Brain Research Bulletin最新文献

{"title":"GABAB receptors regulate the neural stem cell potential of Pkd2l1+ cerebrospinal fluid-contacting neurons via the PI3K/Akt signaling pathway","authors":"Liang Cao ,&nbsp;Wei-Hong Yan ,&nbsp;Wenjun Pi ,&nbsp;Yi Zhang ,&nbsp;Yan-Xiang Xiong ,&nbsp;V. Wee Yong ,&nbsp;Mengzhou Xue ,&nbsp;Qing Li ,&nbsp;Chunfu Zheng ,&nbsp;Leiluo Yang","doi":"10.1016/j.brainresbull.2025.111217","DOIUrl":"10.1016/j.brainresbull.2025.111217","url":null,"abstract":"<div><div>Cerebrospinal fluid-contacting neurons (CSF-cNs) exhibit neural stem cell (NSC) properties both <em>in vitro</em> and <em>in vivo</em>, and they may play a critical role in recovery after spinal cord injury (SCI). GABA_B receptors (GABABRs) are expressed in Pkd2l1⁺ CSF-cNs. However, their role in Pkd2l1⁺ CSF-cNs still needs to be discovered. In this study, we observed a significant reduction in GABA_BR expression in a murine model 7 d after SCI. We further discovered that GABA_BR activation enhanced the proliferation of Pkd2l1⁺ CSF-cNs while inhibiting apoptosis. Additionally, this activation mitigated vacuole loss and neuronal damage in the pericentral canal region of the spinal cord, attenuated myelin and axonal loss within the spinal cord, and facilitated motor function recovery in SCI model mice. Mechanistically, GABA_BR primed quiescent Pkd2l1⁺ CSF-cNs for cell cycle reentry through the activation of PI3K/Akt signaling. Our findings suggest that GABA_BR activation enhances the NSC potential of Pkd2l1⁺ CSF-cNs, ultimately enabling post-SCI recovery in murine models.</div></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":"221 ","pages":"Article 111217"},"PeriodicalIF":3.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143022262","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":"JAK/STAT3 signaling promotes pain and depression-like behaviors in rats with bone cancer pain by regulating Th17 cell differentiation","authors":"Shuyan Wu ,&nbsp;Jundan Jiang ,&nbsp;Danfeng Wang ,&nbsp;Daoyi Lin ,&nbsp;Mingxue Lin ,&nbsp;Pinzhong Chen ,&nbsp;Jianghu Chen ,&nbsp;Honghong Zhang ,&nbsp;Ying Wang ,&nbsp;Xiaohui Chen ,&nbsp;Xiaochun Zheng","doi":"10.1016/j.brainresbull.2025.111218","DOIUrl":"10.1016/j.brainresbull.2025.111218","url":null,"abstract":"<div><h3>Background</h3><div>Pain and depression are common complications in patients with advanced cancer, which significantly affects their quality of life and survival. Dysregulation of the JAK/STAT3 pathway in the central nervous system is associated with pain and brain inflammatory disorders, but its role in bone cancer pain (BCP) remains unclear. This study aimed to investigate the specific role of the JAK/STAT3 pathway in the amygdala in BCP.</div></div><div><h3>Methods</h3><div>A BCP rat model was established by intratibial injection of MRMT-1 carcinoma cells. Pain behavior was assessed using the mechanical withdrawal threshold, while depression-like behavior was assessed using the sucrose preference and forced swim test. Changes in inflammatory factors and related protein expression levels in the amygdala were detected using western blotting, immunofluorescence, and reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The effects of intra-amygdala injections of a lentivirus targeting retinoic acid-related orphan receptor γt (RORγt) (LV-shRORγt), nifuroxazide (a STAT3 antagonist), and colivelin (a STAT3 agonist) were evaluated.</div></div><div><h3>Results</h3><div>Rats with BCP demonstrated increased microglial activation in the amygdala. Rats experiencing RORγt knockout in the amygdala showed reduced microglial activation levels. Nifuroxazide reduced Th17 cell differentiation, potentially alleviating pain and depression-like behaviors. To further explore the underlying relationship between the JAK/STAT3 pathway and Th17 cells, LV-shRORγt and a STAT3 agonist were co-administered. The inhibitory effect of LV-shRORγt counteracted the STAT3 agonist’s active effects.</div></div><div><h3>Conclusions</h3><div>Our study showed that targeting JAK/STAT3 signaling alleviated pain- and depression-like behaviors in rats with BCP by inhibiting Th17 cell differentiation.</div></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":"221 ","pages":"Article 111218"},"PeriodicalIF":3.