Current Neuropharmacology最新文献

{"title":"Neuroimmune Dynamics of the Microglia-astrocyte Axis: Implications for Neurodegenerative Disorders as a Double-edged Sword.","authors":"Dhrubajyoti Borah, Piyali Devroy, Asis Bala","doi":"10.2174/011570159X507671260924120425","DOIUrl":"https://doi.org/10.2174/011570159X507671260924120425","url":null,"abstract":"<p><strong>Introduction: </strong>Maintaining homeostasis in the Central Nervous System (CNS) requires constant, bidirectional molecular interactions between microglia and astrocytes. This intercellular communication, mediated by cytokines, extracellular vesicles, purinergic signals, and connexin hemichannels, synchronizes immune surveillance, neurogenesis, and synaptic pruning under physiological conditions. However, this interaction can drive persistent neuroinflammation in chronic Neurodegenerative Disorders (NDDs) such as Multiple Sclerosis (MS), Parkinson's Disease (PD), and Alzheimer's Disease (AD).</p><p><strong>Methods: </strong>Gene disease association analyses and review of existing literature were employed to identify shared glial regulators and molecular mediators across multiple neurodegenerative disorders, supported by schematic diagrams illustrating intercellular signaling dynamics Results: Deregulated astrocytes sustain microglial activation, creating self-amplifying inflammatory loops, while activated M1 microglia induce the conversion of astrocytes into neurotoxic A1 astrocytes via factors such as IL-1α, TNF-α, and complement C1q. Important mediators, such as prostaglandins, IL-1β, and IL-18, further contribute to demyelination, astrogliosis, and excitotoxicity. A convergent glial activation axis identifies shared regulators across several neurodegenerative disorders, including TREM2, GRN, LRRK2, and BDNF.</p><p><strong>Discussion: </strong>Active research targeting reactive astrogliosis and microglial reprogramming towards homeostatic phenotypes shows therapeutic promise. Nevertheless, CNS immune complexity, translational challenge, and inter-patient immunological variability underscore the need for individualized, combinatorial therapeutic strategies and human-relevant experimental models.</p><p><strong>Conclusion: </strong>The microglia-astrocyte axis plays a dual role in neuro-immune homeostasis and neurodegeneration, representing critical therapeutic targets for NDDs and requiring further mechanistic and translational investigation.</p>","PeriodicalId":10905,"journal":{"name":"Current Neuropharmacology","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149164446","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":"Nanomedicines are Reshaping Neuropharmacology and Central Nervous System Therapeutics.","authors":"Ziwei Chen, Xiaoxue Xie, Hua Hua, Junning Zhao","doi":"10.2174/011570159X525880260928115016","DOIUrl":"https://doi.org/10.2174/011570159X525880260928115016","url":null,"abstract":"","PeriodicalId":10905,"journal":{"name":"Current Neuropharmacology","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149135349","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":"Efficacy and Molecular Mechanism of Epigallocatechin-3-gallate in Spinal Cord Injury: A Meta-analysis, Network Pharmacology Analysis, and Molecular Docking Study.","authors":"Jia-Xin Wen, Ai-Fang Zhou, Yu Xiao, Shi-Pian Li, Hao-Wen Lin, Yue-Li Sun, Bi-Meng Zhang, Yong-Jun Wang, Xue-Jun Cui, Yun-Zhao Gong, Min Yao","doi":"10.2174/011570159X484893260922110130","DOIUrl":"https://doi.org/10.2174/011570159X484893260922110130","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Introduction: &lt;/strong&gt;Spinal Cord Injury (SCI) remains a major clinical challenge because of limited therapeutic options and poor prognosis. Epigallocatechin-3-gallate (EGCG) can cross the blood-brain barrier and has demonstrated neuroprotective properties. However, its therapeutic efficacy and underlying mechanisms in SCI remain incompletely understood.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;A comprehensive literature search was conducted in PubMed, ScienceDirect, Web of Science, the China National Knowledge Infrastructure, and Wanfang databases through August 2025 to identify studies evaluating the effects of EGCG in animal models of SCI. Meta-analyses and subgroup analyses were performed using Review Manager version 5.3. Network pharmacology was used to identify potential therapeutic targets and signaling pathways, followed by molecular docking and Molecular Dynamics (MD) simulations to evaluate the interactions between EGCG and core targets.