Neurochemistry international最新文献

{"title":"The C. elegans glutamate transporters GLT-4 and GLT-5 regulate protein expression, behavior, and lifespan","authors":"Grace J. Bronstone ,&nbsp;Moriah Harton ,&nbsp;Maya Muldowney ,&nbsp;James Reigle ,&nbsp;Adam J. Funk ,&nbsp;Sinead M. O'Donovan ,&nbsp;Robert E. McCullumsmith ,&nbsp;Deborah E. Bauer","doi":"10.1016/j.neuint.2025.105966","DOIUrl":"10.1016/j.neuint.2025.105966","url":null,"abstract":"<div><div>Glutamate transporters are important for regulating extracellular glutamate levels, impacting neural function and metabolic homeostasis. This study explores the behavioral, lifespan, and proteomic profiles in <em>Caenorhabditis elegans</em> strains with either <em>glt-4</em> or <em>glt-5</em> null mutations, highlighting contrasting phenotypes. Δ<em>glt-4</em> mutants displayed impaired mechanosensory and chemotactic responses, reduced lifespans, and decreased expression levels of ribosomal proteins and chaperonins involved in protein synthesis and folding. In contrast, Δ<em>glt-5</em> mutants displayed heightened chemorepulsion, extended lifespans, and upregulation of mitochondrial pyruvate carriers and cytoskeletal proteins. Proteomic profiling via mass spectrometry identified 53 differentially expressed proteins in Δ<em>glt-4</em> mutants and 45 in Δ<em>glt-5</em> mutants. Δ<em>glt-4</em> mutants showed disruptions in ribonucleoprotein complex organization and translational processes, including downregulation of glycogen phosphorylase and V-type ATPase subunits, while Δ<em>glt-5</em> mutants revealed altered metabolic protein expression, such as increased levels of mitochondrial pyruvate carriers and decreased levels of fibrillarin and ribosomal proteins. Gene ontology enrichment analysis highlighted differential regulation of protein biosynthesis and metabolic pathways between the strains. Overall, these findings underscore the distinct, tissue-specific roles of GLT-4 and GLT-5 in <em>C. elegans</em>, with broader implications for glutamate regulation and systemic physiology. The results also reinforce the utility of <em>C. elegans</em> as a model for studying glutamate transporters' impact on behavior, longevity, and proteostasis.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"186 ","pages":"Article 105966"},"PeriodicalIF":4.4,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143724325","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Morphine self-administration decreases intrinsic excitability of accumbal medium spiny neurons and suppresses the innate immune system in male Wistar rats","authors":"Louise Adermark ,&nbsp;Davide Cadeddu ,&nbsp;Erika Lucente ,&nbsp;Klara Danielsson ,&nbsp;Bo Söderpalm ,&nbsp;Mia Ericson","doi":"10.1016/j.neuint.2025.105965","DOIUrl":"10.1016/j.neuint.2025.105965","url":null,"abstract":"<div><h3>Introduction</h3><div>Morphine alleviates severe pain but is addictive and associated with weakened immune system. Interestingly, the immunosuppressive effects have been linked to central circuits including the nucleus accumbens shell (NAc), suggesting that there might be a direct link between reward processing in the NAc and weakened immune system. The overall aim with this study was to assess the impact displayed by morphine self-administration on neuroplasticity in the NAc shell and circulating white blood cells.</div></div><div><h3>Methods</h3><div>Wistar rats received morphine injections over ten days, and locomotor activity was monitored. Next, morphine self-administration, and relapse drinking after forced abstinence, were assessed. Lastly, electrophysiological recordings were conducted in the NAc <em>ex vivo</em> to define neurophysiological adaptations, and hematological analysis were conducted in parallel.</div></div><div><h3>Results</h3><div>While ten days of morphine injections were not sufficient to affect morphine self-administration, behavioral sensitization to the locomotor stimulatory properties of morphine was observed and further correlated with the amount of morphine consumed following forced abstinence. Electrophysiological slice recordings demonstrated no effect on excitatory neurotransmission, but the intrinsic excitability of NAc neurons was significantly depressed compared to water drinking controls. In addition, hematological analysis demonstrated a significant decline in the number of white blood cells, especially monocytes and neutrophils, while erythrocytes were not affected. The amount of circulating white blood cells further correlated with morphine intake, but not with neurophysiological parameters.