Journal of integrative neuroscience最新文献

{"title":"Brain Functional Alterations Associated With Postural Stability Across the Frailty Continuum: A Resting-State fMRI Study.","authors":"Sheng Huang, Yongyi Xu, Yaping Li, Shizhu Lin, Xinya Lan, Cai Jiang, Xiaohua Ke, Zhonghua Lin","doi":"10.31083/JIN51891","DOIUrl":"https://doi.org/10.31083/JIN51891","url":null,"abstract":"<p><strong>Background: </strong>Frailty is a common geriatric syndrome characterized by a progressive decline in physical function and an increased susceptibility to adverse outcomes, including falls. Although diminished postural stability is a hallmark of frailty, the neural correlates associated with balance impairments throughout the progression of the syndrome remain unclear. This study aims to elucidate the brain functional activity of older adults with varying degrees of frailty during a resting state, as well as the relationship between this activity and postural stability.</p><p><strong>Methods: </strong>Sixty-eight older adults were divided into non-frail (n = 23), pre-frail (n = 30), and frail (n = 15) groups based on the Fried frailty phenotype. Postural stability was assessed using the Huber®360 neuromuscular control training and assessment system. Resting-state functional magnetic resonance imaging (rs-fMRI) data were acquired on a 3.0 T scanner, and the amplitude of low-frequency fluctuations (ALFF) and regional homogeneity (ReHo) were utilized as indicators of brain functional activity. Spearman correlation analysis was employed to examine the correlations between the brain functional activity and the postural stability.</p><p><strong>Results: </strong>Compared to the non-frail group, the frail and pre-frail groups were significantly older and exhibited poorer performance in grip strength, Short Physical Performance Battery (SPPB) scores, and Timed Up and Go Test (TUGT) results, as well as a greater burden of comorbidities-such as depressive symptoms and sleep disturbances (all <i>p</i> < 0.05). Significant inter-group differences were observed across all postural stability parameters. Relative to the non-frail group, the pre-frail group exhibited significantly decreased ALFF in the left inferior frontal gyrus (pars opercularis) extending to the insula, while the frail group demonstrated reduced ALFF in bilateral posterior cerebellum; additionally, the frail group showed decreased ReHo in the left posterior cerebellum/pons and increased ReHo in the right middle temporal/occipital gyrus. ALFF was significantly correlated with right single-leg sway area, the limits of stability, SPPB score, and TUGT completion time, whereas ReHo was significantly correlated only with SPPB score and TUGT completion time (all <i>p</i> < 0.05).</p><p><strong>Conclusions: </strong>Resting-state brain function exhibits significant differences among older adults in varying states of frailty, primarily involving spontaneous activity and local synchronization within the cerebellum-pons circuitry and cognition-related brain regions. These functional brain abnormalities are closely associated with diminished postural stability, suggesting that alterations in central nervous system function may represent a significant neural correlate of impaired balance in frail older adults. This study provides neuroimaging evidence to support the early screening of frailty a","PeriodicalId":16160,"journal":{"name":"Journal of integrative neuroscience","volume":"25 7","pages":"51891"},"PeriodicalIF":3.3,"publicationDate":"2026-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148620306","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Knockdown of Smox Protects Against Cerebral Ischemia/Reperfusion Injury by Suppressing Neuronal Autophagy via the AKT/AMPK/mTOR Phosphorylation Pathway.","authors":"Zhihui Li, Qian Wang, Kaixuan Ma, Mengna Yu, Yanyan Wang, Zhongqiao Ge, Peng Lin, Hui Wang, Lexun Lin, Yang Chen, Lina Jia, Heming Li, Zhongqiu Fu, Zhaohua Zhong, Guangtian Wang","doi":"10.31083/JIN50711","DOIUrl":"https://doi.org/10.31083/JIN50711","url":null,"abstract":"<p><strong>Background: </strong>Stroke is a major cause of morbidity and mortality, characterized by neuronal damage and complex cell death pathways. This study aimed to investigate the protective role of spermine oxidase (Smox) in ischemic stroke and its effect on neuronal autophagy.