Wei-wei Luan , Han-wen Gu , Di Qiu , Xin Ding , Pan-miao Liu , Kenji Hashimoto , Jian-jun Yang , Xing-ming Wang
{"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 , Han-wen Gu , Di Qiu , Xin Ding , Pan-miao Liu , Kenji Hashimoto , Jian-jun Yang , 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 , Dimitrinka Atanasova , Desislava Krushovlieva , Darina Barbutska , Milena Atanasova , Pavel Rashev , Zlatina Nenchovska , Milena Mourdjeva , 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}
Yang An , Gang Su , Wei Chen , Jinyang Song , Miao Chai , Longni Zhu , Zhenchang Zhang
{"title":"Research progress on the mechanisms of microglial extracellular vesicles affecting the prognosis of ischemic stroke","authors":"Yang An , Gang Su , Wei Chen , Jinyang Song , Miao Chai , Longni Zhu , 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 , Linghui Zeng , 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}
Sen Zhang , Chengdi Liu , Wan Li , Yizhi Zhang , Yihui Yang , Hong Yang , Ziyuan Zhao , Fang Xu , Wanxin Cao , Xiaoxue Li , Jinhua Wang , Linglei Kong , Guanhua Du
{"title":"Kaempferol promotes angiogenesis through HIF-1α/VEGF-A/Notch1 pathway in ischemic stroke rats","authors":"Sen Zhang , Chengdi Liu , Wan Li , Yizhi Zhang , Yihui Yang , Hong Yang , Ziyuan Zhao , Fang Xu , Wanxin Cao , Xiaoxue Li , Jinhua Wang , Linglei Kong , 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<sup>−1</sup>). 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}
Zi-Lin Ren , Xin Lan , Jia-Lin Cheng , Yu-Xiao Zheng , Cong-Ai Chen , Ying Liu , Yan-Hui He , Jin-Hua Han , Qing-Guo Wang , Fa-Feng Cheng , Chang-Xiang Li , Xue-Qian Wang
{"title":"Astrocyte-neuron metabolic crosstalk in ischaemic stroke","authors":"Zi-Lin Ren , Xin Lan , Jia-Lin Cheng , Yu-Xiao Zheng , Cong-Ai Chen , Ying Liu , Yan-Hui He , Jin-Hua Han , Qing-Guo Wang , Fa-Feng Cheng , Chang-Xiang Li , Xue-Qian Wang","doi":"10.1016/j.neuint.2025.105954","DOIUrl":"10.1016/j.neuint.2025.105954","url":null,"abstract":"<div><div>Ischemic stroke (IS) is caused by temporary or permanent obstruction of the brain's blood supply. The disruption in glucose and oxygen delivery that results from the drop in blood flow impairs energy metabolism. A significant pathological feature of IS impaired energy metabolism. Astrocytes, as the most prevalent glial cells in the brain, sit in between neurons and the microvasculature. By taking advantage of their special anatomical location, they play a crucial part in regulating cerebral blood flow (CBF) and metabolism. Astrocytes can withstand hypoxic and ischemic conditions better than neurons do. Additionally, astrocytes are essential for maintaining the metabolism and function of neurons. Therefore, the \"neurocentric\" perspective on neuroenergetics is gradually giving way to a more comprehensive perspective that takes into account metabolic interaction between astrocytes and neurons. Since neurons in the core region of the infarct are unable to undergo oxidative metabolism, the focus of attention in this review is on neurons in the peri-infarct region. We'll go over the metabolic crosstalk of astrocytes and neurons during the acute phase of IS using three different types of metabolites: lactate, fatty acids (FAs), and amino acids, as well as the mitochondria. After IS, astrocytes in the peri-infarct zone can produce lactate, ketone bodies (KBs), glutamine (Gln), and <span>l</span>-serine, shuttling these metabolites, along with mitochondria, to neurons. This process helps maintain the energy requirements of neurons, preserves their redox state, and regulates neurotransmitter receptor activity.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"185 ","pages":"Article 105954"},"PeriodicalIF":4.4,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143481884","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}
Victoria R. Vella , Garrett Ainsworth-Cruickshank , Carolina Luft , Kingston E. Wong , Laura W. Parfrey , A. Wayne Vogl , Parker J. Holman , Tamara S. Bodnar , Charlis Raineki
