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Age-related Macular Degeneration (AMD) is a leading cause of vision loss. There is no cure for AMD. Current treatments focus on preventing disease progression and preserving vision. In recent years, the role of brain-derived neurotrophic factor (BDNF) in AMD has attracted increasing attention. BDNF is widely involved in the physiology and pathophysiology of the retina. These include the development of photoreceptors during early development and synaptic communication between photoreceptors and retinal neurons. Under pathological conditions, BDNF affects the functions of multiple cell types in the retina including photoreceptors, ganglion cells, Müller cells, microglia cells, amacrine cells, and the retinal pigment epithelium (RPE). Importantly, BDNF does not act alone. Its function relates with other neurotrophic factors such as basic fibroblast growth factor (bFGF), ciliary neurotrophic factor (CNTF), and glial cell derived neurotrophic factor (GDNF). Meanwhile, the dynamic interaction between BDNF, its precursor protein proBDNF and the BDNF receptor TrkB not only affects the survival of retinal cells in AMD but may also guide the treatment strategy. Various approaches have been taken to deliver BDNF in animal models for managing AMD. Despite the exciting progress, challenges remain in implementing BDNF therapy as an effective treatment. In this review, we summarize the current research progress of BDNF in AMD and highlight the issues that need to be addressed before translation into clinical practice. Show less

A high-fat diet (HFD) induces oxidative stress and reduces hippocampal neurotrophic factors, contributing to cognitive impairment. Hydrogen sulfide (H₂S) is an endogenous gaseous signaling molecule with recognized neuroprotective and antioxidant properties. This study investigated the effects of sodium hydrosulfide (NaHS), an H₂S donor, on hippocampal brain-derived neurotrophic factor (BDNF), insulin-like growth factor-1 (IGF-1), and oxidative stress in rats fed an HFD. Forty-two adult male Wistar rats were assigned to control or HFD groups, with or without daily NaHS administration (3 or 5 mg/kg) for 11 weeks. HFD feeding significantly decreased hippocampal BDNF and IGF-1 protein levels and reduced the activity of superoxide dismutase (SOD), catalase (CAT), and glutathione reductase (GSR). NaHS treatment, particularly at 5 mg/kg, restored neurotrophic protein levels and normalized antioxidant enzyme activities. These effects occurred without consistent changes in mRNA expression, suggesting post-transcriptional regulation. Collectively, these findings demonstrate that H₂S mitigates HFD-induced neurotrophic and oxidative deficits, supporting its potential as a therapeutic strategy for obesity-related hippocampal dysfunction. Show less

As a result of individual genetic variations, some patients show no response to initial antidepressant medications. This study aims to investigate the association between specific genetic polymorphisms and the efficacy of antidepressant drugs and to improve the accuracy and effectiveness of treatment under the guidance of genetic testing. A retrospective screening was conducted on medical records from, Suixian People's Hospital between January 2022 and December 2024. A total 202 patients with depression carrying the CYP2C19 gene were selected after the application of exclusion criteria. They were assigned to three groups in accordance with their genetic metabolism types: the rapid metabolism group (Group A, n = 65), the intermediate metabolism group (Group B, n = 94) and the poor metabolism group (Group C, n = 43). All three groups were treated with sertraline for a six-week treatment cycle. The observation indicators included scores on the Hamilton Depression Scale (HAMD); onset time of drug effect; rates of response and remission; scores on the Clinical Global Impression-Improvement (CGI-I) scale; levels of the neurotransmitter factors 5-hydroxytryptamine (5-HT), γ-aminobutyric acid (GABA) and brain-derived neurotrophic factor (BDNF); incidence of adverse events; and scores on the Morisky Medication Adherence Scale-8 (MMAS-8). The baseline data of the three groups of patients were comparable before medication (p > 0.05). Compared with those in Groups A and B, patients in Group C showed a significantly greater reduction in HAMD scores (all p < 0.05), along with higher response rates (all p < 0.05) and remission rates (all p < 0.05). Amongst the three groups, Group C had a shorter onset time of drug effect (all p < 0.05); more significant improvement in CGI-I scores (all p < 0.05); and more prominent upregulation of neurotransmitter factors, namely, 5-HT (all p < 0.05), GABA (all p < 0.05) and BDNF (all p < 0.05). Regarding the incidence of adverse events, Group C had the highest rate, whereas Group A had the lowest (10.8% vs. 24.5% vs. 41.9%). Compared with other groups, Group B exhibited a more significant increase in MMAS-8 scores (all p < 0.05). Metabolic phenotype exerts substantial effects on the therapeutic outcome of sertraline in patients with depression carrying the CYP2C19 gene. Amongst groups, Group C showed better therapeutic efficacy but an elevated incidence of adverse events and lower medication adherence; Group A had relatively poor efficacy; and Group B demonstrated superior adherence. In clinical practice, individualised treatment can be implemented on the basis of CYP2C19 metabolic typing to improve therapeutic efficacy and reduce adverse events and medical burden. Show less