</div></div><div><h3>Conclusion</h3><div>The data presented here demonstrates that morphine self-administration produces accumbal neuroplasticity and biological transformations that could contribute to the addictive and immunosuppressive properties of morphine.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"186 ","pages":"Article 105965"},"PeriodicalIF":4.4,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143697504","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"METTL3/IGF2BP2/IκBα axis participates in neuroinflammation in Alzheimer's disease by regulating M1/M2 polarization of microglia","authors":"Ling Zhu ,&nbsp;Congyan Liu ,&nbsp;Yang Wang ,&nbsp;Xuanang Zhu ,&nbsp;Lei Wu ,&nbsp;Lvan Chen ,&nbsp;Jing Zhou ,&nbsp;Fan Wang","doi":"10.1016/j.neuint.2025.105964","DOIUrl":"10.1016/j.neuint.2025.105964","url":null,"abstract":"<div><h3>Background</h3><div>Microglia-mediated neuroinflammation is closely related to the development of Alzheimer's disease (AD). This study further elucidated the regulatory mechanism of microglia polarization in AD.</div></div><div><h3>Method</h3><div>Microglia polarization was assessed using RT-qPCR, ELISA, and immunofluorescence (IF). Western blot (WB) analyzed inflammation-related, p-tau, and apoptosis-related proteins. Neuronal damage was evaluated by immunofluorescence, and neuronal apoptosis by flow cytometry and TUNEL assay. METTL3 and IκBα expression were detected using RT-qPCR and WB. N⁶-methyladenosine (m⁶A) levels were quantified with a colorimetric assay. RNA pull-down assay examined METTL3, IGF2BP2, and IκBα mRNA binding. IGF2BP expression was assessed by RT-qPCR. Learning and memory abilities were evaluated using morris water maze (MWM) test and novel object recognition (NOR) test. Inflammation-related proteins were detected using IF.</div></div><div><h3>Results</h3><div>Stimulation with Aβ_1-42 led to microglia M1 polarization, upregulation of inflammation-related proteins, and exacerbation of neuronal injury and apoptosis, along with increased p-tau expression in neurons. METTL3/IGF2BP2 modulated IκBα m⁶A modification through binding to IκBα mRNA, enhancing its expression. Enhanced METTL3 or IGF2BP2 expression suppressed M1 polarization, inflammation, and neuronal apoptosis in microglia, reversed by knockdown of IκBα. AD model mice exhibited cognitive impairments, neuroinflammation, and elevated M1 polarization. METTL3 or IGF2BP2 overexpression improved cognitive function, reduced neuroinflammation, and inhibited M1 polarization, and this effect was similarly reversed by knockdown of IκBα.</div></div><div><h3>Conclusion</h3><div>Our study demonstrates that the METTL3/IGF2BP2/IκBα axis is involved in neuroinflammation in AD by modulating microglia M1/M2 polarization, which sheds light on the treatment of AD.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"186 ","pages":"Article 105964"},"PeriodicalIF":4.4,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143661810","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nicotine enhances object recognition memory through activation of the medial prefrontal cortex to the perirhinal cortex pathway","authors":"Hirohito Esaki ,&nbsp;Kanta Imai ,&nbsp;Keisuke Nishikawa,&nbsp;Naoya Nishitani,&nbsp;Satoshi Deyama,&nbsp;Katsuyuki Kaneda","doi":"10.1016/j.neuint.2025.105963","DOIUrl":"10.1016/j.neuint.2025.105963","url":null,"abstract":"<div><div>Nicotine enhances recognition memory across species; however, the underlying neuronal mechanisms remain incompletely understood. Our previous study using a novel object recognition (NOR) test and electrophysiological recordings of mouse brain slices demonstrated that nicotine enhanced object recognition memory by stimulating nicotinic acetylcholine receptors in the medial prefrontal cortex (mPFC). To elucidate this further, we conducted the NOR test combined with pharmacology, chemogenetics, optogenetics, and <em>ex vivo</em> electrophysiology in male C57BL/6J mice. Chemogenetic inhibition of mPFC excitatory neurons suppressed nicotine-induced enhancement of object recognition memory, whereas their activation alone was sufficient to enhance memory. Anatomical studies indicate that the mPFC sends projections to the perirhinal cortex (PRH), a brain region involved in object recognition memory. Therefore, we focused on mPFC-PRH projections. Whole-cell patch-clamp recordings with optogenetic stimulation revealed that PRH pyramidal neurons received monosynaptic and glutamatergic