</p><p><strong>Methods: </strong>We employed transient middle cerebral artery occlusion (tMCAO) models and oxygen-glucose deprivation/reoxygenation (OGD/R) experiments in HT22 cells to explore the protective effects of Smox knockdown against ischemic injury and to evaluate changes in autophagy.</p><p><strong>Results: </strong>Smox levels were significantly elevated following stroke, and correlated with increased autophagic activity and neuronal apoptosis. In contrast, knockdown of Smox reduced neuronal death and improved neurological function while decreasing autophagy activation. Mechanistically, Smox may regulate autophagy via the phosphorylation of protein kinase B (AKT), AMP-activated protein kinase (AMPK), and mechanistic target of rapamycin (mTOR); Smox knockdown increased AKT and mTOR phosphorylation, while reducing AMPK phosphorylation, suggesting a potential shift in the regulation of neuronal autophagy.</p><p><strong>Conclusions: </strong>Our findings suggest a dual role for Smox in stroke pathology, indicating that it may influence autophagy via the AKT/AMPK/mTOR signaling, which could be critical for neuronal survival after ischemic injury. Targeting Smox may offer a therapeutic strategy for neuronal protection and recovery in stroke management, suggesting the potential importance of autophagy modulation in ischemic brain injury.</p>","PeriodicalId":16160,"journal":{"name":"Journal of integrative neuroscience","volume":"25 7","pages":"50711"},"PeriodicalIF":3.3,"publicationDate":"2026-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148620328","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of Succinate Accumulation in Prolonged Febrile Seizure-Induced Neuronal Injury and Epileptic Seizures in Sprague-Dawley Rats.","authors":"Yi Yuan, Xiaoqian Wang, Hua Zhou, Yunrong Zhang, Xiangdong Wu, Shuping Yin, Beiqi Zhang, Qiaoyun Wang, Shuang Li, Hongliu Sun, Yan Zhan","doi":"10.31083/JIN53240","DOIUrl":"https://doi.org/10.31083/JIN53240","url":null,"abstract":"<p><strong>Background: </strong>Though succinate accumulation is a vital contributor to overexcitation and reactive oxygen species (ROS) production, whether it contributes to febrile seizures (FS) is unclear. We sought to mechanistically explore the role of succinate in prolonged FS.</p><p><strong>Methods: </strong>Prolonged FS were induced by hyperthermic treatment in Sprague-Dawley pups. Inhibitors of succinate dehydrogenase (SDH), purine nucleotide cycle (PNC), and malate/aspartate shuttle (MAS) were administered, respectively. Succinate levels and oxidative stress damage were assessed, and epileptic seizures and learning and memory ability were assessed after hyperthermic treatment.</p><p><strong>Results: </strong>Succinate levels increased significantly, accompanied by oxidative stress injury, seizures, and learning and memory defects, following prolonged FS. Treatment with the SDH inhibitor reduced succinate levels, accompanied by reduced levels of oxidative stress injury, attenuated seizures, and learning and memory deficits. Treatment with inhibitors of MAS and PNC, respectively, played similar protective roles, accompanied by decreased succinate levels.</p><p><strong>Conclusions: </strong>Increased succinate levels promote prolonged FS-induced oxidative stress injury and epileptogenesis. Reducing succinate accumulation may be a potential method for prolonged FS treatment. Moreover, elevated succinate levels may result from the reverse catalysis of SDH-targeting fumarate, which was produced from PNC and MAS.</p>","PeriodicalId":16160,"journal":{"name":"Journal of integrative neuroscience","volume":"25 7","pages":"53240"},"PeriodicalIF":3.3,"publicationDate":"2026-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148620460","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cancer Neuroscience of Kinase Inhibitors: On-Target Effects on the Nervous System.","authors":"Thị Lam Thái, Sun-Young Han","doi":"10.31083/JIN51974","DOIUrl":"https://doi.org/10.31083/JIN51974","url":null,"abstract":"<p><p>Cancer neuroscience has emerged as a field that explores the bidirectional interactions between tumors and the nervous system. From this perspective, we review the pharmacological and neurobiological effects of kinase inhibitors, which are widely used as anticancer therapeutics. Certain kinase inhibitors not only