Current Neuropharmacology最新文献

{"title":"Therapeutic Targeting of IL-33 in Ischemia-Reperfusion Injury: Progress and Prospects.","authors":"Dong-Heng Yang, Dai-Qiang Liu, Xi-Jian Ke, Nan Chen, Ya-Qun Zhou","doi":"10.2174/011570159X516426260907110654","DOIUrl":"https://doi.org/10.2174/011570159X516426260907110654","url":null,"abstract":"<p><p>Ischemia-Reperfusion Injury (IRI) is a prototypical sterile inflammatory process that complicates solid-organ transplantation, reperfusion therapy for acute myocardial infarction, and revascularization procedures. Clinical management relies largely on supportive and procedural measures; no specific targeted therapy is available. Interleukin-33 (IL-33), a multifunctional member of the IL-1 cytokine family, is constitutively localized to the nucleus in several structural cell types and acts extracellularly as an alarmin after release. The IL-33/ST2 signaling axis has been implicated in multiple phases of IRI. This review describes the conserved core of the IL-33/ST2 signaling cascade. It also examines the regulatory mechanisms and functional heterogeneity of IL-33 across six major IRI-susceptible organ systems: the cardiovascular system, kidney, liver, lung, brain, and gastrointestinal tract. Available evidence suggests a recurrent but not universal pattern: IL-33 can amplify acute sterile inflammation in some organs and models, yet support inflammation resolution and tissue repair in other settings or at later stages. The effects of IL-33 depend on the organ involved, the cellular source of IL-33, the spatial distribution of ST2-expressing target cells, the local microenvironment, and the phase of injury and timing of intervention. This review summarizes recent preclinical advances in IL-33/ST2-targeted strategies and discusses the principal challenges to their clinical translation. These include limited human efficacy and safety data, the lack of clinically feasible intervention strategies, and the absence of validated companion biomarkers. The IL-33/ST2 axis may be an organ- and context-specific therapeutic target for IRI, but further validation is required before clinical application.</p>","PeriodicalId":10905,"journal":{"name":"Current Neuropharmacology","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149036674","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":"GABA Signaling in Glioma: Paradoxes and Therapeutic Perspectives.","authors":"Zhao-Qi Tang, Jing Pan, Shoutang Wang, Hong-Bin Xu","doi":"10.2174/011570159X500457260911110701","DOIUrl":"https://doi.org/10.2174/011570159X500457260911110701","url":null,"abstract":"<p><p>Glioma is the most common primary malignant brain tumor in adults and is characterized by an extremely poor prognosis. A distinctive feature of glioma is its profound dependence on the unique brain microenvironment. Gamma-Aminobutyric Acid (GABA), the principal inhibitory neurotransmitter in the central nervous system, has been implicated in the regulation of glioma pathophysiology. However, evidence regarding its influence on tumor progression remains highly contradictory. Current findings indicate that GABA can exert either tumor-suppressive or tumor-promoting effects depending on multiple interconnected factors, including Isocitrate Dehydrogenase 1 (IDH1) mutation status, intracellular chloride ion concentration governed by Na+-K+-Cl- Cotransporter 1 (NKCC1) and K+-Cl- Cotransporter 2 (KCC2) transporters, heterogeneous GABAA and GABAB receptor expression patterns, and dynamic glioma-neuron synaptic interactions. Among these, the NKCC1/KCC2 balance emerges as a central molecular switch governing intracellular chloride homeostasis and, consequently, the functional polarity of GABAA receptor activation. This review provides a comprehensive overview of the complex and paradoxical roles of GABA signaling in glioma biology, with particular emphasis on dysregulated GABA synthesis and catabolism as well as divergent GABA receptor-mediated mechanisms. Furthermore, we discuss potential explanations for the conflicting findings reported in the literature and highlight promising therapeutic targets within the GABAergic system, including metabolic enzymes, chloride cotransporters, and specific receptor antagonists that may be exploited for clinical intervention.