The origins of major depressive disorder (MDD) are complex, involving both environmental influences and a substantial genetic contribution. Genetic polymorphisms have been implicated in modulating susceptibility, disease course, and treatment response, yet findings are often modest, population-dependent, and sometimes inconsistent. This narrative review synthesizes current evidence on genetic variants associated with MDD, highlighting well-replicated results while distinguishing exploratory or emerging findings. Key systems reviewed include serotonergic ( Show less

Alzheimer's disease (AD) is a neurodegenerative disorder and the predominant cause of dementia, characterized by amyloid β (Aβ) plaques and tau tangles that disrupt neurons in memory-related brain regions. This study explores the therapeutic potential of santonin using integrated Show less

Glaucoma is increasingly recognized as an ischemic neurodegenerative disorder that extends beyond elevated intraocular pressure (IOP) to involve complex vascular, metabolic, and inflammatory mechanisms. Retinal ganglion cells are particularly vulnerable to ischemia-reperfusion injury, oxidative stress, and chronic neuroinflammation, leading to progressive disconnection from central visual pathways. Current therapies primarily target IOP reduction but fail to address ischemia-driven neurodegeneration or to restore lost neuronal connectivity. Ischemia triggers excitotoxicity, oxidative stress, and a maladaptive inflammatory response involving activated microglia and astrocytes, perpetuating neuronal injury and suppressing intrinsic regenerative capacity. Thus, restoring neural plasticity and mitigating neuroinflammation represent key unmet therapeutic needs. Psychoplastogens are a class of compounds capable of rapidly enhancing structural and functional neuroplasticity and have recently emerged as promising multitarget agents. Compounds such as ketamine, psilocybin, N,N-dimethyltryptamine (DMT), and some newly synthesized non-hallucinogenic analogs act through convergent signaling pathways involving BDNF-TrkB-mTOR, promoting dendritic growth, synaptogenesis, and glial modulation. Beyond their neurotrophic effects, psychoplastogens seem to exert potent immunomodulatory actions. In this review we will explore the interplay between ischemia, neurodegeneration, neuroinflammation, and impaired plasticity in glaucoma, integrating mechanistic insights from cerebral ischemia. We discuss emerging preclinical evidence supporting psychoplastogens as neurorestorative and anti-inflammatory agents, propose their potential application in ocular ischemic neurodegeneration, and outline translational challenges for future studies. Show less

Erectile dysfunction (ED) is one of the most prevalent and disabling complications of diabetes mellitus (DM), thought to arise from the interaction of metabolic, vascular, and neural injury. Recent evidence indicates that diabetic neuropathy, affecting both somatic and autonomic pathways, plays a central role in the development of ED and is strongly associated with increased disease burden. Early neurophysiological studies documented impaired penile sensory conduction and abnormalities of sacral reflex pathways in diabetic men with ED, while more recent investigations have confirmed the contribution of cardiovascular autonomic neuropathy and small-fibre loss. At the molecular level, oxidative stress, advanced glycation end-product signalling, impaired nitric oxide bioavailability, and reduced neurotrophic support, particularly involving brain-derived neurotrophic factor (BDNF), emerge as key mechanisms linking diabetes to neural and neurovascular dysfunction. Although phosphodiesterase type-5 inhibitors remain first-line therapy, reduced responsiveness in patients with significant neuropathy highlights the importance of recognising the role of neurogenic mechanisms. Overall, the available evidence supports the conceptualisation of diabetic ED as a neurovascular manifestation within the broader spectrum of diabetic neuropathy rather than as a purely vasculogenic disorder. This review integrates historical and contemporary literature addressing the epidemiology, neurophysiology, pathophysiology and therapeutic implications of ED in diabetes, with a specific focus on its neuropathic substrate. These findings support a paradigm shift toward an integrated neurovascular approach to diabetic ED, highlighting the importance of early neuropathy-oriented assessment and paving the way for future regenerative and neuroprotective therapeutic strategies. Show less