{"title":"Dysregulation of immune system markers, gut microbiota and short-chain fatty acid production following prenatal alcohol exposure: A developmental perspective","authors":"Victoria R. Vella , Garrett Ainsworth-Cruickshank , Carolina Luft , Kingston E. Wong , Laura W. Parfrey , A. Wayne Vogl , Parker J. Holman , Tamara S. Bodnar , Charlis Raineki","doi":"10.1016/j.neuint.2025.105952","DOIUrl":"10.1016/j.neuint.2025.105952","url":null,"abstract":"<div><div>Prenatal alcohol exposure (PAE) can severely impact fetal development, including alterations to the developing immune system. Immune perturbations, in tandem with gut dysbiosis, have been linked to brain and behavioral dysfunction, but this relationship is poorly understood in the context of PAE. This study takes an ontogenetic approach to evaluate PAE-induced alterations to brain and serum cytokine levels and both the composition and metabolic output of the gut microbiota. Using a well-established rat model of PAE, cytokine levels in the serum, prefrontal cortex, amygdala, and hypothalamus as well as gut microbiota composition and short-chain fatty acid (SCFA) levels were assessed at three postnatal (P) timepoints: P8 (infancy), P22 (weaning), and P38 (adolescence). Male PAE rats had increased cytokine levels in the amygdala and hypothalamus, but not prefrontal cortex, at P8. This altered neuroimmune function was not seen in the PAE females. The effect of PAE on central cytokine levels was reduced at P22/38, the same age at which PAE-induced alterations in serum cytokine levels emerge in both sexes. PAE reduced bacterial diversity in both sexes at P8, but only in females at P38, where a PAE-induced unique community composition emerged. Both sexes had alterations to specific bacterial taxa (e.g., Firmicutes), some of which are important in producing the SCFA butyric acid, which was decreased in PAE animals at P22. These results demonstrate that PAE leads to sex- and age-specific alterations in immune function, gut microbiota and SCFA production, highlighting the need to consider both age and sex in future work.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"185 ","pages":"Article 105952"},"PeriodicalIF":4.4,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143474875","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}
Cheng-Wei Lu , Tzu-Yu Lin , Kun-Chieh Yeh , Pei‐Wen Hsieh , Kuan-Ming Chiu , Ming-Yi Lee , Su-Jane Wang
{"title":"Reduction in presynaptic glutamate release and the prevention of glutamate excitotoxicity by lupeol in rats","authors":"Cheng-Wei Lu , Tzu-Yu Lin , Kun-Chieh Yeh , Pei‐Wen Hsieh , Kuan-Ming Chiu , Ming-Yi Lee , Su-Jane Wang","doi":"10.1016/j.neuint.2025.105951","DOIUrl":"10.1016/j.neuint.2025.105951","url":null,"abstract":"<div><div>This study aimed to investigate whether lupeol, a pentacyclic triterpenoid, affects glutamate release in isolated nerve terminals (synaptosomes) from the rat cerebral cortex and whether lupeol affects the excitotoxicity induced by kainic acid (KA) in rats. In rat cerebrocortical synaptosomes, lupeol reduced glutamate release in a manner that could be blocked by extracellular Ca<sup>2+</sup>-free medium or P/Q-type Ca<sup>2+</sup> channel antagonism. The synaptosomal membrane potential was not affected by lupeol treatment. Docking data also revealed that lupeol formed a hydrogen bond with amino acid residues of the P/Q-type Ca<sup>2+</sup> channel. In the KA-induced acute excitotoxicity model, lupeol pretreatment ameliorated cortical neurodegeneration and downregulated the expression of glutamate release-related proteins vesicular glutamate transporter 1 (VGLUT1) and phospho-synapsin I, thereby reducing the glutamate levels in the cortices of rats. Our findings suggest that lupeol may exert a neuroprotective effect by reducing glutamate excitotoxicity through the inhibition of presynaptic glutamate release. These results indicate that lupeol could be a promising candidate for the treatment of glutamatergic excitotoxicity and related neurological diseases.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"185 ","pages":"Article 105951"},"PeriodicalIF":4.4,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143472084","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}
Ye-ji Yu , Mujeeb Ur Rahman , Rengasamy Balakrishnan , Jong-Min Kim , Jae Ho Kim , Dong-Kug Choi
{"title":"The novel peptide DBCH reduces LPS-stimulated NF-κB/MAPK signaling in BV-2 microglia and ameliorates cognitive impairment in scopolamine-treated mice by modulating BDNF/CREB","authors":"Ye-ji Yu , Mujeeb Ur Rahman , Rengasamy Balakrishnan , Jong-Min Kim , Jae Ho Kim , Dong-Kug Choi","doi":"10.1016/j.neuint.2025.105946","DOIUrl":"10.1016/j.neuint.2025.105946","url":null,"abstract":"<div><div>Microglial-mediated neuroinflammation significantly impacts cognitive impairment, and modulating neuroinflammatory responses has emerged as a promising target for treatment. However, the specific role of microglial-mediated neuroinflammation in cognitive impairment associated with Alzheimer's disease (AD) remains unclear. In our continuous endeavors to seek potent anti-Alzheimer's agents, we recently