inputs from the mPFC. Chemogenetic suppression of mPFC neurons projecting to the PRH blocked the nicotine-induced enhancement of object recognition memory, whereas activation of these neurons alone was sufficient to enhance memory. To achieve precise temporal control, optogenetic inhibition of the mPFC-PRH pathway during the training session blocked the effects of nicotine, and its activation alone enhanced memory. Furthermore, unilateral intra-mPFC nicotine infusion enhanced object recognition memory, and this effect was suppressed by ipsilateral intra-PRH infusion of an α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor antagonist. These findings indicate that nicotine enhances object recognition memory by activating glutamatergic projections from the mPFC to PRH.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"185 ","pages":"Article 105963"},"PeriodicalIF":4.4,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143612926","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biochemical and medical aspects of vitamin B1 research","authors":"Alexander F. Makarchikov ,&nbsp;Pierre Wins ,&nbsp;Lucien Bettendorff","doi":"10.1016/j.neuint.2025.105962","DOIUrl":"10.1016/j.neuint.2025.105962","url":null,"abstract":"<div><div>Vitamin B₁ is an indispensable food factor for the human and animal body. In animals, vitamin B₁ is found in the form of thiamine and its phosphate esters – thiamine mono-, di- and triphosphate, as well as an adenylated derivative – adenosine thiamine triphosphate. At present, the only vitamin B₁ form with biochemical functions being elucidated is thiamine diphosphate, which serves as a coenzyme for several important enzymes involved in carbohydrate, amino acid, fatty acid and energy metabolism. Here we review the latest developments in the field of vitamin B₁ research in animals. Transport, metabolism and biological role of thiamine and its derivatives are considered as well as the involvement of vitamin B₁-dependent processes in human diseases and its therapeutic issues, a field that has gained momentum with several important recent developments.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"185 ","pages":"Article 105962"},"PeriodicalIF":4.4,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584155","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Repeated administration of esketamine ameliorates mechanical allodynia in mice with chemotherapy-induced peripheral neuropathy: A role of gut microbiota and metabolites","authors":"Wei-wei Luan ,&nbsp;Han-wen Gu ,&nbsp;Di Qiu ,&nbsp;Xin Ding ,&nbsp;Pan-miao Liu ,&nbsp;Kenji Hashimoto ,&nbsp;Jian-jun Yang ,&nbsp;Xing-ming Wang","doi":"10.1016/j.neuint.2025.105961","DOIUrl":"10.1016/j.neuint.2025.105961","url":null,"abstract":"<div><div>Chemotherapy-induced peripheral neuropathy (CIPN) severely diminishes the quality of life for cancer survivors, yet effective treatments remain scarce. Esketamine, a commonly used anesthetic, has demonstrated neuroprotective effects by restoring gut microbiome dysbiosis. In this study, we investigated the impact of esketamine on nociceptive sensitivity in a mouse model of CIPN and explored the potential involvement of the gut microbiome. In mice treated with oxaliplatin, repeated esketamine doses (in contrast to a single dose) significantly improved the paw withdrawal threshold (PWT). Western blot and qPCR analyses further revealed that repeated esketamine administration markedly reduced microglial activation and neuroinflammation in the dorsal root ganglion (DRG), underscoring its potent anti-inflammatory properties. Moreover, fecal 16S rRNA analysis indicated that esketamine partially restored the abnormal gut microbiota composition (β-diversity). Plasma metabolome analysis showed that repeated esketamine treatment significantly lowered the elevated levels of 6H-indolo[2,3-b]quinoline and restored the reduced levels of (3-exo)-3-[3-methyl-5-(1-methylethyl)-4H-1,2,4-triazol-4-yl]-8-azabicyclo[3.2.1]octane observed in oxaliplatin-treated mice. In addition, fecal microbiota transplantation from esketamine-treated CIPN mice notably improved both the diminished PWT and DRG neuroinflammation in oxaliplatin-treated mice. Collectively, these findings suggest that repeated esketamine administration may alleviate mechanical allodynia in CIPN mice by modulating neuroinflammation, gut microbiota, and associated metabolites.