug resistance and seizure risk and development of epilepsy and cognitive and behavioral problems. Alongside it explains how GWAS data with the help of epigenetics to identify significant modifying genes with control on neurotransmission and the immune response and metabolic pathways and ion channel regulation such as SCN1A and KCNQ2. The major functional mechanisms of genetic modifiers and the control they exert on network excitability and the control on the blood-brain barrier and neurodevelopmental pathways has been emphasized and explained in specific sections. The final section in this overview discusses the future possibility with precision medicine through genetic modifier-directed treatments and new drug development strategies and will develop tailored epilepsy treatment strategies.

Emerging evidence indicates that apelin, an adipokine, plays a critical role in numerous biological functions and may hold potential for therapeutic applications; however, its efficacy is constrained by rapid plasma degradation. Thus, the search for novel apelin analogues with reduced susceptibility to plasma degradation is ongoing. We have previously shown novel modified apelin-13 analogues, providing exciting opportunities for potential therapeutic development against Alzheimer's disease. In this study we explored novel insights into the neuroprotective effects of stable fatty acid modified (Lys8GluPAL) apelin-13-amide and amidated apelin-13 amide in mitigating cellular damage in SH-SY5Y neuroblastoma cells exposed to palmitic acid (PA) and lipopolysaccharide-induced (LPS) stress. Both apelin-13 analogues were found to modulate ER stress response and reduce oxidative stress by suppressing PA- and LPS-induced ROS production (36 % and 42 % reductions in GSH/GSG (p < 0.005). The peptides attenuated apoptosis by reducing caspase 3/7 activity and restoring bcl2 expression (p < 0.05) in cells treated with PA and LPS. They also downregulated pro-apoptotic genes, protected neurites from stress-induced damage, and promoted neurite outgrowth. The observed protective effects could be due to activation of the AMPK pathway, a critical regulator of cellular energy homeostasis and survival. These findings provide insight into novel, enzymatically stable apelin-13 analogues and highlight their potential to be developed as therapeutic agents against neuroinflammation and neurodegenerative disease, including Alzheimer's disease.

Traumatic brain injury (TBI) can produce chronic limb coordination and gait deficits that are associated with ongoing white matter damage. In rodent TBI models, chronic motor deficits may be obscured by aging or motor compensation. In addition, there are no treatments for TBI. The murine closed head injury (CHI) model produces diffuse, chronic white matter injury that may underlie chronic white matter dysfunction and motor deficits. Evoked compound action potentials (CAP) assess corpus callosum function from 3 to 180-days post injury (DPI). CHI acutely decreases total CAP amplitudes that recover by 90 DPI and increase further at 180 DPI. Total CAP amplitude changes are blocked by dosing of minocycline and N-acetylcysteine beginning 12 h post-injury (MN12). Injured or sham mice have similar times to traverse or number of foot faults on beam walk. DeepLabCut™ markerless limb tracking provides limb positions used to develop novel assays to assess beam walk and simple/complex wheel. Absition analysis integrates the duration and extent of foot faults during beam walk. Injured mice develop absition deficits at 90 DPI that worsen at 180 DPI suggesting a chronic and progressive decline. Chronic absition deficits are blocked by MN12 treatment. Speed typically assesses performance on simple/complex wheel. Novel limb coordination assays show that at 180 DPI, injured mice decrease coordination that significantly correlates with increased total CAP amplitude. MN12 alleviates chronic corpus callosum dysfunction and motor deficits suggesting a strong efficacy to treat TBI. DeepLabCut™ limb tracking reveals chronic deficits and motor compensation not seen with standard outcomes.