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;A total of 22 studies were included. Pooled analyses showed that EGCG significantly improved motor function in animals with SCI, as demonstrated by higher Basso, Beattie, and Bresnahan (BBB) scores on day 28 (9 studies, n = 139/99, WMD = 3.96 (2.79, 5.13), p &lt; 0.00001) and higher inclined plane test scores (3 studies, n = 59/37, WMD = 13.14 (12.48, 13.79), p &lt; 0.00001). Subgroup analyses indicated greater improvements following intrathecal administration (4 comparisons from 2 studies, (27, 28), n = 44/22, WMD = 2.95 (2.03, 3.88), p &lt; 0.00001) and in female animals (8 comparisons from 4 studies (24, 27, 28, 30), n = 74/41, WMD = 2.40 (1.82, 2.97), p &lt; 0.00001). EGCG also significantly reduced lipid peroxidation and inflammatory responses and exerted anti-apoptotic effects (MDA: 14 comparisons from 7 studies (22-24, 34, 35, 37, 38), n = 93/49, SMD = -3.18 (-3.88, -2.48), p &lt; 0.00001; iNOS: 7 comparisons from 3 studies (22, 25, 35), n = 44/19, SMD = -3.19 (-4.12, -2.25), p &lt; 0.00001; Bcl-2: 13 comparisons from 6 studies (24, 27, 28, 35, 37, 43), n = 75/35, SMD = 3.61 (2.64, 4.58), p &lt; 0.00001). Network pharmacology analysis identified the MAPK and PI3K-AKT signaling pathways as key pathways potentially underlying the therapeutic effects of EGCG in SCI. Molecular docking and MD simulations further supported stable interactions between EGCG and the core targets AKT1 and MMP9.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Discussion: &lt;/strong&gt;The integrated findings suggest that EGCG exerts neuroprotective effects through coordinated regulation of oxidative stress, inflammation, apoptosis, autophagy, astrocyte function, and angiogenesis via multiple interconnected signaling pathways. Subgroup analyses further suggested greater therapeutic efficacy in female animals and following intrathecal administration, although the biological mechanisms underlying these differences require further investigation.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;EGCG demonstrates therapeutic potential in experimental SCI by promoting ","PeriodicalId":10905,"journal":{"name":"Current Neuropharmacology","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149135139","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 Neurochemical Basis of High-Altitude Sleep Disruption: Disentangling Respiratory and Sleep-Circuit Mechanisms Toward Targeted Pharmacotherapy.","authors":"Yue Dong, Zhihao Zou, Qinghai Shi","doi":"10.2174/011570159X504204260824094138","DOIUrl":"https://doi.org/10.2174/011570159X504204260824094138","url":null,"abstract":"<p><p>High-altitude sleep disruption is a complex syndrome that many lowlanders experience when they reach plateaus above 2,500 meters, characterized by frequent awakenings, reduced slow-wave sleep, nocturnal hypoxemia, and central sleep apnea related to unstable ventilation. A prevailing assumption in high-altitude sleep medicine holds that stabilising ventilation, chiefly via acetazolamide, is sufficient to restore sleep quality. This assumption is challenged by a randomised controlled trial demonstrating that acetazolamide significantly reduced the apnoea-hypopnoea index (AHI) and improved oxygenation at 3,100 m while failing to restore N3 slow-wave sleep fraction, total sleep time, or sleep efficiency, parameters that remained impaired in both drug and placebo groups. This dissociation between respiratory and sleep-architectural outcomes constitutes the central scientific premise of the present review. An integrative neurochemical framework identifies four distinct sleep-circuit nodes disrupted by hypobaric hypoxia: impaired serotonergic synthesis, an adenosinergic paradox, orexin/hypocretin arousal instability, and locus coeruleus norepinephrine hyperactivation. Each node is mechanistically distinguishable yet interconnected with respiratory loop gain dynamics through shared neurotransmitter pathways, such as serotonin. Additionally, hypoxia-inducible factor-1α (HIF-1α) is examined as a molecular bridge linking hypoxic signalling to circadian clock suppression and dysrhythmia of neurotransmitter synthesis. Current pharmacological agents are reappraised within this dual-target framework, and emerging therapeutic candidates, including GABA-A α₁-selective agents (Z-drugs), α₂-adrenoceptor agonists, orexin receptor antagonists, and adenosine A1-selective antagonists, are critically evaluated. A paradigm shift is proposed: effective management of high-altitude sleep disruption requires simultaneous targeting of both ventilatory control and sleep-circuit neurochemistry.