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"185 ","pages":"Article 105961"},"PeriodicalIF":4.4,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584167","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Age-related memory decline is accelerated by pinealectomy in young adult and middle-aged rats via BDNF / ERK / CREB signalling","authors":"Jana Tchekalarova ,&nbsp;Dimitrinka Atanasova ,&nbsp;Desislava Krushovlieva ,&nbsp;Darina Barbutska ,&nbsp;Milena Atanasova ,&nbsp;Pavel Rashev ,&nbsp;Zlatina Nenchovska ,&nbsp;Milena Mourdjeva ,&nbsp;Yvetta Koeva","doi":"10.1016/j.neuint.2025.105960","DOIUrl":"10.1016/j.neuint.2025.105960","url":null,"abstract":"<div><div>Memory decline is considered a normal part of aging, while the relationship between melatonin deficiency and cognitive function is complex and not fully understood. The present study investigated the role of melatonin deficiency at different ages on working and short-term recognition and spatial memory in rats. An age-related decline in memory function was tested using the Y-maze, the object recognition test, and the radial arm maze. The brain-derived neurotrophic factor (BDNF), TrkB receptor, the extracellular signal-regulated kinase (ERK)1/2 and pERK1/2 expression in the hippocampus was assessed by immunohistochemistry. The pCREB/CREB ratio in the frontal cortex (FC) and hippocampus was evaluated by ELISA. Young adult and middle-aged rats with pinealectomy had memory impairment whereas old melatonin-deficient rats were unaffected. Aging was associated with reduced expression of BDNF and its receptor throughout the hippocampus and reduced ratio of pCREB/CREB in the FC and hippocampus, whereas pinealectomy exacerbated this process in 3- and 14-month-old rats. The region-specific reduced expression of the ERK1/2 and pERK1/2 was observed in young adult rats with pinealectomy. However, in middle-aged rats, the expression of these signaling molecules was either downregulated or upregulated in different regions of the hippocampus. Our study provides insights into the molecular pathways involved in age-related memory changes associated with melatonin deficiency, highlighting the importance of the BDNF/ERK1/2/CREB pathway in the hippocampus and suggesting a critical period for intervention.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"185 ","pages":"Article 105960"},"PeriodicalIF":4.4,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143562109","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Research progress on the mechanisms of microglial extracellular vesicles affecting the prognosis of ischemic stroke","authors":"Yang An ,&nbsp;Gang Su ,&nbsp;Wei Chen ,&nbsp;Jinyang Song ,&nbsp;Miao Chai ,&nbsp;Longni Zhu ,&nbsp;Zhenchang Zhang","doi":"10.1016/j.neuint.2025.105949","DOIUrl":"10.1016/j.neuint.2025.105949","url":null,"abstract":"<div><div>Ischemic stroke is the major type of stroke and one of the main causes of morbidity, mortality, and long-term disability worldwide. Microglia play a complex and crucial role in stroke. They are the primary immune cells in the brain and can rapidly respond to the pathological changes caused by stroke. They promote neuroprotection and repair after ischemic stroke through various mechanisms, such as activation and polarization, dynamic interactions with other cells (neurons, astrocytes, oligodendrocytes, vascular endothelial cells, etc.), and phagocytosis to clear dead cell debris. Among the multiple pathways through which microglia exert their neuroprotective effects, the secretion of extracellular vesicles is one of the most important. The focus of this review is to analyze the latest progress in research on ischemic stroke related to microglia-derived extracellular vesicles, discuss their mechanisms of action, and provide new strategies for improving stroke prognosis. To obtain relevant articles, we conducted a comprehensive search in Pubmed and Web of Science, with keywords related to ischemic stroke and microglia-derived extracellular vesicles or exosomes. A total of 59 articles were included in the review. Existing studies have shown that after a stroke occurs, microglia release extracellular vesicles containing proteins, nucleic acids, metabolites, etc. These vesicles target corresponding receptor cells and can slow down the development of stroke and improve stroke outcomes through various means, such as reducing neuronal apoptosis, inhibiting neuronal autophagy, suppressing neuronal ferroptosis, preventing neuronal pyroptosis, alleviating inflammatory responses, reducing glial scar formation, promoting myelin regeneration and repair, and facilitating blood-brain barrier repair.