haFGF improves cognitive impairment in animal models of Alzheimer's disease (AD), but the effects and mechanisms of astrocytes on the neuroprotection mediated by haFGF remain unclear. Here, a neuron-astrocyte co-culture system was established to investigate the functions of astrocytes. The results showed that astrocytes strengthened the protective effect of haFGF on Aβ-treated neurons. This enhanced protective function of haFGF correlates with phenotypic transition in astrocytes, as demonstrated by the suppression of Aβ-induced A1-like genes and the elevation of A2-like markers in vitro. These observations are consistent with the reduction of GFAP and C3 levels in the hippocampus and prefrontal cortex of APP/PS1 mice treated with haFGF. haFGF modified the function of astrocytes by activating the AKT/CREB/BDNF pathway, thereby promoting neurite growth. Moreover, haFGF up-regulated the expression of Furin and MMP9 in astrocytes, leading to the processing of pro-BDNF. This effect was replicated in APP/PS1 mice administered with haFGF. Compared to the Aβ group, the BDNF level in the co-culture system supernatant was increased, while the IL-1β level was decreased following haFGF treatment. Additionally, haFGF inhibited neuronal apoptosis in the co-culture system, as evidenced by a decrease in pro-BDNF/P75, an increase in Bcl-2, and a reduction of Bad and Cleaved-caspase-3. In conclusion, current results demonstrate that astrocytes are crucial for mediating the protective effect of haFGF against neuronal damage, and underline the importance of the AKT/CREB/BDNF pathway in promoting neurite growth and attenuating neuronal apoptosis.

Astrocytes interact with neighboring cells by releasing extracellular vesicles (EVs). Tools to study astrocyte EV-mediated communication with other brain cells in vivo are essential. In this study, we crossed the Exomap1 transgenic mouse expressing Cre-activated human-specific CD81 (HsCD81) fused to the fluorescent protein mNeonGreen (HsCD81mNG), to a transgenic mouse expressing Cre under the astrocyte-expressing GFAP promoter resulting in Exomap1::Gfap-Cre mice, referred to here as AstroGreen. We characterized HsCD81mNG-expressing astrocytes and shedded EVs loaded with HsCD81mNG and Cre, both in vitro and in mouse brains. Using this model, we show that HsCD81mNG can be used to track EV content, production, and functional Cre transfer in vitro and in the brain, allowing evaluation of the interaction of astrocytes with neighboring cells mediated by EVs. We anticipate that this model will improve our understanding of astrocytes transferring EVs within their surroundings during normal physiological processes and in the context of neuropathological conditions.

Spinal cord injury (SCI) is a devastating neurological condition associated with high rates of disability and mortality, placing substantial burdens on patients, families, and healthcare systems. Current treatment strategies, including surgical decompression, pharmacological intervention, and rehabilitation, offer only limited functional recovery. Exosomes, extracellular vesicles with a double-membrane structure, range in diameter from 30 to 150 nm and play a key role in intercellular communication by transporting proteins, lipids, and nucleic acids. Recent studies have highlighted their potential as natural nanocarriers for the treatment of neurodegenerative disorders. Due to their low immunogenicity and multifunctional reparative properties, exosomes have shown considerable efficacy in promoting neurological recovery following SCI. They exert therapeutic effects through multiple mechanisms, including modulation of the inflammatory response, promoting axonal regeneration and angiogenesis, and inhibiting apoptosis. This review summarizes the pathophysiological mechanisms underlying SCI and elucidates the therapeutic roles of exosomes and exosomal microRNAs (exo-miR) in SCI repair. Furthermore, it discusses current challenges and prospects for the clinical translation of exosome-based therapies, aiming to provide valuable insights for future research and clinical applications.

Alzheimer's disease (AD) is a neurodegenerative disease that greatly impairs the health status of human beings and creates significant burdens on individuals, families, and society. AD is characterized by the buildup of pathological proteins and glial cell dysregulated activity. Additional hallmark features include oxidative stress, neuroinflammation, impaired autophagy, cellular senescence, mitochondrial dysfunction, epigenetic alterations, reduced neurogenesis, increased blood-brain barrier permeability, and age-inappropriate intestinal dysbiosis. There is significant evidence that shows that microbiota in the gut affects the development and progression of AD. As a result, gut microbiota modulation has been identified as a new method of clinical management of AD, and more and more efforts have been devoted to identifying new methodologies for its prevention and treatment. This paper will discuss the role of gut microbiome in the etiopathogenesis of AD and consider the possibilities of fecal microbiota extract (FME) supplementation, commonly referred to as fecal microbiota transplantation (FMT). It is both a prophylactic and curative approach. The FMT therapy is grounded on the premise that anti-inflammatory effects, modifications of amyloid β, improved synaptic plasticity, short-chain fatty acids, and histone acetylation are the principles behind the enhancement of AD. The current review will present an overview of the linkage between FMT and AD as well. It further examines and evaluates the effects of FMT on aging-based mechanisms that support the development of AD. It also provides a broad description of the recent clinical and preclinical evidence on the application of FMT to AD.