With the aim of identifying key proteins that play a role in the disorder tinnitus, interactions between proteins involved in thalamo-amygdala signaling under conditions of normal hearing (NH), acoustic stimulation (AS), and tinnitus (Tin) were studied. Three gene lists compiled from the GeneCards database using keywords were characterized by analyses of overlap, protein-protein interaction (PPI) networks, and by protein-enrichment analysis. Key proteins were selected on the basis of the degree and combined score value of the corresponding PPI network. In the NH process, BDNF, CASP3, and PVALB were identified as high-degree proteins (HDPs). In the AS process, BDNF, PVALB, and DLG4 are the top three HDPs; in the Tin process, these are BDNF, APP, and TNF. In the Tin process, key proteins appear that differ pre- and postsynaptically from those detectable in NH or AS. The glucocorticoid receptor NR3C1 and its interaction with FKBP5, a glucocorticoid receptor-induced co-chaperone, appear to be of particular importance for the emotional aspects of tinnitus. In tinnitus, the HDPs, together with their high-score interaction proteins, indicate processes of chronic neurodegeneration and of changes in transcription, intercellular communication, and in the survival and growth of neurons. Show less

Shatavarin IV, a steroidal saponin in Cells were treated with shatavarin IV (10 ng/ml) or proprietary ethanolic extract of shatavari root extract (SheVari4 In LPS-induced cells treated with shatavarin IV, IL6 and TNFα levels were reduced by 46% and 50%, respectively, and those of IL-10 and TGF-β were upregulated by 2.74 and 4.4 times with significant reductions in ROS and NO levels. Similar results were observed in presence of SheVari4 The results suggested that the primary bioactive component of Show less

Neurodegenerative diseases, including Alzheimer's disease, are marked by cholinergic dysfunction, oxidative stress, and reduced neurotrophic support, which drives the quest for multifunctional therapeutic agents. This pilot study presents four novel monoterpene-aminoadamantane conjugates (MACs 1-4) designed to combine the antioxidant and neuromodulatory characteristics of monoterpenes with the neuroprotective properties of aminoadamantane derivatives. Their physicochemical characteristics, blood-brain barrier permeability, and binding affinity to human acetylcholinesterase (AChE) were evaluated using molecular docking and in silico descriptor analysis. In vivo, the neuroprotective efficacy of the MACs was investigated in a scopolamine-induced dementia model in rats, employing behavioral tests. Biochemical assays conducted in the hippocampus and prefrontal cortex assessed AChE activity, antioxidant enzyme performance, lipid peroxidation levels, total glutathione content, and BDNF concentrations. The findings indicate that MAC1, MAC3, and MAC4 demonstrate favorable calculated blood-brain barrier permeability, strong predicted affinity for AChE, and significant in vivo alleviation of scopolamine-induced memory deficits, in conjunction with improvement of key markers of oxidative stress and cholinergic function. These results show that the structural hybridization of myrtenal with aminoadamantane frameworks produces promising multifunctional ligands that are relevant for Alzheimer's-type neurodegeneration. Show less

In vitro maturation (IVM) is highly susceptible to influences of the culture environment, which can lead to increased intracellular reactive oxygen species (ROS) levels and thereby induce a stress response in oocytes, ultimately reducing the developmental potential of early embryos. Brain-derived neurotrophic factor (BDNF) is an ovarian endocrine factor that can enhance the function of follicular granulosa cells and promote oocyte maturation, but the specific pathways remain unclear. We supplemented IVM cultures of sheep oocytes with BDNF and examined aspects of oocyte nuclear and cytoplasmic maturation. The addition of 50 ng/mL BDNF promoted the expansion of cumulus cells and increased the rates of first polar body extrusion, cleavage, and blastocyst formation. Compared with untreated controls, BDNF-treated oocytes had improved Ca Show less

Chronic pain is a highly prevalent and disabling condition with a well-documented female predominance in incidence, severity and persistence. These sex differences are driven by sexually dimorphic neuroimmune mechanisms rather than psychosocial factors alone. This systematic review was conducted to comprehensively synthesize human clinical and translational evidence on sex-specific neuroimmune and glial cell pathways underlying chronic pain. Scientific literature was systematically searched from database inception to December 2025 across multiple biomedical databases to identify relevant clinical and translational studies. Across pain conditions, convergent evidence demonstrated that chronic pain mechanisms diverge by sex at cellular and molecular levels. Male-predominant pathways were characterized by microglial activation, particularly P2X4 receptor-mediated signaling and brain-derived neurotrophic factor-dependent neuronal disinhibition, supported by neuroimaging, transcriptomic, and pharmacological data. In contrast, female-predominant mechanisms involved adaptive immune processes, including CD4 Show less