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"185 ","pages":"Article 105949"},"PeriodicalIF":4.4,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143522229","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DOT1L in neural development and neurological and psychotic disorders","authors":"Feiyan Shen ,&nbsp;Linghui Zeng ,&nbsp;Yanpan Gao","doi":"10.1016/j.neuint.2025.105955","DOIUrl":"10.1016/j.neuint.2025.105955","url":null,"abstract":"<div><div>Disruptor of Telomeric Silencing 1-Like (DOT1L) is the sole methyltransferase in mammals responsible for catalyzing the mono-, di-, and trimethylation of histone H3 at lysine 79 (H3K79), a modification crucial for various cellular processes, including gene transcription, cell cycle regulation, DNA repair, and development. Recent studies have increasingly linked DOT1L to the nervous system, where it plays a vital role in neurodevelopment and neuronal function. It has been shown to regulate the proliferation and differentiation of neural progenitor cells, promote neuronal maturation, and influence synaptic function, all of which are essential for proper neural circuit formation and brain function. Moreover, dysregulation of DOT1L has been associated with several neurological disorders, highlighting its potential role in disease pathology. Abnormal expression or activity of DOT1L has been implicated in cognitive deficits and neurodegenerative diseases, underscoring the enzyme's significance in both the development and maintenance of the nervous system. This review synthesizes recent findings on DOT1L's role in the nervous system, emphasizing its importance in neurodevelopment and exploring its potential as a therapeutic target for treating neurological disorders.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"185 ","pages":"Article 105955"},"PeriodicalIF":4.4,"publicationDate":"2025-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143480487","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Kaempferol promotes angiogenesis through HIF-1α/VEGF-A/Notch1 pathway in ischemic stroke rats","authors":"Sen Zhang ,&nbsp;Chengdi Liu ,&nbsp;Wan Li ,&nbsp;Yizhi Zhang ,&nbsp;Yihui Yang ,&nbsp;Hong Yang ,&nbsp;Ziyuan Zhao ,&nbsp;Fang Xu ,&nbsp;Wanxin Cao ,&nbsp;Xiaoxue Li ,&nbsp;Jinhua Wang ,&nbsp;Linglei Kong ,&nbsp;Guanhua Du","doi":"10.1016/j.neuint.2025.105953","DOIUrl":"10.1016/j.neuint.2025.105953","url":null,"abstract":"<div><div>Stroke is a severe disease characterized by the obstruction of blood vessels in the central nervous system. An essential therapeutic strategy for ischemic stroke is strengthening angiogenesis, which effectively promotes the long-term recovery of neurological function. Therefore, it is critical to explore and develop new drugs that promote angiogenesis after ischemic stroke. Kaempferol has been employed to treat ischemic diseases; However, its proangiogenic effects in ischemic stroke remain unclear. In the study, we explored the long-term therapeutic effects and mechanisms of kaempferol on ischemic stroke <em>in vivo</em> and <em>in vitro</em>. A rat model of autologous thrombus stroke and oxygen–glucose deprivation (OGD)-induced human brain microvascular endothelial cells (HBMECs) model was established to assess the effects of kaempferol <em>in vivo</em> (50 mg/kg/d, ig, 14 d) and <em>in vitro</em> (0.1, 0.3, 1 μmol L⁻¹). The results showed that long-term administration of kaempferol ameliorated neurological deficits and infarct volume in ischemic stroke rats. In addition, kaempferol relieved vascular embolization; enhanced microvascular endothelial cell survival, proliferation, migration, and lumen formation; increased the density of microvessels in the peri-infarct cortex; and promoted neovascular structure remodeling by increasing the coverage of astrocyte end-feet and expression of tight–junction proteins (TJPs). Further analysis revealed that the HIF-1α/VEGF-A/Notch1 signaling pathway was activated by kaempferol, and that inhibition of Notch1 blocked kaempferol-induced angiogenesis. Taken together, our results indicate that kaempferol exerts neuroprotective effects by stimulating endogenous angiogenesis and neovascular structural remodeling via the HIF-1α/VEGF-A/Notch1 signaling pathway, suggesting the therapeutic potential of kaempferol in ischemic stroke.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"185 ","pages":"Article 105953"},"PeriodicalIF":4.4,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143481886","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}