Cold induced traumatic brain injury (Ci-TBI), is a lethal and highly debilitating neurodegenerative condition with limited therapeutic options. Metabolic perturbations like deregulated glycolysis is perceived as a hallmark of TBIs including Ci-TBIs. Elucidation of the underlying mechanisms regulating Ci-TBI are essential devising effective therapeutic strategies. In the present study, induction of Ci-TBI in-vitro and in a mice model down regulated the long noncoding RNA LINC00094. Our mechanistic studies revealed that LINC00094 targeted and inhibited miR-19a-3p both in the neuronal culture based in vitro model of Ci-TBI vitro and a Ci-TBI mice model in vivo. The elevated expression of miR-19a-3p further targeted and inhibited the adiponectin receptor 2 (AdipoR2) and repressed glycolysis, glucose uptake and lactate production. Collectively, our results elucidated the molecular cascade and underscored the significance of the LINC00094/miR-19a-3p signalling in regulation of glycolysis mediating Ci-TBI. These novel findings indicate that LINC00094 and miR-19a-3p could be of prognostic and diagnostic value as potential biomarkers of Ci-TBI progression.

Moyamoya disease (MMD) is a chronic disease characterized by the progressive narrowing of the terminal internal carotid artery, accompanied by abnormal angiogenesis at the base of the skull and defective formation of the vascular network, with a complex clinical picture and a risk of cognitive impairment and dementia in addition to ischemic and hemorrhagic events. The glymphatic system is a cerebrospinal fluid and interstitial fluid drainage pathway that acts throughout the brain to remove metabolic wastes from the brain parenchyma. Clinical studies have found that cognitive decline in patients with MMD is linked to metabolite accumulation and reduced diffusion tensor image analysis along the perivascular space (DTI-ALPS), highlighting the potential impact of glymphatic system impairment. This dysfunction may stem from a combination of chronic hypoperfusion, systemic microstructural damage and inflammatory response, and is an important link to further deterioration of vascular cognitive function. This article discusses the recent findings on glymphatic system disorders in MMD, with the objective of providing new approaches to the disease.

Spinal cord injury (SCI) triggers complex pathological processes-including neuroinflammation, glial scar formation, and impaired neuronal regeneration-that hinder recovery. Macrophages and microglia centrally regulate these processes through dynamic polarization states across a spectrum of pro-/anti-inflammatory phenotypes. While single-cell technologies reveal glial and immune heterogeneity and interactions in the SCI microenvironment, translating these insights into immunomodulatory therapies remains challenging. This review therefore examines mechanisms driving macrophage/microglia polarization in the microenvironment of SCI, focusing on their therapeutic targeting potential.

Nitrogen compounds are increasingly recognized as key modulators in nutrigenomics, with profound implications for understanding and influencing the aging process. Traditionally central to human nutrition, these compounds are now understood to play critical roles in regulating gene expression, cellular signalling, and metabolic pathways that are essential for maintaining health during aging. Nitrogen-containing molecules, such as amino acids, polyamines, and nitric oxide, contribute to vital processes including protein synthesis, mitochondrial function, and oxidative stress management. These mechanisms are crucial for cellular homeostasis but become increasingly vulnerable to disruption during aging, leading to tissue degeneration and heightened susceptibility to age-related diseases. Disruptions in nitrogen metabolism can impair proteostasis, mitochondrial bioenergetics, and antioxidant defences, accelerating cellular decline. Recent research has expanded our understanding of how nitrogen compounds interact with nutrient-sensing pathways such as mTOR and AMPK, as well as epigenetic regulators that influence DNA repair, autophagy, and inflammation. These findings highlight the therapeutic potential of optimizing nitrogen metabolism to enhance health span and mitigate the effects of aging. The emerging field of nitrogen nutrigenomics offers promising opportunities for developing targeted nutritional strategies aimed at improving quality of life and delaying age-related decline. By integrating historical perspectives with contemporary discoveries, this review underscores the complex interplay between nitrogen compounds and aging while inspiring future research into innovative interventions that harness their benefits for longevity and well-being. Ultimately, optimizing nitrogen metabolism could pave the way for new approaches to extending health span and addressing age-related health challenges.