While essential trace minerals are known to influence DNA methylation (DNAm), molybdenum's (Mo) role in epigenetic regulation remains largely unexplored. This study examined associations between Mo status and DNAm of the brain-derived neurotrophic factor (BDNF) gene, a critical regulator of neurogenesis, in children aged 9-11 years, focusing on 107 CpG sites across BDNF and its antisense transcript (BDNF-AS).BDNF and BDNF-AS methylation was analyzed in blood samples from 72 children randomly selected from a cohort of 292 participants. Dietary Mo intake was estimated from food records, and creatinine-adjusted urinary Mo levels were quantified. Higher urinary molybdenum was significantly associated with decreased methylation at five BDNF 5'UTR sites (p<.05) and increased methylation of BDNF-AS (p =  .0001), consistent with enhanced BDNF transcriptional activity. African American children exhibited lower urinary Mo excretion than European American children, suggesting greater retention, and showed cortisol-associated increases in BDNF methylation not observed in European American children.These findings demonstrate associations between molybdenum status and DNA methylation patterns at the BDNF locus in children. While functional validation through BDNF protein measurement is needed, results suggest molybdenum may influence neurotrophin gene regulation through epigenetic mechanisms, highlighting the importance of trace mineral nutrition during neurodevelopment. Show less

To explore the effect of Ninety-five SPF male rats were selected and randomly divided into a sham-operation group (15 rats) and an operation group (80 rats). Using Longa's suture-occluded method and chronic unpredictable mild stress method, PSD rat models were prepared. A total of 75 successfully modeled rats were randomly divided into a model group, an acupuncture group, a paroxetine group, a dacomitinib (ErbB4 inhibitor) group, and an acupuncture+dacomitinib group, with 15 rats in each one. In the acupuncture group, acupuncture was delivered at "Baihui" (GV20), "Shenting" (GV24), and bilateral "Neiguan" (PC6) and "Taichong" (LR3); and the electric stimulation with electroacupuncture instrument was exerted at "Neiguan" (PC6) and "Taichong" (LR3) on the same side, using continuous wave, at a frequency of 2 Hz, and an intensity of 0.1 mA to 1 mA, for 30 min in each intervention. In the paroxetine group, the intragastric administration was given with paroxetine, 5 mg/kg; and in the dacomitinib group, the intragastric administration was given with dacomitinib, 7.5 mg/kg. In the acupuncture+ dacomitinib group received the same interventions as the acupuncture group and the dacomitinib group. The above intervention measures were delivered once a day for consecutive 28 days in each group. Longa's score was compared, and the behavior of rats was observed using the open field test and sucrose preference test in each group. Using ELISA method, the hippocampal levels of malonaldehyde (MDA), catalase (CAT), 5-hydroxytryptamine (5-HT), dopamine (DA), and norepinephrine (NE) were detected. With HE staining and Nissl staining adopted, the hippocampal neuron morphology was observed. Golgi staining was employed to observe the morphological changes of dendritic spines in the hippocampal neurons. Immunohistochemistry was used to observe the positive expression of brain-derived neurotrophic factor (BDNF) and synaptophysin (SYN1) in the hippocampal tissue, and Western blot was used to detect the protein expression of NRG1 and ErbB4 in the hippocampal tissues. Compared with the sham-operation group, the Longa's score and hippocampal MDA level in the model group increased ( Show less