exert potent antitumor activity but also modulate neural function as a consequence of kinase inhibition. Representative examples include small molecules and therapeutic antibodies targeting the tropomyosin receptor kinase (Trk), rearranged during transfection (RET), vascular endothelial growth factor/ vascular endothelial growth factor receptor (VEGF/VEGFR), epidermal growth factor receptor (EGFR), and anaplastic lymphoma kinase (ALK) signaling pathways. These agents influence the nervous system through molecular mechanisms, examples of which include TrkA-mediated pain perception and growth differentiation factor 15/RET signaling-dependent appetite regulation. Elucidating these mechanistic intersections between oncogenic and neural signaling can broaden our understanding of tumor-nerve crosstalk.</p>","PeriodicalId":16160,"journal":{"name":"Journal of integrative neuroscience","volume":"25 7","pages":"51974"},"PeriodicalIF":3.3,"publicationDate":"2026-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148620322","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Orexinergic-Opioidergic Interactions Within the Nucleus Accumbens in the Modulation of Acute Pain: Evidence From the Tail-Flick Test in Rats.","authors":"Mohammad Sajad Jolani, Mahsa Mohammadi, Roghayeh Mozafari, Abbas Haghparast","doi":"10.31083/JIN50757","DOIUrl":"https://doi.org/10.31083/JIN50757","url":null,"abstract":"<p><strong>Background: </strong>The nucleus accumbens (NAc) plays a central role in integrating motivational, reward-related, and nociceptive inputs. Opioid and orexin systems within the NAc are both implicated in pain modulation, yet their functional interaction in acute nociception is not fully understood. This study examined the interplay between opioidergic and orexinergic signaling in the NAc during acute pain processing.</p><p><strong>Methods: </strong>Adult male Wistar rats underwent unilateral intra-NAc administration of morphine (5, 10, 25, and 50 mmol) to assess dose-dependent antinociception using the tail-flick test. Orexinergic involvement was evaluated by intra-NAc injection of orexin-A (0.25, 0.5, 1, and 2 nmol), the orexin receptor type 1 (OX1R) antagonist SB334867 (3, 10, 30, and 100 nmol), or the orexin receptor type 2 (OX2R) antagonist TCS OX2 29 (3, 10, 30, and 100 nmol). To assess functional interactions, naloxone was administered prior to orexin-A, and SB334867 or TCS OX2 29 were given before morphine.</p><p><strong>Results: </strong>Intra-NAc injections of morphine and orexin-A produced significant and dose-dependent antinociceptive effects. Pre-treatment with SB334867 or TCS OX2 29 markedly reduced the analgesic responses induced by both morphine and orexin-A. Likewise, naloxone pre-treatment significantly attenuated orexin-A-evoked antinociception.</p><p><strong>Conclusions: </strong>These findings indicate a bidirectional interaction between opioidergic and orexinergic systems within the NAc in regulating acute nociception. The demonstrated functional crosstalk suggests that targeting orexinergic pathways may enhance endogenous analgesic mechanisms and could potentially reduce opioid requirements in clinical pain management.</p>","PeriodicalId":16160,"journal":{"name":"Journal of integrative neuroscience","volume":"25 7","pages":"50757"},"PeriodicalIF":3.3,"publicationDate":"2026-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148620295","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Brain-Wide Connectivity of GLP1R Neurons in the Thalamic Reticular Nucleus.","authors":"Xiao Zhang, Shanghui Zhu, Jiangzhong Lan, Shumin Duan, Yong Han, Peng Shi","doi":"10.31083/JIN52117","DOIUrl":"https://doi.org/10.31083/JIN52117","url":null,"abstract":"<p><strong>Background: </strong>Glucagon-like peptide-1 receptor (GLP1R) is a G-protein-coupled receptor recognized for its essential role in metabolic homeostasis and insulin secretion. Emerging evidence suggests that central GLP-1 signaling also modulates sensory information processing and cognitive functions. The thalamic reticular nucleus (TRN) serves as a critical inhibitory hub that filters and prioritizes sensory transmission between the thalamus and the cerebral cortex. We have identified a distinct population of GLP1R-expressing neurons distributed within the TRN; however, their long-range structural connectivity remains largely uncharacterized.