Traumatic brain injury is not constrained only to the brain but delayed secondary events disturb the end organ functioning via intense response of three homeostatic mechanisms such as sympathetic activity, inflammation, and immunosuppression. Current study involved weight drop model to induce TBI in Swiss albino mice. Eprosartan was administered orally after 30-45 min post injury to mice in 0.35 mg/kg and 0.7 mg/kg doses. Mice were tested for neurobehavioral alterations and multiple organs, including brain, heart, lungs, liver, and kidney were excised for further edema, biochemical, inflammatory, catecholamine, gene expression and histopathological estimations at both acute and chronic phases of injury. Results highlighted that Epro improved neurobehavioral performance, maintained the BBB and lung integrity. It also ameliorated the oxidative stress as well as docking studies exhibited strong binding affinity of Epro for HMGB1 and PDL-1, that further supported by low tissue HMGB1 and serum IL-6 and TNF-α cytokines levels which halted the systemic hyperinflammation. Moreover, Epro treatment successfully restored the cardiac, hepatic and kidney function through stabilized serum biomarkers with declined plasma noradrenaline levels that subsides the sympathetic storm. Considerably, a bizarre cellular morphology was displayed by the organs in acute phase of injury whereas Epro reversed the morphological changes at chronic stage. Also, epro encouraged the PD-1/PDL-1 and IL-10 gene expression in the tissues that regulates immune response. Thus, it is concluded that Epro exerts its organ protective effect against MODS via AT/SNS pathway inhibition.

Parkinson's disease (PD) is a complex neurodegenerative disorder characterized by dopaminergic neuronal loss, protein aggregation, and neuroinflammation. Current symptomatic therapies have not demonstrated disease-modifying effects. Covalent inhibitors represent a promising multifactorial therapeutic approach due to their ability to form irreversible and specific bonds with target proteins. This narrative review incorporates recent experimental and computational findings on emerging covalent inhibitors that target key molecular mechanisms implicated in PD. This includes α-synuclein aggregation, LRRK2 kinase hyperactivity, monoamine oxidase B (MAO-B) dysfunction, glutathione S-transferase Pi 1 (GSTP1)-mediated oxidative stress, and modulation of the Nrf2 signaling pathway. We discuss structure-guided drug design strategies, warhead chemistry, and unique inhibition modalities that contribute to improved pharmacological profiles and neuroprotective potential. In addition to classical covalent inhibition, the review explores emerging targeted covalent degrader strategies that expand therapeutic possibilities by promoting selective protein degradation rather than mere functional suppression. Furthermore, recent preclinical advances and clinical translation challenges are evaluated, positioning covalent approaches as leading candidates for targeted and sustained PD interventions. Lastly, we address developmental obstacles, such as enhancing selectivity and blood-brain barrier penetration while minimizing off-target effects, highlighting the role of activity-based protein profiling, covalent PROTACs, and bifunctional covalent degraders as next-generation strategies to optimize therapeutic efficacy in PD treatment.

Microglial and astrocytic activation is the main reason for the neuroinflammatory responses, which damages neurons resulting in neurological disorders. Currently, there are few drugs that directly target neuroinflammation in clinical practice, which highlights the urgent need for effective inhibitors. In this study, we identified agrimonolide, from a screen of 40 compounds, as an inhibitor of glia activation, and further confirmed its efficacy in vitro and in vivo. In cellular models, agrimonolide significantly reduced the expression levels of proinflammatory cytokines (IL-1β, IL-6 and TNFα) in LPS stimulated BV2 cells and primary astrocytes. Mechanistic investigation revealed that agrimonolide suppresses the activation of both NF-κB and MAPK signaling pathways, combined the molecular docking results, it is suggested that agrimonolide may have multiple targets. In ICR mice, our measurements showed that agrimonolide treatment decreased LPS-induced glial activation, as evidenced by the protein levels of IBA-1 and GFAP. Additionally, it significantly inhibited the activation of TLR4-mediated signaling pathways. Our findings suggest that agrimonolide suppresses neuroinflammatory responses by inhibiting microglial and astrocytic activation, providing insight into potential treatment strategies for neuroinflammation-related diseases.