Spinal cord injury (SCI) remains difficult to treat, and current interventions provide limited functional restoration and often require invasive procedures. Existing cell- or extracellular vesicles (EV)-based approaches are frequently administered alongside surgery, limiting therapeutic reach and overall efficacy. In this study, we developed an engineered extracellular vesicle (EV) platform by displaying a single-chain variable fragment (scFv) against integrin αvβ8 (αITGEV) and loading brain-derived neurotrophic factor mRNA (mBDNF). The construct maintained canonical EV identity and morphology, and showed predominant single particle co-positivity for targeting ligand and cargo. In neuron-microglia co-culture, mBDNF@αITGEV preferentially entered both cell types under injury-relevant stress, shifted microglia toward a repair-associated phenotype, reduced TNF-α and IL-1β, increased IL-4 and IL-10, and preserved neuronal architecture. Our results indicate that mBDNF@αITG-EVs significantly promote functional motor recovery by modulating the inflammatory microenvironment and inhibiting neuronal ferroptosis. Mechanistically, the delivery of BDNF mRNA bolstered GPX4 expression and stabilized mitochondrial dynamics, thereby mitigating secondary oxidative damage. This study provides a non-invasive strategy for precision nanomedicine in neuro-regeneration. Collectively, this study supports a non-invasive systemically administered, targeted EV-mRNA therapeutic strategy for spinal cord injury with translational potential. Show less

Findings of previous studies on associations between dairy consumption and metabolic health status were inconsistent. This study aimed to assess the link between consumption of dairy foods and metabolic health status, brain-derived neurotrophic factor (BDNF) and adropin levels in adults. Cross-sectional. An observational study in Isfahan, Iran. Adults (n=527) selected by multistage cluster random sampling. Dietary intakes were assessed via a validated 168-item food frequency questionnaire. Anthropometric indices, blood pressure and biochemical parameters were assessed. The criteria proposed by Wildman Participants had a mean age of 42.66 years (45.7% women). Moderate consumption of total dairy was, respectively, linked to 58% lower odds of MU (OR Moderate consumption of total and low-fat dairy was associated with lower odds of being metabolically unhealthy in Iranian adults, but high-fat dairy intake was not. Hypertension was less common among individuals with higher dairy intake. No association was found between dairy intake and serum levels of BDNF or adropin. Show less

Sepsis elevates the risk of depression and cognitive impairment. Glucagon-like peptide-1 (GLP-1) analogues exhibit neuroprotective potential, yet their effects on sepsis-induced depression (SID) remain unelucidated. This study explored whether exenatide (Exe) alleviates depressive-like behaviors and cognitive deficits in a murine SID model. SID mice were intraperitoneally administered exenatide (1 mg/kg/day) or vehicle for 14 days. Behavioral assessments included the Open Field Test, Forced Swimming Test, Tail Suspension Test, Sucrose Preference Test, Morris Water Maze, Novel Object Recognition, Novel Location Recognition, Three-Chamber Social Interaction Test, and IntelliCage system. Murine sepsis clinical scores and Nissl staining evaluated the model behaviorally and histologically. High-performance liquid chromatography quantified hippocampal 5-hydroxytryptamine (5-HT) and dopamine (DA), while enzyme-linked immunosorbent assay measured hippocampal and plasma biomarkers. Chronic exenatide treatment significantly reduced immobility time in the Forced Swimming and Tail Suspension Tests, improved cognitive performance in the Morris Water Maze, enhanced sucrose preference, and boosted novel object/location recognition and social interaction. Exenatide downregulated tumor necrosis factor-α, interleukin-6, and adrenocorticotropic hormone levels, while upregulating 5-HT, DA, phosphorylated cAMP response element-binding protein, and brain-derived neurotrophic factor. Exenatide exerts antidepressant-like and pro-cognitive effects in SID mice, likely via GLP-1 receptor-mediated suppression of hippocampal inflammation and promotion of neuroplasticity. GLP-1 analogues are promising dual-action therapeutics for comorbid depression and cognitive deficits, pending validation in further models and clinical trials. Show less

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social impairments, and repetitive and aggressive behaviors. The pathophysiology of ASD still remains unclear, while the population with ASD is 1/36 in children in the USA in 2024. Evidence suggests a wide range of inconsistent changes in brain-derived neurotrophic factor (BDNF), the most important neurotrophin in the central nervous system, in ASD. The present systematic review investigated studies that examined BDNF levels in three main ASD-like models in rodents [induced by valproic acid (VPA) and propionic acid (PPA), and in the BTBR mouse strain] in accord with PRISMA guidelines and in PubMed database. Forty-two studies were included. Most studies used male rats/mice. The results showed ASD model induced by VPA often leads to decreased BDNF, although unchanged or increased BDNF levels were also reported. ASD model induced by PPA leads to both increased and decreased BDNF. BDNF changes in BTBR mouse strain were also inconsistent. We found that the type of molecular assay appears to be important in evaluating BDNF. Also, few evidence showed a role for postnatal day and sex difference in BDNF changes in ASD-like rodent models. In addition, some studies have shown the potential role of the brain region in BDNF changes in different ASD-like models. In conclusion, it was suggested that inconsistencies in BDNF changes in rodent models of ASD may be related to the type of the molecular assay, the brain region, ASD model, sex, or even the postnatal day. However, evidence is still insufficient. Show less