</p>","PeriodicalId":10905,"journal":{"name":"Current Neuropharmacology","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149036985","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":"The Interaction Between Gut Microbiota and Neuroinflammation in the Gut-Brain Axis of Autism Spectrum Disorder.","authors":"Cong Hu, Heli Li, Yunjie Li, Shan Huang, Wenjia Wang, Feiyan Zhang, Yu Zhao, Yan Hao","doi":"10.2174/011570159X478343260906114952","DOIUrl":"https://doi.org/10.2174/011570159X478343260906114952","url":null,"abstract":"<p><p>Autism Spectrum Disorder (ASD) is characterized primarily by social deficits and repetitive behaviors, often accompanied by gastrointestinal dysfunction. Its etiology involves interactions among genetic, environmental, and biological factors. Current studies indicate that neuroinflammation and gut microbiota imbalance are key factors in the development of ASD. Neuroinflammation is characterized by elevated levels of pro-inflammatory factors and abnormal glial cell activation, whereas gut microbiota imbalance is evidenced by dysbiosis and compromised intestinal barrier function. The gut-brain axis regulates neuroinflammation and synaptic function through pathways such as short-chain fatty acids (SCFAs), tryptophan metabolism, γ-aminobutyric acid (GABA) metabolism, and the hypothalamic-pituitary-adrenal (HPA) axis. Although modulation of the microbiota, for example, fecal microbiota transplantation (FMT) and probiotics, could improve ASD symptoms by repairing the intestinal barrier and alleviating neuroinflammation, the molecular mechanisms underlying these effects remain to be elucidated. This article reviews the interaction between gut microbiota and neuroinflammation in ASD, aiming to provide insights for treatment and research.</p>","PeriodicalId":10905,"journal":{"name":"Current Neuropharmacology","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149036714","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":"Therapeutic Strategies Targeting TREM2 for Alzheimer's Disease: Current Advances and Future Perspectives.","authors":"Yixiang Yu, Yanji Xu, Meihua Xu","doi":"10.2174/011570159X509125260907101247","DOIUrl":"https://doi.org/10.2174/011570159X509125260907101247","url":null,"abstract":"<p><strong>Background: </strong>Alzheimer's disease is a progressive neurodegenerative disorder characterized by cognitive decline and protein aggregation. The Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) has been identified as a key regulator of pathogenesis. This review summarizes current understanding of the receptor's structure, ligands, signaling, roles in disease, and therapeutic targeting strategies.</p><p><strong>Methods: </strong>A structured narrative review was conducted using targeted searches of PubMed, Web of Science, and Scopus, supplemented by citation tracking and searches of ClinicalTrials.gov.</p><p><strong>Results: </strong>TREM2 is a microglial immunoreceptor that recognizes apolipoprotein E and amyloid-β. Through the canonical DAP12-SYK axis, TREM2 regulates microglial phagocytosis, metabolism, and inflammatory responses. In Alzheimer's disease, it modulates amyloid-β clearance, tau hyperphosphorylation, and neuroinflammation in a stage-dependent manner. Loss-of-function variants increase disease risk. Therapeutic strategies include direct membrane-TREM2 agonistic antibodies, shedding-modifying antibody fragments, soluble TREM2-based approaches, gene-delivery platforms, small-molecule agonists, and indirect TREM2-associated natural-product modulators. These approaches differ in target-binding evidence, TREM2 dependence, disease-model relevance, safety, and clinical maturity.</p><p><strong>Discussion: </strong>TREM2 functions within a context-dependent framework in which gene dosage, disease stage, pathological substrate, microglial state, and activation duration jointly determine protective or maladaptive outcomes. Therapeutic modalities differ in specificity, brain exposure, reversibility, and translational readiness, while target engagement alone does not guarantee clinical benefit.</p><p><strong>Conclusions: </strong>TREM2 remains a promising but context-sensitive therapeutic target. Successful translation will require controllable modulation, stage- and pathology-specific treatment windows, biomarkers of functional response, and patient stratification according to genotype, amyloid-β and tau burden, and microglial state.</p>","PeriodicalId":10905,"journal":{"name":"Current Neuropharmacology","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149036709","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":"Crosstalk and Convergence in Alzheimer's Disease: Integrating Brain Injury, Neuroinflammation, and Precision Medicine for Next-Generation Therapeutics.","authors":"Desh Deepak Singh","doi":"10.2174/011570159X488166260907100652","DOIUrl":"https://doi.org/10.2174/011570159X488166260907100652","url":null,"abstract":"<p><p>Alzheimer's Disease (AD) is a complex disorder whose underlying biology is not fully explained by traditional single-pathway models. For several decades, research has largely focused on the roles of amyloid-β and tau in the formation and deposition of plaques and neurofibrillary tangles associated with AD pathology and neurodegeneration. Despite this sustained focus, therapeutic strategies targeting amyloid-β and tau alone have shown limited success in altering the natural course of the disease. Accordingly, there is a clear need for an adaptive and integrative framework that better captures the heterogeneity and dynamic nature of disease progression over time. This review proposes conceptualizing Alzheimer's disease as a neural circuit disorder that emerges from sustained crosstalk among multiple interacting pathways, including brain injury, neuroinflammation, mitochondrial and metabolic dysfunction, neurovascular dysfunction (impaired supply chain), synaptic dysfunction, and individual vulnerability. Evidence is presented to illustrate (1) how the traumatic and chronic nature of brain injury predisposes the brain to persistent inflammation and neurodegeneration; (2) how astrocytic and microglial activation states contribute to synaptic dysfunction and neuronal damage; and (3) how pathological interactions among amyloid pathology, tau dysregulation, and immune signaling collectively exacerbate neuroinflammatory responses and accelerate disease progression in AD.