</p><p><strong>Methods: </strong>In this study we used <i>Glp1r</i>-Cre mice combined with viral-genetic tracing strategies to map the whole-brain inputs and outputs of GLP1R-linked neurons. To identify direct monosynaptic inputs, a Cre-dependent retrograde rabies virus system was employed. To delineate the efferent axonal projections, a Cre-dependent synaptophysin-based tracing strategy was employed.</p><p><strong>Results: </strong>GLP1R neurons exhibited a distinct rostrocaudal distribution, with most located in the middle region of the TRN. The starter neurons, identified by the colocalization of adeno-associated virus (AAV)-double-floxed inverted orientation (DIO)-enhanced green fluorescent protein (EGFP)-tumor virus A receptor (TVA), AAV-DIO-rabies virus glycoprotein from the CVS-N2c strain (N2cG), and rabies virus (RV)-envelope protein A (EnvA)-glycoprotein-deleted (ΔG)-mCherry, were primarily located in the TRN. Retrograde-labeled neurons were identified across numerous brain regions. Dense clusters of input neurons were observed in the primary and secondary motor cortices (M1 and M2, respectively) and the primary somatosensory cortex (S1). Substantial inputs were observed, including from the ventrolateral (VL), central lateral (CL), and posterior (Po) thalamic nuclei. Additionally, notable presynaptic labeling was detected in subcortical regions such as the zona incerta (ZI) and lateral hypothalamic area (LH), as well as midbrain structures including the substantia nigra pars reticulata (SNR) and the deep mesencephalic nucleus (DpMe). Anterograde synaptophysin-based mapping revealed that TRN^GLP1R neurons selectively project to the ventral medial nucleus (VM), paracentral thalamic nucleus (PC), mediodorsal thalamus, lateral part (MDL), and lateral habenula (LHb) nuclei.</p><p><strong>Conclusions: </strong>The results confirm the existence of complex long-range afferent and efferent circuits associated with TRN^GLP1R neurons, providing a morphological basis for studying their role in integrating metabolic states with sensory gating.</p>","PeriodicalId":16160,"journal":{"name":"Journal of integrative neuroscience","volume":"25 7","pages":"52117"},"PeriodicalIF":3.3,"publicationDate":"2026-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148620315","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microglia as Double-Edged Players in Ischemic Stroke.","authors":"Shiyuan Lin, Zejing Lin, Ying Chen, Xingyong Chen","doi":"10.31083/JIN49507","DOIUrl":"https://doi.org/10.31083/JIN49507","url":null,"abstract":"<p><p>Stroke has long been a leading cause of death and long-term disability worldwide. In recent years, more and more research has revealed that microglial responses to ischemic injury are highly heterogeneous and exhibit dynamic evolution over time, across brain regions, and under different metabolic states. This endows microglia with a dual regulatory role in both neurotoxicity and neuroprotection after ischemia: on one hand, they drive inflammatory responses, exacerbating secondary neuronal damage, blood-brain barrier disruption, and synaptic loss; on the other hand, they orchestrate debris clearance, vascular rebuilding, and neural repair. The traditional pro-inflammatory versus anti-inflammatory dichotomy is no longer sufficient to fully describe their complex functions. In this review we summarize recent advances in understanding the dual regulatory roles of microglia after ischemic stroke, with a focus on key mechanisms such as metabolic reprogramming, lipid metabolism regulation, inflammasome activation, and epigenetic modification. Furthermore, emerging therapeutic strategies targeting microglia and the challenges they face are discussed.</p>","PeriodicalId":16160,"journal":{"name":"Journal of integrative neuroscience","volume":"25 7","pages":"49507"},"PeriodicalIF":3.3,"publicationDate":"2026-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148620316","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Multi-Frequency Self-Supervised Fusion Model for EEG-Based Dementia Classification.","authors":"Jinhua Sheng, Jiaqi Lin, Qiao Zhang, Zhaozhe Gong, Rong Zhang, Ming Wu, Yuhan Cheng, Xinrui Zhu, Zhongyuan Sun","doi":"10.31083/JIN50737","DOIUrl":"https://doi.org/10.31083/JIN50737","url":null,"abstract":"<p><strong>Background: </strong>Brain source localization technology enables precise characterization of the spatial distribution of neural activity, serving as a crucial tool for exploring the pathological mechanisms underlying dementia. However, effectively integrating complementary diagnostic information from source localization features across multiple frequency bands remains a major challenge to enhancing classification performance and model interpretability.