(1) Background: The increasing environmental concentration of polystyrene nanoplastics (PS-NPs) may pose a risk of human exposure and health threats. Previous studies have demonstrated that exposure to PS-NPs poses a threat to neural synaptic plasticity, yet the underlying mechanisms remain unclear. (2) Methods: Hippocampal astrocytes and neurons were co-cultured, exposed to PS-NPs at concentrations of 10, 50, and 100 μg/mL, and cytotoxicity was assessed. We investigated PS-NP-induced impairment of synaptic plasticity by regulating the brain-derived neurotrophic factor (BDNF). (3) Results: Calmodulin-dependent protein kinase II (CaMKII) is a central molecular organizer of synaptic plasticity, learning, and memory, and its activity is intrinsically linked to intracellular calcium ion concentration. Our research indicates that PS-NPs may interfere with calcium ion signaling and CaMKIIα activity, thereby reducing CaMKIIα activity. This subsequently downregulates the expression of cAMP response element-binding protein (CREB), modulates BDNF expression, and impacts synaptic plasticity. (4) Conclusions: In summary, this study primarily focused on the effects of PS-NPs exposure on hippocampal synaptic plasticity. Show less

Survivors with chronic sequelae of carbon monoxide (CO) poisoning after the 1963 Miike-Mikawa coal mine disaster can exhibit persistent higher brain dysfunction in late life. We examined whether serum metabolic alterations remained detectable ~60 years later and assessed serum brain-derived neurotrophic factor (BDNF). In this cross-sectional case-control study, outpatients with chronic CO-poisoning sequelae (CO; n = 14) and former miners without CO exposure (CON; n = 16), all aged ≥ 75 years, underwent targeted serum metabolomics (1183 metabolites) and clinical assessments. Between-group differences were evaluated using Welch's Relative to controls, the CO group showed higher valine, alanine, and betaine and lower 3-hydroxybutyric acid, inosine, and hypoxanthine; these contrasts persisted with concordant direction after matching. Serum BDNF was lower in the CO group (unadjusted trend) and was significantly reduced after age/MMSE adjustment ( Six decades after exposure, chronic CO sequelae were associated with a reproducible serum profile combining amino-acid elevations with relative suppression of ketone-body and purine-related metabolites, suggesting enduring alterations in systemic substrate handling and bioenergetics. If replicated in larger cohorts, such signatures-potentially alongside BDNF-should be regarded as hypothesis-generating; biomarker development would require external validation, longitudinal tracking, and assessment of intervention responsiveness before any clinical use is considered. Show less

Ischemic stroke triggers hypoxia, inflammation, and oxidative stress. Local oxygen delivery may prevent secondary injuries. Herein, we implanted a catalase-incorporated thiolated gelatin-based oxygen-releasing hydrogel sheet in a rat model of photothrombosis to evaluate early infarct attenuation and feasibility. Male Sprague-Dawley rats were allocated to four groups (n = 6/group): control at 24 h (G1), with hydrogel sheet at 24 h (G2), control at 72 h (G3), and with hydrogel sheet at 72 h (G4). Focal ischemia was induced with Rose Bengal and targeted illumination through a 6.0-mm cranial defect. A hydrogel sheet was applied to the cortex after surgery. The infarct burden was assessed by 2,3,5-triphenyltetrazolium chloride (TTC) staining and magnetic resonance imaging (MRI), while mRNA expression levels of tumor necrosis factor-α (TNF-α), brain-derived neurotrophic factor (BDNF), and superoxide dismutase (SOD) were measured by quantitative reverse transcription PCR. Body weight was monitored as a safety measure. At 24 h, TTC showed a significant infarct reduction in G2 compared with G1. At 72 h, infarct measures did not differ significantly between G4 and G3. MRI and gene expression analyses did not show statistically significant between-group differences and are presented as exploratory outcomes. Weight and perioperative status were similar across groups, indicating short-term tolerability. The hydrogel sheet was associated with reduced TTC-defined infarct burden at 24 h in this model; confirmatory studies will require larger, powered cohorts, longer follow-up with functional testing, and in vivo oxygen release profiling to optimize dose, placement, and exposure time. Show less