Lobeglitazone, an oral antidiabetic medication, acts as a peroxisome proliferator-activated receptor γ (PPARγ) agonist and demonstrates neuroprotective effects. This study investigated beneficial effects and mechanisms of lobeglitazone treatment in an experimental intracerebral hemorrhage (ICH) rat model. ICH was induced in the left striatum of Sprague-Dawley rats by administration of 0.6 units of collagenase type IV. Rats with ICH were assigned randomly to three treatment groups: (1) control group, (2) lobeglitazone 2 mg/kg, and (3) lobeglitazone 4 mg/kg (N = 6, in each group). Medications were administered orally for 3 days following ICH. Outcomes were measured based on brain edema on the third day after ICH. Behavioral outcomes were evaluated on days 1, 3, 6, and 13 following ICH utilizing the modified neurological severity score (mNSS). On the third day after ICH, inflammatory cytokines were evaluated using western blotting, and inflammatory cells were examined through immunohistochemistry. Administration of lobeglitazone at a dosage of 4 mg/kg reduced brain edema significantly (15 %) in comparison to the control and 2 mg/kg (7 %) groups. Moreover, lobeglitazone administration at a dosage of 4 mg/kg suppressed infiltration of macrophages and neutrophils in perihematomal areas. Expression of several inflammatory cytokines, including interleukin-1 beta (IL-1b), extracellular signal-regulated kinase (ERK), and cyclooxygenase-2 (COX2) were also reduced. Regarding functional outcomes, a high dose of lobeglitazone (4 mg/kg) improved the mNSS significantly on days 3 and 13 after ICH. The results suggest that lobeglitazone, a PPARγ agonist, has potential neuroprotective effects on ICH by modulating brain edema and brain inflammation via IL-1β-ERK-COX-2 pathway inhibition.

Autism Spectrum Disorder (ASD) exhibits a clear male bias, with males being approximately four times more likely to be affected than females. This difference has sparked curiosity about possible neurological elements that provide protection to females. One such neurological element that has shown promise is brain-derived neurotrophic factor (BDNF), essential for neuronal development, synaptic plasticity, and neuroprotection. ASD may be less common in females due to increased BDNF levels, which may be influenced by sex-specific epigenetic control and estrogen hormone. Research studies indicate that increased baseline BDNF in females promotes neurodevelopmental resilience and mitigates the environmental and genetic risk factors linked to ASD. Also, this protective impact may be enhanced by the regulatory function of estrogen in BDNF expression and the interaction of BDNF with X-linked genes. The processes by which BDNF contributes to sex differences are still not well understood despite strong evidence. Interpreting results is made more difficult by the variability of ASD symptoms and variations in study methodologies. In addition to that, it is yet unknown whether increased BDNF levels represent compensatory processes or actually provide protection. Longitudinal studies that monitor BDNF expression across developmental stages and look at sex-specific treatment approaches that target BDNF pathways should be the main focus of future research. Thus, a thorough understanding of how BDNF prevents sex differences in ASD may pave the way for innovative strategies destined to diminish the risk of ASD. In this milieu, this review explores the current research, highlighting the complex relationship between sex differences, BDNF, and the incidence of ASD.

Death-associated protein kinase 1 (DAPK1) is critically involved in regulating cell death in various neurodegenerative disorders. However, the role of DAPK1 in the pathogenesis of amyotrophic lateral sclerosis (ALS) remains unclear. Here, we found that the expression of DAPK1 significantly increased in ALS, showing a negative correlation with miR-501-3p. Upregulating DAPK1 led to an increase in motor neuron apoptosis by inhibiting Xiap. Conversely, silencing of DAPK1 protected motor neurons against hSOD1-induced apoptosis by activating Xiap. Furthermore, we demonstrate that the neuroprotective impact of DAPK1-knockdown was inhibited by Embelin, an inhibitor of Xiap. These results suggest that modulating the DAPK1/Xiap signaling cascade protects motor neurons from apoptosis, indicating its potential as a therapeutic target in ALS. Significantly, these findings offer new directions for treatment options for ALS patients.