</p>","PeriodicalId":10905,"journal":{"name":"Current Neuropharmacology","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149036901","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":"Roles of the Neuregulin 1/ErbB4 Signaling Pathway in the Pathogenesis of Autism Spectrum Disorder.","authors":"Ziwei Du, Liping Ma, Bingyan Peng, Fengge Shen, Xianwei Wang, Yinghua Zhang","doi":"10.2174/011570159X479511260904044527","DOIUrl":"https://doi.org/10.2174/011570159X479511260904044527","url":null,"abstract":"<p><p>Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder that first manifests in the early stages of childhood. The exact underlying mechanism of ASD remains unknown, and its etiology is rather complex. Neuronal migration, cognitive development, and continuous neural plasticity are strongly influenced by the Neuregulin 1 (NRG1)/ErbB4 signaling pathway. Hence, the pathogenesis of ASD may be closely connected to dysfunction of the NRG1/ErbB4 pathway. According to our current review, either the activation or inhibition of this pathway can lead to the development of ASD, and GABAergic system dysfunction can result in ASD-like behaviors. Moreover, NRG1 binds to ErbB to promote GABA release, and abnormal NRG1 activity affects GABAergic neuron development and function, thus impairing cognition and social interactions. Additionally, the activity of the PI3K/AKT/mTOR pathway differs in various brain regions, and its activation or inhibition can lead to the development of ASD. By activating ErbB CTY-1, NRG1 promotes the development of neurodevelopmental disorders through further activation of the PI3K/AKT/mTOR pathway. Therefore, the NRG1/ErbB4 pathway can regulate GABAergic system functions and affect the activity of the PI3K/AKT/mTOR pathway, thereby resulting in abnormal social interactions and cognitive impairment. Targeting dysfunctions of the GABAergic system, the PI3K/AKT/mTOR pathway, and the NRG1/ErbB4 pathway are currently promising strategies for the treatment of ASD. Candidate agents that modulate these pathways have been shown to be effective in preclinical animal models. However, the limitations of these models and the considerable etiologic and phenotypic heterogeneity among patients with ASD continue to hinder their clinical translation. This article reviews evidence suggesting that the pathogenesis of ASD is closely associated with the NRG1/ErbB4 signaling pathway, the GABAergic system, and the PI3K/AKT/mTOR pathway. This article also analyzes the main obstacles to pharmacological interventions and provides a theoretical basis for understanding the pathogenesis of ASD and for identifying potential targets for future therapeutic strategies.</p>","PeriodicalId":10905,"journal":{"name":"Current Neuropharmacology","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149036972","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":"Mapping Cell-Type-Specific Regulatory Variants in Vascular Dementia by Integrating Single-Cell Chromatin Accessibility and Gene Expression.","authors":"Qiuhan Xu, Zhaohui Chai, Yuning Zhang, Jian Shen","doi":"10.2174/011570159X509150260909052949","DOIUrl":"https://doi.org/10.2174/011570159X509150260909052949","url":null,"abstract":"<p><strong>Background: </strong>Vascular dementia (VaD), the second most common form of dementia, is a growing burden in aging populations and lacks disease-modifying therapy. Although immunerelated regulatory mechanisms are increasingly implicated, the role of immune cell-specific chromatin accessibility variants remains poorly understood.</p><p><strong>Methods: </strong>Using 379 instruments across 377 chromatin accessibility peaks in 17 immune cell types, we performed Mendelian randomization against FinnGen GWAS data, with independent evaluation in the UK Biobank. Because most loci were instrumented by a single variant, formal heterogeneity and horizontal-pleiotropy testing was not feasible. Candidate effector genes were then investigated by regulatory annotation and Bayesian colocalization of single-cell eQTLs with the VaD GWAS.