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143045617","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":"Working-memory load decoding model inspired by brain cognition based on cross-frequency coupling","authors":"Jing Zhang ,&nbsp;Tingyi Tan ,&nbsp;Yuhao Jiang ,&nbsp;Congming Tan ,&nbsp;Liangliang Hu ,&nbsp;Daowen Xiong ,&nbsp;Yikang Ding ,&nbsp;Guowei Huang ,&nbsp;Junjie Qin ,&nbsp;Yin Tian","doi":"10.1016/j.brainresbull.2025.111206","DOIUrl":"10.1016/j.brainresbull.2025.111206","url":null,"abstract":"<div><div>Working memory, a fundamental cognitive function of the brain, necessitates the evaluation of cognitive load intensity due to limited cognitive resources. Optimizing cognitive load can enhance task performance efficiency by preventing resource waste and overload. Therefore, identifying working memory load is an essential area of research. Deep learning models have demonstrated remarkable potential in identifying the intensity of working memory load. However, existing neural networks based on electroencephalogram (EEG) decoding primarily focus on temporal and spatial characteristics while neglecting frequency characteristics. Drawing inspiration from the role of cross-frequency coupling in the hippocampal region, which plays a crucial role in advanced cognitive processes such as working memory, this study proposes a Multi-Band Multi-Scale Hybrid Sinc Convolutional Neural Network (MBSincNex). This model integrates multi-frequency and multi-scale Sinc convolution to facilitate time-frequency conversion and extract time-frequency information from multiple rhythms and regions of the EEG data with the aim of effectively model the cross-frequency coupling across different cognitive domains. Due to its unique structural design, the proposed model proficiently extracts features in temporal, frequency, and spatial domains while its feature extraction capability is validated through post-hoc interpretability techniques. On our collected three-class working memory dataset, the proposed model achieved higher classification accuracy compared to other state-of-the-art methods. Furthermore, by analyzing the model’s classification performance during different stages of working memory processes, this study emphasizes the significance of the encoding phase and confirms that behavioral response does not accurately reflect cognitive load.</div></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":"221 ","pages":"Article 111206"},"PeriodicalIF":3.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143000577","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":"Electroacupuncture and Tongbian decoction ameliorate CUMS-induced depression and constipation in mice via TPH2/5-HT pathway of the gut-brain axis","authors":"Yi Chen ,&nbsp;Peihua Shen ,&nbsp;Qi Li ,&nbsp;Shun Seng Ong ,&nbsp;Yunzhi Qian ,&nbsp;Hai Lu ,&nbsp;Ming Li ,&nbsp;Tianshu Xu","doi":"10.1016/j.brainresbull.2025.111207","DOIUrl":"10.1016/j.brainresbull.2025.111207","url":null,"abstract":"<div><div>Depression is commonly associated with gastrointestinal (GI) disorders, such as constipation, which can potentially intensify depressive symptoms. The interplay between these conditions is believed to be facilitated by the gut-brain axis, which suggests a complex bidirectional interaction. Current treatments, such as antidepressants and prokinetics, are often associated with side effects and high recurrence rates, highlighting the need for effective treatments targeting both depression and constipation. This study was designed to assess the therapeutic efficacy of electroacupuncture (EA) in conjunction with Tongbian decoction (TB) for the management of both depression and constipation, while also investigating the underlying mechanisms through the lens of the gut-brain axis. Chronic unpredictable mild stress (CUMS) was employed to induce a comorbidity model of depression and constipation in mice, followed by the administration of EA, EA + TB, and fluoxetine (FLX). The findings of the study demonstrated that the antidepressant effects of electroacupuncture (EA) in combination with Tongbian decoction (TB) were more pronounced than those of EA alone. The EA + TB treatment significantly ameliorated depression and anxiety-like behaviors, restored cognitive function, and enhanced gastrointestinal motility in chronic unpredictable mild stress (CUMS) mice. Furthermore, EA + TB reduced intestinal inflammation, restored neuronal morphology, increased the expression of tryptophan hydroxylase 2 (TPH2) in both the prefrontal cortex (PFC) and colon, elevated the serum levels of 5-hydroxytryptophan (5-HTP)—a molecule that acts as a gut-brain connector—and promoted the synthesis and production of serotonin (5-HT) in both the gastrointestinal tract and the brain. Contrastingly, FLX showed limited efficacy in improving constipation. In conclusion, EA + TB regulates the TPH2/5-HT pathway via the gut-brain axis, demonstrating synergistic regulation of the nervous and gastrointestinal systems, with favorable antidepressant and prokinetic effects.