Molecular Neurobiology最新文献

{"title":"The Role of Choroid Plexus in Hydrocephalus from the Perspective of Structure and Function: a Therapeutic Target.","authors":"Ziang Deng, Haoxiang Wang, Kunhong Zhong, Yuanyou Li, Huajiang Deng, Baocheng Gao, Keru Huang, Aiping Tong, Liangxue Zhou","doi":"10.1007/s12035-025-04823-7","DOIUrl":"10.1007/s12035-025-04823-7","url":null,"abstract":"<p><p>Hydrocephalus is one of the most common neurological diseases, characterized by abnormal excessive accumulation of cerebrospinal fluid (CSF) in the ventricular system. Its pathophysiological mechanism is believed to be related to the imbalance of CSF circulation and homeostasis. As the main source of CSF secretion, the choroid plexus is closely related to hydrocephalus. The choroid plexus is a specialized vascularized tissue located within the cerebral ventricles. It has multiple physiological functions including regulating CSF, immune response, endocrine metabolism, etc. Strategies that reduce choroid plexus CSF secretion have been shown to be effective in the treatment of hydrocephalus. However, the role of other physiological functions of the choroid plexus in hydrocephalus is still unclear. Recent studies on the choroid plexus and the blood-CSF barrier have deepened our understanding of the structure and function of the choroid plexus. The idea of targeting the choroid plexus to treat hydrocephalus has spawned many branches: choroid plexus epithelial cells, choroid plexus immune cells, choroid plexus peptides, and choroid plexus cilia, etc. This review introduces the basic structure and function of the choroid plexus, summarizes their changes in hydrocephalus, and analyzes the possibility of the choroid plexus as a therapeutic target for hydrocephalus.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"9133-9150"},"PeriodicalIF":4.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143630630","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GDF11 Regulates M1 and M2 Polarization of BV2 Microglial Cells via p38 MAPK Signaling Pathway.","authors":"Xiangyu Zhao, Rui Qin, Guopeng Li, Gaorong Lv, Di Zhao, Linghua Kong, Meiling Qi, Ping Li","doi":"10.1007/s12035-025-04837-1","DOIUrl":"10.1007/s12035-025-04837-1","url":null,"abstract":"<p><p>Growth differentiation factor 11 (GDF11), a member of the transforming growth factor β (TGF-β) superfamily, exhibits great neurological and mental diseases modulating potential. However, its specific effects on microglia, which are the primary immune cells of the nervous system, remain unclear. To investigate the mechanism by which GDF11 affects BV2 microglial cells in vitro and to elucidate its regulatory mechanisms, we carried out a systematic examination of how GDF11 affects the various functions of lipopolysaccharide (LPS)-induced BV2 microglial cells and found that endogenous GDF11 could significantly inhibit cell proliferation, apoptosis, and migration. Specifically, GDF11 inhibited the polarization of BV2 cells to the proinflammatory M1 phenotype and promoted their polarization to the anti-inflammatory M2 phenotype, precipitating a reduction in the expression of CD86 and nitric oxide synthase 2 (NOS2), and an increase in the expression of CD206 and arginase-1. Additionally, RNA-seq and Western blotting experiments revealed that GDF11 activated the p38 MAPK (mitogen-activated protein kinase) pathway, mediating its effects on BV2 cells. Taken together, GDF11 could crucially regulate microglial responses and promote an anti-inflammatory microglial phenotype through the p38 MAPK signaling axis, which may have potential therapeutic implications in neuroinflammatory diseases.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"9290-9305"},"PeriodicalIF":4.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143657814","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cannabinoid Receptor-2 Alleviates Sepsis-Induced Neuroinflammation by Modulating Microglia M1/M2 Subset Polarization Through Inhibiting Nogo-B Expression.","authors":"Shuxian Chen, Zhen Li, Liu Yang, Zujin Xu, Anpeng Liu, Qianwen He, Fei Xiao, Jia Zhan","doi":"10.1007/s12035-025-04836-2","DOIUrl":"10.1007/s12035-025-04836-2","url":null,"abstract":"<p><p>Few studies have investigated how Nogo-B affects sepsis-associated encephalopathy (SAE). Cannabinoid receptor 2 (CB2R) plays a critical role in regulating M1/M2 polarization in microglia. This study aimed to