Calpains are a family of calcium-dependent cysteine proteases that are activated within the brain minutes after a traumatic brain injury (TBI). Sustained calpain activation contributes to the secondary injury cascade of TBI and has been linked to neuronal and axonal degeneration and impairment of neurological function. Calpastatin is an endogenous protein encoded by the CAST gene which serves as a potent and highly selective inhibitor of calpains. This study investigates the potential of overexpressing human calpastatin (hCAST) via the ubiquitous prion protein promoter in a mouse model to alleviate TBI-induced brain damage and neurobehavioral dysfunction. Transgenic mice overexpressing hCAST and wildtype controls received a controlled cortical impact to induce contusive TBI or a sham injury. Overexpression of calpastatin significantly attenuated motor deficits over the first week in brain-injured mice. Visuospatial learning ability assessed in a Morris water maze on days 6 through 9 and novel object recognition on day 10 were impaired following TBI in wildtype mice. Both learning and memory function were improved in brain-injured hCAST overexpressing mice compared to wildtype mice. At 10 days post-injury brains were evaluated for cortical tissue damage and hippocampal neuron death. Analysis of Nissl-stained brain sections revealed no significant difference in the size of the cortical contusion between hCAST and wildtype animals. Similarly, hippocampal neurodegeneration associated with TBI was not modulated by hCAST overexpression. These findings demonstrate that inhibition of calpains aids in restoration of neurobehavioral function following TBI without protecting against cortical or hippocampal neuron death.

Chronic traumatic encephalopathy (CTE), a progressive neurodegenerative disease marked by perivascular deposition of hyperphosphorylated tau (P-tau), is strongly linked to repetitive concussive traumatic brain injuries (TBIs). Emerging evidence implicates disruptions in the clearance of interstitial fluid (ISF) and cerebrospinal fluid (CSF) from the brain-specifically within the glymphatic and meningeal lymphatic systems-as a pivotal driver of disease onset and progression. TBI disrupts glymphatic ISF-CSF exchange, compromising the clearance of pathogenic proteins-including P-tau, TDP-43, and inflammatory mediators-while promoting perivascular accumulation and neuroinflammation. Simultaneously, meningeal lymphatic dysfunction impedes CSF drainage and sustains neuroimmune activation, further amplifying glymphatic failure. Developmental trajectories of these systems suggest age-dependent susceptibilities to injury, potentially shaping both acute outcomes and long-term neurodegenerative risk. Species-specific differences between rodents and humans in brain fluid clearance pathways add translational complexity, emphasizing the need for refined models. This review reconceptualizes CTE as a disorder driven by disrupted brain fluid clearance, highlighting the convergent roles of glymphatic and meningeal lymphatic dysfunction in linking TBI to chronic neurodegeneration and identifying therapeutic targets to restore clearance and resilience.

Indoleamine 2,3-dioxygenase (IDO) modulates the kynurenine pathway and may influence post-mild traumatic brain injury (mTBI) outcomes. This study tested whether IDO knockout (IDO-KO) mice exhibit distinct behavioral profiles and neurotrophic factor levels after a mTBI.

Ischemic stroke (IS) reduces the blood flow to the brain regions that trigger oxidative stress-induced biochemical, behavioural, molecular, and cellular impairments. Current treatment strategies are limited due to their narrow therapeutic window as, there is an urgent need to identify alternative therapeutic strategies in clinical settings to promote beneficial outcomes in stroke patients. Current study, focused on the neuro-protective potential of Arbutin (AR) in ischemic brain injury via modulation in Nrf-2/HO-1/HIF-1α/TFAM pathway. MCAO surgery was performed for 90 min, followed by reperfusion on male wistar rats, and the drug was administered intra-peritoneally. Animals were then sacrificed to estimate infarct volume, brain edema, BBB permeability, oxidative stress, inflammation, mitochondrial dysfunction, gene expression along with behavioural and morphological studies at different time intervals, i.e., 24 h and 21 days post-stroke. The results revealed that AR treatment improved neurological functions by maintaining BBB integrity and reducing edema, infarct volume, oxidative stress, and neuro-inflammation. It also improved the mitochondrial functions by increasing the gene expression of HIF-1α and TFAM along with reducing caspase-3 activation and iNOS gene expression through enhancing Nrf-2/HO-1 expression that supports the antioxidant activity of AR. Further, strong binding affinity of AR with the Nrf2 as revealed by the docking studies, reinforces our finding especially given the lack of prior target specific investigations exploring the detailed patho-mechanism of IS. Overall, AR exerts neuro-protective effect by modulating the Nrf-2/HO-1/HIF-1/TFAM pathways leading to improved mitochondrial functions, enhanced neurological outcomes, and increased neuronal survival which underscore its potential to as a therapeutic candidate for the treatment of IS.