</div></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":"221 ","pages":"Article 111207"},"PeriodicalIF":3.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143000595","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":"Automated quantification of axonal and myelin changes in contusion, dislocation, and distraction spinal cord injuries: Insights into targeted remyelination and axonal regeneration","authors":"Xuan Li ,&nbsp;Yuan He ,&nbsp;Fangyao Chen ,&nbsp;Xin Tong ,&nbsp;Yunlong Fan ,&nbsp;Yuzhe Langzhou ,&nbsp;Jie Liu ,&nbsp;Kinon Chen","doi":"10.1016/j.brainresbull.2025.111193","DOIUrl":"10.1016/j.brainresbull.2025.111193","url":null,"abstract":"<div><div>Quantifying axons and myelin is essential for understanding spinal cord injury (SCI) mechanisms and developing targeted therapies. This study proposes and validates an automated method to measure axons and myelin, applied to compare contusion, dislocation, and distraction SCIs in a rat model. Spinal cords were processed and stained for neurofilament, tubulin, and myelin basic protein, with histology images segmented into dorsal, lateral, and ventral white matter regions. Custom MATLAB scripts identified axons and myelin through brightness-based object detection and shape analysis, followed by an iterative dilation process to differentiate myelinated from unmyelinated axons. Validation showed a high correlation with manual counts of total and myelinated axons, with no significant differences between methods. Application of this method revealed distinct injury-specific changes: dislocation caused the greatest axonal loss, while distraction led to the lowest myelin-to-axon-area ratio, indicating preserved axons but severe demyelination. All injuries resulted in increased axon diameter and a decreased myelin-sheath-thickness-to-axon-diameter ratio, suggesting disrupted myelination. These results indicate that remyelination therapies may be most effective for distraction injuries, where preserved axons make remyelination crucial, while axonal regeneration therapies are likely better suited for dislocation injuries with extensive axonal loss. Contusion injuries, involving both axonal and myelin damage, may benefit from a combination of neuroprotective and remyelination strategies. These findings highlight the importance of tailoring treatments to the distinct pathophysiological features of each SCI type to optimize recovery outcomes.</div></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":"221 ","pages":"Article 111193"},"PeriodicalIF":3.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142944969","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":"Cortical excitability on sleep deprivation measured by transcranial magnetic stimulation: A systematic review and meta-analysis","authors":"Yihui Zhang ,&nbsp;Yuan Shi ,&nbsp;Ye Zhang,&nbsp;Jian Jiao,&nbsp;Xiangdong Tang","doi":"10.1016/j.brainresbull.2025.111190","DOIUrl":"10.1016/j.brainresbull.2025.111190","url":null,"abstract":"<div><div>Sleep deprivation is a common public problem, and researchers speculated its neurophysiological mechanisms related to cortical excitatory and inhibitory activity. Recently, transcranial magnetic stimulation combined with electromyography (TMS-EMG) and electroencephalography (TMS-EEG) have been used to assess cortical excitability in sleep-deprived individuals, but the results were inconsistent. Therefore, we conducted a meta-analysis to summarize relevant TMS-evoked indices of excitability and inhibition for exploring the cortical effects of sleep deprivation. In TMS-EMG studies, short-interval cortical inhibition (SICI) significantly decreased in sleep-deprived subjects; while the intracortical facilitation (ICF), resting motor threshold (RMT), and cortical silent period (CSP) were not significant compared to healthy controls. In TMS-EEG studies, the amplitude and slope of TMS-evoked potential (TEP) increased in sleep-deprived subjects. This study indicated that cortical inhibition decreased following sleep deprivation based on the TMS-EMG results and cortical excitability enhanced in the TMS-EEG results, supporting the disturbance of cortical excitability in sleep-deprived individuals.</div></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":"221 ","pages":"Article 111190"},"PeriodicalIF":3.