explore the association between CB2R and Nogo-B by assessing changes in microglial polarization markers.C57BL/6 mice with SAE induced by cecal ligation and puncture (CLP) surgery were intraperitoneally injected with HU308 for 3 consecutive days at the same time after that, and changes in cognitive function were assessed. After Lipopolysaccharides (LPS) and Interleukin-4 (IL-4) were used to induce BV2 microglial cell models respectively, HU308 and AM630 were applied to assess changes in inflammatory factors, microglial polarization markers, and the expression levels of CB2R and Nogo-B in microglial cells. We established a stable Nogo-B overexpression cell line. ELISA, Western blot, and flow cytometry were utilized to verify whether Nogo-B is a crucial protein in controlling BV2 cell polarization by HU308. There was an increase in Nogo-B protein expression during SAE. HU308 treatment alleviated the cognitive impairment of the CLP mice and markedly decreased the level of Nogo-B in the hippocampus tissues. The efficacy of CB2R activation to promote microglia polarization from M1 to M2 was diminished in BV2 cells overexpressing Nogo-B, although its anti-inflammatory effect was not entirely reversed. Inhibiting the Nogo-B expression, which in turn encourages the conversion of BV2 microglia to M2, attenuates inflammatory responses, and promotes neuronal repair, could be a key mechanism whereby activation of CB2R ameliorates septic encephalopathy.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"9258-9270"},"PeriodicalIF":4.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143657700","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Preoperative Sleep Deprivation Exacerbates Anesthesia/Surgery-induced Abnormal GABAergic Neurotransmission and Neuronal Damage in the Hippocampus in Aged Mice.","authors":"Yun Li, Siwen Long, Jiafeng Yu, Jingyu Feng, Shuqi Meng, Yize Li, Lina Zhao, Yonghao Yu","doi":"10.1007/s12035-025-04851-3","DOIUrl":"10.1007/s12035-025-04851-3","url":null,"abstract":"<p><p>Older adults with anesthesia and surgery often suffer from postoperative cognitive dysfunction (POCD), which puts a heavy burden on rehabilitation. Preoperative sleep disorder, a common phenomenon in elderly anesthesia patients, is closely associated with POCD, but the underlying mechanism is still not fully understood. Hippocampal gamma-aminobutyric acid (GABA)ergic neurotransmission has been reported to play an important role in sleep disorder and cognitive impairment. The aim of this study was to elucidate the effect of preoperative acute sleep deprivation (SD) on anesthesia/surgery-induced POCD and the potential mechanism of hippocampal GABAergic neurotransmission. In the aged (18-20-month-old) male mice, we used a rotating rod to deprive sleep for 24 h and induced a POCD model using sevoflurane exposure combined with laparotomy exploration. A sequential set of behavioral tests, including open field test (OFT), Y-maze, and novel object recognition (NOR), was conducted to assess cognitive performances. In vivo magnetic resonance imaging (MRI) technique was used to observe hippocampal axonal microstructural changes. The levels of GABAergic neurotransmitter markers glutamic acid decarboxylase (GAD) 67, vesicular GABA transporter (VGAT), GABA transporter (GAT)-1, and GABA in the hippocampus were detected with enzyme-linked immunosorbent assay (ELISA). The reactivity of GABAergic neurons and neuronal damage in different subregions of the hippocampus were observed by immunofluorescence and Nissl staining, respectively. Compared the anesthesia/surgery (A/S) mice, 24-h SD combined with A/S induced shorter stay time in the central area of the open field, less the percent of novel arm preference in the Y maze, and lower recognition index in the NOR, as well as significantly enhanced hippocampal GABAergic neurotransmission, decreased hippocampal axonal integrity and density, and increased GAD67 reactivity and reduced the number of neurons in hippocampal CA1. Preoperative 24-h SD exacerbated anesthesia/surgery-induced POCD in aged mice, with the cumulative effect of abnormal GABAergic neurotransmission and neuronal damage in the hippocampus.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"9385-9398"},"PeriodicalIF":4.