synthesized and developed a series of peptidomimetic compounds, including dipeptide-68 bis-cyclohexylpropyl histidinamide (DBCH), derived from a caryopsis-1 peptide that has demonstrated anti-inflammatory and anti-microbial properties in various infectious diseases. Among the bioactive peptides synthesized, DBCH exhibited good neuroprotective and anti-inflammatory activity and high potency. Therefore, in this study, the neuroprotective and anti-inflammatory effects of DBCH were assessed in lipopolysaccharide (LPS)-stimulated BV-2 microglial cells and a scopolamine-induced C57BL/6 N amnesic mouse model. In the <em>in vitro</em> study, DBCH effectively suppressed the production and expression of nitric oxide (NO) and proinflammatory cytokines in BV-2 microglial cells stimulated with LPS. Furthermore, it effectively inhibited the LPS-triggered phosphorylation and activation of NF-κB/MAPK signaling and modulated inflammatory mediators, including iNOS and COX-2, in BV-2 microglial cells. <em>In vivo</em> results showed that DBCH administration of 5 or 10 mg/kg improved spatial memory learning and cognitive function in scopolamine-induced amnesic mice. Furthermore, DBCH treatment upregulated phosphorylated cAMP-response element-binding protein (p-CREB) and brain-derived neurotrophic factor (BDNF) levels and downregulated the inflammatory response. Overall, DBCH effectively prevented both scopolamine-induced cognitive impairment and neuroinflammation. Our research findings suggest that DBCH may serve as a medication for cognitive decline associated with AD.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"185 ","pages":"Article 105946"},"PeriodicalIF":4.4,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143456385","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}
Hao Tang , Jun Wen , Ling Wang , Qinghuan Yang , Ting Qin , Yu Ren , Yong Zhao , Changqing Li , Jiani Li , Hui Cao , Jianfeng Xu , Qin Yang
{"title":"Vagus nerve stimulation inhibits PANoptosis and promotes neurofunctional recovery of cerebral ischemic stroke in a Sirt1-dependent manner","authors":"Hao Tang , Jun Wen , Ling Wang , Qinghuan Yang , Ting Qin , Yu Ren , Yong Zhao , Changqing Li , Jiani Li , Hui Cao , Jianfeng Xu , Qin Yang","doi":"10.1016/j.neuint.2025.105950","DOIUrl":"10.1016/j.neuint.2025.105950","url":null,"abstract":"<div><div>Vagus nerve stimulation (VNS) can promote neurofunctional recovery following cerebral ischemic stroke (CIS), but the underlying mechanism remains unclear. PANoptosis, a novel form of inflammatory programmed cell death, may play a role in the progression of CIS. Our previous studies have indicated that Sirt1 exerts neuroprotection against CIS by modulating various programmed cell death pathways. It needs to be clarified whether and how VNS regulates PANoptosis through Sirt1, thereby affecting the recovery of CIS. This study aims to clarify the role of VNS in modulating neuronal PANoptosis following CIS, and elucidate its underlying mechanisms. Models of middle cerebral artery occlusion/reperfusion (MCAO/R) in rats and oxygen-glucose deprivation/reoxygenation (OGD/R) in primary neurons were established to assess the occurrence of neuronal PANoptosis following CIS. Circulating Sirt1 levels were measured in two independent cohorts of acute ischemic stroke (AIS) patients. VNS was administered to activate Sirt1, and its effects on PANoptosis and neurological recovery were evaluated. We found that neuronal PANoptosis was induced following CIS, which was reversed via VNS intervention. Sirt1 levels in serum of AIS patients were significantly increased, and positively correlated with infarct volume and National Institutes of Health Stroke Scale scores. In contrast, Sirt1 was downregulated in brain tissue from rodent models and AIS patients. This discrepancy in expression levels can be attributed to the increased generation of Sirt1 by peripheral macrophages. VNS upregulated Sirt1 expression, while the Sirt1 inhibitor EX527 negated the effects of VNS on PANoptosis, infarct volume, and neurofunctional recovery. These findings indicate that VNS may inhibit PANoptosis and promote neurofunctional recovery following CIS in a Sirt1-dependent manner, which may be a new potential target for stroke therapy. Sirt1 may also serve as a blood biomarker for patient stratification with independent prognostic value in AIS patients.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"184 ","pages":"Article 105950"},"PeriodicalIF":4.4,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143436682","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}