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142930670","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":"MO-GCN: A multi-omics graph convolutional network for discriminative analysis of schizophrenia","authors":"Haiyuan Wang ,&nbsp;Runlin Peng ,&nbsp;Yuanyuan Huang ,&nbsp;Liqin Liang ,&nbsp;Wei Wang ,&nbsp;Baoyuan Zhu ,&nbsp;Chenyang Gao ,&nbsp;Minxin Guo ,&nbsp;Jing Zhou ,&nbsp;Hehua Li ,&nbsp;Xiaobo Li ,&nbsp;Yuping Ning ,&nbsp;Fengchun Wu ,&nbsp;Kai Wu","doi":"10.1016/j.brainresbull.2025.111199","DOIUrl":"10.1016/j.brainresbull.2025.111199","url":null,"abstract":"<div><div>The methodology of machine learning with multi-omics data has been widely adopted in the discriminative analyses of schizophrenia, but most of these studies ignored the cooperative interactions and topological attributes of multi-omics networks. In this study, we constructed three types of brain graphs (BGs), three types of gut graphs (GGs), and nine types of brain-gut combined graphs (BGCGs) for each individual. We proposed a novel methodology of multi-omics graph convolutional network (MO-GCN) with an attention mechanism to construct a classification model by integrating all BGCGs. We also identified important brain and gut features using the Top<em>k</em> pooling layer and analyzed their correlations with the Positive and Negative Syndrome Scale (PANSS) and MATRICS Consensus Cognitive Battery (MCCB) scores. The results showed that the novel MO-GCN model using BGCGs outperformed the GCN models using either BGs or GGs. In particular, the accuracy of the best model by 5-fold cross-validation reached 84.0 %. Interpretability analysis revealed that the top 10 important brain features were primarily from the hippocampus, olfactory, fusiform and pallidum, which were involved in the brain systems of memory, learning and emotion. The top 10 important gut features were primarily from <em>Dorea</em>, <em>Ruminococcus</em>, <em>Subdoligranulum</em> and <em>Clostridium</em>, etc. Moreover, the important brain and gut features were significantly correlated with the PANSS and MCCB scores, respectively. In conclusion, the MO-GCN can effectively improve the classification performance and provide a potential gut microbiota-brain perspective for the understanding of schizophrenia.</div></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":"221 ","pages":"Article 111199"},"PeriodicalIF":3.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142945052","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":"The emerging role of 12/15-lipoxygenase in ischemic stroke","authors":"Xuening Wang ,&nbsp;Qiuji Shao ,&nbsp;Yuan Gao","doi":"10.1016/j.brainresbull.2025.111194","DOIUrl":"10.1016/j.brainresbull.2025.111194","url":null,"abstract":"<div><div>The arachidonic acid metabolic pathway is a classic inflammatory pathway. 12/15-lipoxygenase (LOX), a member of the lipoxygenase family that metabolizes arachidonic acid, has been implicated in the pathogenesis of numerous central nervous system (CNS) diseases. Ischemic stroke is a devastating disease in which the occlusion of cerebral arteries leads to a series of pathophysiological changes in brain tissue, triggering an inflammatory cascade within the brain that results in neuroinflammation. Prior research has shown that 12/15-LOX levels in the brain are elevated following stroke. In this review, we elaborate on the key pathological mechanisms that unfold following ischemic stroke, including neuroinflammation, oxidative stress, neuronal apoptosis, and blood-brain barrier disruption, and present evidence demonstrating that 12/15-LOX inhibition could be used to treat ischemic stroke through various avenues. Furthermore, we list currently available inhibitors of 12/15-LOX and the preclinical or clinical applications, offering novel insights for the early diagnosis, prognosis evaluation, and targeted therapy in neurological diseases.</div></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":"221 ","pages":"Article 111194"},"PeriodicalIF":3.