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143663990","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synergistic Sedative Activity of Indirubin on Diazepam in Thiopental Sodium-induced Sleeping Mice: A Potential GABAergic Transmission.","authors":"Tamanna Khatun, Abdul Malik, Abdullah K Alshememry, Rubel Hasan, Md Shimul Bhuia, Raihan Chowdhury, Sabiha Fatima, Dipu Bishwas, Sonaly Akter Mukty, Ishrat Jahan Disha, Mehedi Hasan Bappi, Muhammad Torequl Islam","doi":"10.1007/s12035-025-05176-x","DOIUrl":"https://doi.org/10.1007/s12035-025-05176-x","url":null,"abstract":"<p><p>Insomnia remains one of the most common sleep disorders and causes significant discomfort as well as impairment in social, interpersonal, and vocational aspects of life. This study focuses on assessing the sedative activity of indigo naturalis indirubin (IND) on thiopental sodium (TS)-induced sleeping mice and evaluating the underlying molecular mechanisms through an in silico study. The adult male Swiss albino mice were used and given IND (5 and 10 mg/kg, i.p.), and diazepam (DZP) (2 mg/kg) in the respective groups individually and in combination to investigate modulatory effects. After 30 min, the treated mice were given TS (20 mg/kg, i.p.) to promote sleep, and the latency and duration of sleep were recorded manually. The in vivo study revealed that a higher dose of test sample (IND-10 mg/kg) showed lower latency and higher sleeping duration than a lower dose. Furthermore, an in silico study was performed to predict the involvement of gamma-aminobutyric acid (GABA) receptors in the sleep mechanism and assess pharmacokinetics and toxicity. Findings revealed that IND increased the duration of sleeping and decreased the latency of sleep induction. Additionally. the combination therapy of IND and DZP demonstrated synergistic sedative activity, as indicated by a greater reduction in locomotor activity and increased duration of sedation compared to either drug alone. IND exhibited a higher binding affinity (-9.1 kcal/mol) than DZP (-8.3 kcal/mol) at the identical binding site in the in silico study. The pharmacokinetic analysis of IND indicated acceptable drug-likeness and good pharmacokinetic properties. In conclusion, IND produced a potent sedative effect in the mouse model, possibly through the GABA_A receptor interaction pathways.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144540961","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Caloric Restriction Attenuated Nerve Damages Mediated Through SIRT-1-a Study Using Nerve Crush Injury Model in Rats.","authors":"Meei-Ling Sheu, Liang-Yi Pan, Szu-Yen Pan, Ying Ju Chen, Jason Sheehan, Weir-Chiang You, Chien-Chia Wang, Hung-Chuan Pan","doi":"10.1007/s12035-025-04786-9","DOIUrl":"10.1007/s12035-025-04786-9","url":null,"abstract":"<p><p>Activation of Sirtuin 1 (SIRT-1) is vital for axonogenesis and nerve regeneration. Caloric restriction (CR) has health benefits and protects against neurodegenerative disorders, largely through SIRT-1 regulation. This study investigates how diet control impacts peripheral nerve injury, focusing on SIRT-1 expression. We prepared nerve tissue cultures for a pharmacological analysis of SIRT-1's effects on nerve degeneration. After two weeks of 70% caloric restriction, we crushed the left sciatic nerve of Sprague-Dawley rats with a vessel clamp. We then administered SIRT-1 agonists or antagonists intraperitoneally. Nerve explant cultures showed increased SIRT-1 expression with SRT-1720, which was reduced by EX527, indicating enhanced regeneration. In the animal study, diet control led to notable SIRT-1 expression in plasma. This expression increased with SIRT-1 agonists and decreased with antagonists. SIRT-1 levels in paw skin were strongly correlated with PGP 9.5 and collagen deposition, while nerve fiber size and regeneration markers (S-100 and NF) also correlated with SIRT-1 expression. Inflammatory markers showed an inverse relationship with SIRT-1. TNF-α and NGF in the dorsal root ganglion responded reciprocally to SIRT-1 expression. Increased acetylcholine receptors and desmin in denervated muscle were parallel to SIRT-1 levels, with similar trends observed in muscle weight and diameter. Neurobehavioral and electrophysiological results aligned with these measurements. Caloric restriction has a preventative effect on nerve damage, mainly through SIRT-1 modulation. From a health perspective, promoting caloric restriction is important for mitigating nerve injury severity.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"8261-8278"},"PeriodicalIF":4.