</p><p><strong>Results: </strong>Four loci reached FDR < 0.05:a risk-increasing B cell/naïve B cell enhancer at chr7:24758459-24759192 (OR = 2.78 and 2.29) and the protective NK/cytotoxic NK cell loci at chr8:20109125-20109944 (OR = 0.63 and 0.62). In the UK Biobank, the B cell association was directionally concordant but, given the few cases, is supportive rather than confirmatory. Regulatory annotation and colocalization nominated GSDME as a candidate effector gene, with moderate evidence in immature B cells.</p><p><strong>Discussion: </strong>These findings are consistent with peripheral immune regulation at cell type-specific regulatory elements; brain-resident populations were not examined. The nomination of GSDME generates the hypothesis of a B cell pyroptosis-related mechanism; this is an association-level, hypothesis- generating result rather than evidence of a causal or mediating role, and remains to be validated.</p><p><strong>Conclusion: </strong>Immune cell-type-specific chromatin accessibility variation-notably a B cell locus nominating GSDME as a candidate effector gene, alongside a protective NK signal-is associated with VaD risk, generating cell-resolved hypotheses. As most instruments were single variants, these results should be read as genetic associations rather than causal inference.</p>","PeriodicalId":10905,"journal":{"name":"Current Neuropharmacology","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149037007","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":"Clinical Predictors of Lithium Response in Patients with Bipolar Disorder: Potential Predictive Role of Chronotype, Rumination and Traumatic Events.","authors":"Andrea Aguglia, Giulia Silvia Breda, Valentina Aprile, Michela Gagliardi, Francesco Stefanini, Benedetta Conio, Alessandra Costanza, Mario Amore, Andrea Amerio, Gianluca Serafini","doi":"10.2174/011570159X482667260909062619","DOIUrl":"https://doi.org/10.2174/011570159X482667260909062619","url":null,"abstract":"<p><strong>Introduction: </strong>Bipolar Disorders (BD) are severe, recurrent, and well-characterized psychiatric conditions with lithium as the first-line approved treatment for BD. This study aims to evaluate lithium response using the ALDA scale and to identify reliable predictors in a cohort of patients with BD.</p><p><strong>Methods: </strong>In this cross-sectional observational study, one hundred and fourteen consecutively recruited patients with a primary diagnosis of BD type I or II were included between June 2022 and June 2025. Sociodemographic and clinical characteristics were collected through a semi-structured interview. Lithium response was retrospectively assessed using the ALDA scale. Psychometric instruments (CTQ, MEQ, MWQ, DDFS, RRS, BIS-11) were administered. Logistic regression analyses were performed to identify independent predictors of lithium response.</p><p><strong>Results: </strong>Forty-one (36%) individuals were classified as lithium responders according to the ALDA Scale. Lithium responders were younger, engaged in physical activity more frequently, were more frequently diagnosed with BD type II, had a shorter illness duration, a Manic-Depressive-Interval (MDI) course, and showed fewer residual symptoms. Non-responders were associated with rapid cycling, psychotic symptoms, more hospitalizations, and illicit substance use. Childhood trauma, impulsivity, and rumination were more common among non-responders, while morning chronotype was more prevalent among responders. In the regression analysis, the MDI pattern, higher total scores for attentional impulsivity and rumination, and morning chronotype were all significantly associated with lithium responsiveness. On the other hand, the presence of psychotic symptoms, a history of ≥ 5 hospitalizations, comorbid substance use, and higher scores of emotional abuse were associated with a lower likelihood of response to lithium.</p><p><strong>Discussion: </strong>Integrating the evaluation of trauma history, impulsive profiles, ruminative tendencies, and circadian features into clinical assessment may enhance the prediction of lithium response.</p><p><strong>Conclusion: </strong>Our findings support the development of personalized treatment strategies for BD.</p>","PeriodicalId":10905,"journal":{"name":"Current Neuropharmacology","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149036866","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 the Dorsal Striatum in Cognitive Functions and Related Disorders with Cognitive Impairment.","authors":"Wen Yan, Shu-Han Zhang, Wen-Jie Yan, Si-Yuan Tian, Ying Zi, Guo-Jin Liu, Tong Xue, Xi-Han He, Zeng-Xin Qi, Qian-Xing Zhuang","doi":"10.2174/011570159X484443260903062736","DOIUrl":"https://doi.org/10.2174/011570159X484443260903062736","url":null,"abstract":"<p><p>The dorsal striatum, recognized as a primary input nucleus of the basal ganglia, has traditionally been viewed as a crucial center for motor control. However, emerging evidence over the past five decades has sparked a paradigm shift, underscoring its vital role in a wide array of higher-order cognitive functions such as procedural learning, habit formation, working