</p><p><strong>Methods: </strong>An attention-based multi-frequency self-supervised fusion model (AM-SSF) is proposed to address this issue. Independent contrastive self-supervised encoders are trained for the θ (4-8 Hz), α (8-13 Hz), β (13-30 Hz), and γ (30-48 Hz) frequency bands to learn band-specific latent representations. Then, an attention-guided adaptive fusion module is introduced to dynamically allocate band weights through cross-entropy-based supervised optimization, thereby achieving effective cross-band information integration. Finally, a random forest classifier is employed to evaluate the model's performance in distinguishing Alzheimer's disease (AD) from frontotemporal dementia (FTD).</p><p><strong>Results: </strong>Experimental results show that the proposed framework achieves a classification accuracy of 93.1% under five-fold cross-validation, significantly outperforming baseline methods such as single-band self-supervised learning (SSL) and average pooling fusion. Further analysis of the attention weight distributions revealed that the θ and β bands contributed most to model decision-making, providing interpretability regarding frequency-specific effects.</p><p><strong>Conclusions: </strong>In summary, the proposed AM-SSF model enhances AD and FTD classification performance while offering valuable insights into the discriminative roles of frequency band features.</p>","PeriodicalId":16160,"journal":{"name":"Journal of integrative neuroscience","volume":"25 7","pages":"50737"},"PeriodicalIF":3.3,"publicationDate":"2026-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148620223","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dl-3-n-Butylphthalide Protects Human Brain Microvascular Endothelial Cells Against Ischemic Injury Through Dual Modulation of HIF1α/VEGF-Mediated Angiogenesis and COX2-Mediated Inflammation.","authors":"Yanyan Wang, Chuanxin Su, Teng Chen, Shijia Chen, Zhenzhong Li, Lihong Zhang","doi":"10.31083/JIN51032","DOIUrl":"https://doi.org/10.31083/JIN51032","url":null,"abstract":"<p><strong>Background: </strong>Stroke remains a leading cause of death and disability worldwide. Endothelial dysfunction plays a central role in both acute ischemic injury and subsequent recovery. In this study, we investigated the protective effects and underlying mechanisms of Dl-3-n-butylphthalide (NBP) on human brain microvascular endothelial cells (HBMECs) subjected to oxygen-glucose deprivation (OGD), an <i>in vitro</i> model of ischemic stroke.</p><p><strong>Methods: </strong>HBMECs were divided into three groups: control (normoxia), OGD (10 h hypoxia, followed by reoxygenation for different durations (0-24 h), and then a subsequent 24 h incubation), and NBP-treated OGD (10 μmol/L NBP during reoxygenation). Cell viability and apoptosis were assessed by Cell Counting Kit 8 (CCK8), lactate dehydrogenase (LDH) release, and flow cytometry. Mitochondrial function was evaluated using MitoTracker fluorescence. Molecular mechanisms were examined using Western blot, quantitative real-time PCR (qRT-PCR), immunofluorescence, and enzyme-linked immunosorbent assay (ELISA), focusing on the hypoxia-inducible factor-1α (HIF1α)/vascular endothelial growth factor (VEGF) angiogenic pathway and cyclooxygenase-2 (COX2)-mediated inflammatory response.</p><p><strong>Results: </strong>NBP at 10 μmol/L significantly improved HBMEC viability (37.5% increase, <i>p</i> < 0.01), reduced apoptosis (<i>p</i> < 0.01), and restored mitochondrial membrane potential (<i>p</i> < 0.05) following OGD injury. Mechanistically, NBP demonstrated dual pathway modulation by: (1) promoting angiogenesis-related gene expression through HIF1α upregulation and subsequent increase in vascular endothelial growth factor receptor 2 (VEGFR2) and endothelial nitric oxide synthase (eNOS) expression (<i>p</i> < 0.05); and (2) suppressing inflammation via COX2 downregulation with concurrent reduction of downstream mediators including inducible nitric oxide synthase (iNOS), tumor necrosis factor-α (TNFα), interleukin-1β (IL-1β), and Thromboxane B₂ (TXB₂, <i>p</i> < 0.05). This coordinated regulation created a favorable microenvironment balancing pro-angiogenic signals with anti-inflammatory effects.