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12209400/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143492918","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MiR-124 Delivered by Extracellular Vesicles from Mesenchymal Stem Cell Exerts Neuroprotective Effects by Stabilizing the p62-Keap1-Nrf2 Pathway after Spinal Cord Injury in Rats.","authors":"Chao Fang, Jun Qian, Bi-Zhi Tu, Xiang Xia, Chong-Yu Jia, Cai-Liang Shen","doi":"10.1007/s12035-025-04755-2","DOIUrl":"10.1007/s12035-025-04755-2","url":null,"abstract":"<p><p>Spinal cord injury (SCI) can cause irreversible trauma to nervous tissue, leading to permanent damage to the patient's motor and sensory functions. Extracellular vesicles derived from mesenchymal stem cells (MSC-EVs) can simulate most of the functions of MSCs and are considered an ideal treatment option for SCI. However, the potential mechanism of MSC-EVs treatment for SCI still needs to be explored. We cultured neurons in vitro to investigate the effect of miR-124 on the p62-Keap1-Nrf2 pathway. Besides, MSC-EVs containing miR-124 were injected into a rat spinal cord injury model to observe their neural repair effect. The accumulation of p62 can be reversed by miR-124, which promotes autophagy and alleviates oxidative stress, thereby exerting neuroprotective effects. Rats who received injection of MSC-EVs overexpressing miR-124 after surgery showed higher BBB scores, lower levels of cell apoptosis, and better spinal cord tissue morphology. Our results indicated that miR-124 can stabilize the p62-Keap1-Nrf2 loop, thereby promoting autophagy and alleviating oxidative stress to exert neuroprotective effects. Our research proposes a novel potential target for treating SCI.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"8328-8340"},"PeriodicalIF":4.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12208983/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143483597","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pectolinarin Promotes Functional Recovery after Spinal Cord Injury by Regulating Microglia Polarization Through the PI3K/AKT Signaling Pathway.","authors":"Chenggui Wang, Jiawei Li, Chenyu Wu, Zhouwei Wu, Zhichen Jiang, Chenglong Hong, Juntao Ying, Fancheng Chen, Qi Yang, Hui Xu, Sunren Sheng, Yongzeng Feng","doi":"10.1007/s12035-025-04793-w","DOIUrl":"10.1007/s12035-025-04793-w","url":null,"abstract":"<p><p>After spinal cord injury (SCI), microglia polarization plays an important role in spinal cord recovery and axon regeneration. In this study, we conducted mRNA microarrays to identify genes associated with different microglial phenotypes. The results showed a correlation between microglial polarization and the PI3K/AKT signaling pathway, a key regulator of inflammatory responses. In addition, we found that Pectolinarin (PTR) could effectively inhibit lipopolysaccharide (LPS)-induced M1 polarization of microglia and facilitate their transition to the M2 phenotype by directly suppressing the PI3K/AKT signaling pathway. In our established animal model of SCI, it was confirmed that PTR treatment induced microglial polarization towards the M2 phenotype, resulting in reduced fibrous scar formation, enhanced myelin reconstitution, and improved axonal regeneration. In conclusion, targeting the PI3K/AKT signaling pathway with PTR presents a promising new direction for SCI treatment.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"8587-8602"},"PeriodicalIF":4.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143516194","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deep Hypothermic Low Flow Results in Multiple Aspects of Neurological Deficits in Mice by eEF2 Hyperphosphorylation.","authors":"Yumei Liao, Dongyang Che, Peng Liu, Xinyu Wang, Yanlin Zhang, Lingling Guo, Jinlin Hu, Tianyao Li, Mei Fong Lam, Nan Ma, Shiqing Zhang, Hua Lu, Lei Shi, Xiaoshen Zhang","doi":"10.1007/s12035-025-04784-x","DOIUrl":"10.1007/s12035-025-04784-x","url":null,"abstract":"<p><p>Postoperative neurological dysfunction is a common complication caused by deep hypothermia with cerebral hypoperfusion during aortic arch surgery, but the exact pathological changes and molecular mechanisms are not yet clear. In this study, we established an adult mouse model of deep hypothermic low flow (DHLF) to simulate the ischemic-reperfusion brain injury during aortic arch surgery. The DHLF-modeled mice showed