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142945053","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":"Neurological function is restored post-ischemic stroke in zebrafish, with aging exerting a deleterious effect on its pathology","authors":"Takamasa Mizoguchi ,&nbsp;Ayumi Maki ,&nbsp;Yuno Nakase ,&nbsp;Mayu Okita ,&nbsp;Yuina Minami ,&nbsp;Misa Fukunaga ,&nbsp;Motoyuki Itoh","doi":"10.1016/j.brainresbull.2025.111225","DOIUrl":"10.1016/j.brainresbull.2025.111225","url":null,"abstract":"<div><div>Ischemic stroke (IS) is a pathological condition characterized by the cessation of blood flow due to factors such as thrombosis, inflicting severe damage to the cranial nervous system and resulting in numerous disabilities including memory impairments and hemiplegia. Despite the critical nature of this condition, therapeutic options remain limited, with a pressing challenge being the development of treatments aimed at restoring neurological function. In this study, we leveraged zebrafish, renowned for their exceptional regenerative capabilities, to analyze the pathology of IS and the subsequent recovery process. We induced photothrombosis in the telencephalon utilizing rose bengal and conducted a temporal investigation of changes in cerebral vascular function and learning ability. Our findings revealed that blood flow in young zebrafish was restored approximately 7 days post-IS induction (dpi), with brain function recuperating by 14 dpi. Furthermore, we observed an escalation in the expression of the neural stem marker gene at 3dpi, followed by an upregulation of the differentiated neuron marker at 7 and 14dpi. In the aged IS model, symptoms were exacerbated. While cerebral blood flow was restored in 7 days, similar to young zebrafish, the recovery of learning ability was protracted in aged fish. Moreover, an upregulation of the differentiated neuron marker seen in young fish was not observed in the aged model. Collectively, our analysis of the zebrafish IS model and its comparison with existing rodent models may lay the groundwork for novel IS treatment strategies. Furthermore, the zebrafish IS model may prove beneficial for analyzing the impact of aging on the pathology of IS and the recovery process.</div></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":"221 ","pages":"Article 111225"},"PeriodicalIF":3.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143045623","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":"Inhibition of platelet activation alleviates diabetes-associated cognitive dysfunction via attenuating blood-brain barrier injury","authors":"Fuxing Xu ,&nbsp;Juan Hu ,&nbsp;Xuying Li ,&nbsp;Lan Yang ,&nbsp;Shiqiu Jiang ,&nbsp;Tao Jiang ,&nbsp;Bo Cheng ,&nbsp;Hailiang Du ,&nbsp;Ruiduo Wang ,&nbsp;Yingying Deng ,&nbsp;Wei Gao ,&nbsp;Yansong Li ,&nbsp;Yaomin Zhu","doi":"10.1016/j.brainresbull.2025.111211","DOIUrl":"10.1016/j.brainresbull.2025.111211","url":null,"abstract":"<div><div>Cognitive dysfunction has become the second leading cause of death among the diabetic patients. In pre-diabetic stage, blood-brain barrier (BBB) injury occurs and induced the microvascular complications of diabetes, especially, diabetes-associated cognitive dysfunction (DACD). Endothelial cells are the major component of BBB, on which the increased expression of CD40 could mediate BBB dysfunction in diabetics. Since platelets play an important role in regulating endothelial cell barrier function and over 95 % of the circulating soluble CD40 ligand (sCD40L) is derived from activated platelets, we speculated that the release of CD40L from activated platelets induced by diabetes was the key mechanism that aggravated BBB injury and leaded to DACD. We performed inhibition of platelet activation on diabetic and non-diabetic mice, with or without cilostazol treatment, and then compared cognitive function, platelet activation, BBB structure and permeability. In vitro, mouse brain microvascular endothelial cell line (b.End3) were exposed to CD40L for 24 h at 5.5 mM or 30 mM glucose media after silencing CD40 and HIF1α or not to investigate the effects of CD40 on BBB disruption and the underlying molecular pathways. Inhibition of platelet activation improved cognitive behaviors in diabetic mice, accompanied with reduced BBB permeability, increased tight junction proteins, balanced Aβ transporters, as well as attenuated Aβ deposition and hippocampal neurons damage. <em>In vitro</em>, CD40L increased HIF1α, diminished tight junction proteins and dysregulated Aβ transporters in b.End3 cells, which could be restored by CD40 siRNA and HIF1α siRNA. Hence, inhibition of platelet activation ameliorates DACD via alleviating BBB injury, which involving the regulation of CD40L-CD40-HIF1α signaling pathway. Our study may demonstrate a potential therapeutic target for the treatment of DACD.</div></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":"221 ","pages":"Article 111211"},"PeriodicalIF":3.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143000476","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}