</p><p><strong>Conclusion: </strong>NBP exerts multi-targeted protection on HBMECs after ischemic injury through associated with the activation of HIF1α/VEGF-mediated angiogenesis and suppression of COX2-driven inflammation. This dual modulation strategy, targeting both vascular repair and inflammatory control, provides preliminary <i>in vitro</i> mechanistic insights that warrant further validation <i>in vivo</i> and in clinical settings.</p>","PeriodicalId":16160,"journal":{"name":"Journal of integrative neuroscience","volume":"25 7","pages":"51032"},"PeriodicalIF":3.3,"publicationDate":"2026-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148620330","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neurotrophic Factors in Stroke, Traumatic Brain Injury, and Neurodegeneration: A Convergent Pathophysiological and Translational Perspective.","authors":"Olesya V Shcheblykina, Darya A Kostina, Mikhail V Pokrovskii, Mikhail V Korokin","doi":"10.31083/JIN51543","DOIUrl":"https://doi.org/10.31083/JIN51543","url":null,"abstract":"<p><p>Neurotrophic factors (NTFs), including nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), glial cell line-derived neurotrophic factor (GDNF), ciliary neurotrophic factor (CNTF), and vascular endothelial growth factor (VEGF), play a central role in neuronal survival, plasticity, and regeneration. Despite their distinct etiologies and temporal profiles, stroke (both ischemic and hemorrhagic), traumatic brain injury (TBI), and neurodegenerative diseases (NDDs), including Alzheimer's disease (AD) and Parkinson's disease (PD), converge on a common pathophysiological phenotype characterized by excitotoxicity, oxidative stress, mitochondrial dysfunction, neuroinflammation, blood-brain barrier (BBB) disruption, and neuronal apoptosis. Neurotrophic factors modulate these pathological cascades through tropomyosin receptor kinase (Trk) receptors, p75 neurotrophin receptor (p75NTR), and related signaling pathways, thereby supporting neuroprotection, neurogenesis, and synaptogenesis. Experimental evidence from preclinical models demonstrates robust beneficial effects of neurotrophin-based interventions in stroke, TBI, AD, and PD across protein, gene, and cell-based strategies. However, clinical translation remains severely limited. Early-phase clinical trials of adeno-associated virus (AAV)-mediated GDNF and neurturin gene therapy for PD, <i>ex vivo</i> NGF gene therapy for AD, and BDNF gene therapy for AD have confirmed acceptable safety profiles but yielded modest or inconsistent efficacy, largely due to constraints in brain delivery, the need for invasive neurosurgical procedures, restricted target coverage, suboptimal control of expression, and marked patient heterogeneity. Consequently, the principal barrier to clinical success is not biological validity, but the lack of safe, effective and scalable delivery platforms capable of bypassing or functionally modulating the BBB. In this review we synthesize shared pathophysiological mechanisms linking stroke, TBI and NDDs; examine the biology, receptor systems, and signaling pathways of key neurotrophic factors; summarize preclinical evidence for their therapeutic potential; and critically evaluate current delivery strategies, including viral vectors, lipid nanoparticles, exosomes, cell-based therapies, small-molecule mimetics, and intranasal administration. We conclude that overcoming delivery barriers through development of improved viral and non-viral platforms, minimally invasive administration routes, controllable expression systems, and rational patient stratification based on disease stage and biomarkers will be essential to fully realize the neuroprotective and neuroregenerative potential of neurotrophin-based therapies for acute and chronic brain disorders.</p>","PeriodicalId":16160,"journal":{"name":"Journal of integrative neuroscience","volume":"25 7","pages":"51543"},"PeriodicalIF":3.3,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148620326","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}