memory, executive function, and inhibitory control. This expanded understanding is grounded in the dorsal striatum's intricate architecture, which includes GABAergic Medium Spiny Neurons (MSNs) that form both the direct and indirect pathways, a diverse array of interneurons, and a compartmental organization characterized by striosomes and matrix. Furthermore, the dorsal striatum plays a pivotal role within the cortico-basal ganglia-thalamo-cortical loops and is influenced by the midbrain dopaminergic system. Dysfunction of the dorsal striatum, marked by neurotransmitter imbalances-such as dopaminergic depletion in Parkinson's Disease (PD) and cholinergic deficits in Alzheimer's Disease (AD)-along with synaptic plasticity impairments and the aggregation of pathological proteins (e.g., α-synuclein in PD and amyloid-β/tau in AD), is closely associated with cognitive decline in major neurodegenerative disorders. This review aims to provide a systematic overview of the structural and functional foundations of the dorsal striatum in cognitive regulation. It delineates the pathological mechanisms that contribute to cognitive impairments observed in PD and AD and addresses current challenges as well as future research directions. The goal is to establish a comprehensive framework that positions the dorsal striatum as a shared therapeutic target for cognitive dysfunction across various diseases, thereby offering valuable insights for the development of early diagnostic biomarkers and innovative intervention strategies.</p>","PeriodicalId":10905,"journal":{"name":"Current Neuropharmacology","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149015977","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":"Kidney-Brain Axis: In Renal Failure, Cardiotonic Steroids Stimulate Collagen-I in the Hypothalamus and Claudins 1 and 7 in the Choroid Plexus.","authors":"Irina V Romanova, Arseny A Pyankov, Elena V Kolmakova, Alina N Isachkina, Irina Y Morina, C David Adair, Natalia I Agalakova, Alexei Y Bagrov","doi":"10.2174/011570159X514186260909055112","DOIUrl":"https://doi.org/10.2174/011570159X514186260909055112","url":null,"abstract":"<p><strong>Introduction: </strong>Uremic rats exhibit elevations of Na/K-ATPase inhibitor Marinobufagenin (MBG). The study investigated whether MBG-induced hypothalamic collagen-1 production occurs in uremic rats. Because choroid plexus cells are involved in transporting substances from the cerebrospinal fluid, the effects of MBG on claudin-1 and claudin-7 were also studied. Whether increased MBG would be associated with plasma procollagen type I C-peptide in patients with chronic kidney disease was also examined.</p><p><strong>Methods: </strong>Male Sprague-Dawley rats underwent 5/6 nephrectomy. 12 patients with chronic kidney disease undergoing hemodialysis were compared to 6 healthy controls.</p><p><strong>Results: </strong>In the hypothalamus and aorta of rats that underwent 5/6 nephrectomy, uremia was associated with a decrease in Fli1 expression and an increase in collagen 1 production. Consistent with these findings in animals, elevated plasma levels of procollagen type I C-peptide (170±7 ng/ml) in 12 patients with chronic kidney disease undergoing hemodialysis, compared to 6 healthy controls (111±10 ng/ml), were observed. In uremic rats treated with anti-MBG antibodies, Fli1 and collagen 1 expression did not change. Uremic rats develop hypothalamic fibrosis, which was associated with the inhibition of claudin-1 and claudin-7 (50%, P < 0.01 for both) in the choroid plexus of the third ventricle and inhibition of Na/K-ATPase in the brainstem; and administration of anti-MBG antibody prevents these effects. Na/K-ATPase in the brainstem was inhibited by 60% while the Na/K ratio increased. When uremic rats were pretreated with anti-MBG antibody, Na/K-ATPase activity did not change, and the Na/K ratio decreased compared to that of uremic rats.</p><p><strong>Discussion: </strong>The study's data demonstrate that the kidney-brain axis, i.e., activation of peripheral MBG and brain fibrosis, and claudin activation contribute to the pathogenesis of renal failure.</p><p><strong>Conclusion: </strong>The main findings of this study are that the CTS (i) affects blood-brain permeability via mechanisms including inhibition of Na/K-ATPase, that (ii) the blood-CSF barrier is regulated by claudins 1 and 7, which are linked to the Na/K ratio in the brain, and (iii) that synthesis of collagen-1 in the hypothalamus comprises a central element in controlling these mechanisms. CKD in rats is associated with central production of collagen-1 and the effect of MBG on brain claudins; antibodies to MBG reverse these pathological changes. These results suggest the importance of the kidneybrain axis in the pathophysiology of kidney diseases.</p>","PeriodicalId":10905,"journal":{"name":"Current Neuropharmacology","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149015838","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}