significant neurological and cognitive dysfunction, accompanied by reduced dendritic spine density and increased glial cell activation in the hippocampus and cortex. DHLF induced proteomic changes primarily involved in synaptic organization in the hippocampus and cortex, with AMPA and NMDA receptor subunits and synaptic activity-dependent proteins markedly downregulated in the hippocampus and/or cortex. Moreover, DHLF also resulted in altered proteome in mRNA translation and inhibition of eukaryotic elongation factor 2 (eEF2), a crucial regulator of translational elongation whose activity is negatively regulated via phosphorylation by eEF2 kinase (eEF2K). Importantly, the administration of the small-molecular eEF2K inhibitor A484954 ameliorated DHLF-induced neurobehavioral dysfunction, dendritic spine reduction, and glial cell activation, suggesting that eEF2K/eEF2 may be a promising therapeutic target in DHLF-induced neurological injury. Our findings revealed new evidence of pathological features, molecular mechanism, and intervention of DHLF-induced cerebral ischemia-reperfusion injury, providing promising insight for developing strategies on reducing postoperative neurological complications after aortic arch surgery.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"8568-8586"},"PeriodicalIF":4.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143516193","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of Peripheral NLRP3 Inflammasome in Cognitive Impairments: Insights of Non-central Factors.","authors":"Mengfan Qiao, Junjun Ni, Hong Qing, Yunjie Qiu, Zhenzhen Quan","doi":"10.1007/s12035-025-04779-8","DOIUrl":"10.1007/s12035-025-04779-8","url":null,"abstract":"<p><p>Cognitive impairments are common clinical manifestation of Alzheimer's disease, vascular dementia, type 2 diabetes mellitus, and autoimmune diseases. Emerging evidence has suggested a strong correlation between peripheral chronic inflammation and cognitive impairments. For example, nearly 40% of individuals with inflammatory bowel disease also suffer from cognitive impairments. In this condition, NLRP3 inflammasome (NLRP3-I) generating pro-inflammatory cytokines like IL-1β serves as a significant effector, and its persistence exerts adverse effects to both periphery and the brain. Moreover, investigations on serum biomarkers of mild cognitive impairments have shown NLRP3-I components' upregulation, suggesting the involvement of peripheral inflammasome pathway in this disorder. Here, we systematically reviewed the current knowledge of NLRP3-I in inflammatory disease to uncover its potential role in bridging peripheral chronic inflammation and cognitive impairments. This review summarizes the molecular features and ignition process of NLRP3-I in inflammatory response. Meanwhile, various effects of NLRP3-I involved in peripheral inflammation-associated disease are also reviewed, especially its chronic disturbances to brain homeostasis and cognitive function through routes including gut-brain, liver-brain, and kidney-brain axes. In addition, current promising compounds and their targets relative to NLRP3-I are discussed in the context of cognitive impairments. Through the detailed investigation, this review highlights the critical role of peripheral NLRP3-I in the pathogenesis of cognitive disorders, and offers novel perspectives for developing effective therapeutic interventions for diseases associated with cognitive impairments. The present review outlines the current knowledge on the ignition of NLRP3-I in inflammatory disease and more importantly, emphasizes the role of peripheral NLRP3-I as a causal pathway in the development of cognitive disorders. Although major efforts to restrain cognitive decline are mainly focused on the central nervous system, it has become clear that disturbances from peripheral immune are closely associated with the dysfunctional brain. Therefore, attenuation of these inflammatory changes through inhibiting the NLRP3-I pathway in early inflammatory disease may reduce future risk of cognitive impairments, and in the meantime, considerations on such pathogenesis for combined drug therapy will be required in the clinical evaluation of cognitive disorders.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"8420-8438"},"PeriodicalIF":4.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143502671","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}