</p>","PeriodicalId":10905,"journal":{"name":"Current Neuropharmacology","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149135329","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":"N1-methylnicotinamide Mediates Multi-Target Cognitive Deficit Relief via AMPK-Lysosome Axis Regulation.","authors":"Xiangjie Qiu, Qilei Zhang, Yuting Meng, Yuan He, Zhongxiang Tang, Ling Chu, Yurong Tan","doi":"10.2174/011570159X482182260914104640","DOIUrl":"https://doi.org/10.2174/011570159X482182260914104640","url":null,"abstract":"<p><strong>Introduction/objective: </strong>Alzheimer's Disease (AD) progresses via interconnected Aβ aggregation, tau hyperphosphorylation, neuroinflammation, and lysosomal failure, while current single-target drugs only relieve cognitive symptoms without halting pathogenesis. Gut microbiota-derived N1-methylnicotinamide (MNAM) is associated with lower AD risk, yet its comprehensive multilevel regulatory mechanism remains unclear. This study systematically elucidated MNAM's neuroprotective network using in vitro neuronal/microglial injury models and two AD-relevant mouse models.</p><p><strong>Methods: </strong>In silico prediction and LC-MS verified MNAM's BBB permeability. TMT proteomics, siRNA knockdown and pharmacological rescue validated the CAB39L-AMPK-lysosomal axis. Immunofluorescence, enzyme assays and molecular docking assessed MNAM's CTSB inhibitory capacity. 16S rRNA sequencing and metabolomics characterized gut microbiota and NAD+ metabolic remodeling.</p><p><strong>Results: </strong>In vitro, MNAM crossed the blood-brain barrier, improved neuronal viability, reduced ROS and pro-inflammatory cytokines (IL-1β, TNF-α). In AD-like mice, it alleviated cognitive deficits, tau hyperphosphorylation, Aβ deposition, microglial activation, and restored SOD activity. MNAM upregulated CAB39L to activate AMPK, stabilized lysosomes, and restrained CTSB leakage. It reshaped protective intestinal flora, suppressed hepatic NNMT, and restored NAD+ balance. In LPS-challenged mice, MNAM selectively alleviated microglial activation and IL-1β accumulation.</p><p><strong>Discussion: </strong>MNAM targets multiple AD pathological nodes (Aβ deposition, tau phosphorylation, neuroinflammation, lysosomal dysfunction, gut microbiota-metabolite interactions) via the CAB39L-AMPK-lysosomal axis and gut microbiota/NAD+ metabolism regulation, which is distinct from single-target drugs. Its ability to cross the BBB and regulate host-microbiota metabolic crosstalk provides a novel mechanistic basis for AD therapy, supporting a shift from single-target to multi-target intervention strategies.</p><p><strong>Conclusion: </strong>MNAM targets the CAB39L-AMPK-lysosomal axis, inhibits CTSB, and remodels gut microbiota-NAD+ metabolism to concurrently suppress core AD pathologies. This metabolite serves as a promising multi-target disease-modifying candidate for AD, warranting further validation in transgenic AD models and human neurons.</p>","PeriodicalId":10905,"journal":{"name":"Current Neuropharmacology","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149135264","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":"Beyond Fuel: Metabolic Intermediates as Signaling Molecules in Neuroinflammation and Neurodegeneration.","authors":"Song Wang, Sichen Wang, Yuhan Sun, Song Zhang, Jiangxu Wu, Dan Xie","doi":"10.2174/011570159X486332260921110838","DOIUrl":"https://doi.org/10.2174/011570159X486332260921110838","url":null,"abstract":"<p><p>Historically, research has viewed substantial brain metabolic activity through the lens of energy production, primarily treating metabolites as substrates and products in bioenergetic pathways. However, this paradigm is now evolving. Key metabolic intermediates are recognized not only as components of Adenosine Triphosphate (ATP) synthesis, but also as potent signaling molecules that establish intricate communication networks. This \"metabolic signaling language\" profoundly influences inflammation, epigenetics, and cell fate by translating cellular metabolic conditions into certain functional outcomes. In this review, three prototypical metabolites, namely succinate, itaconate, and α-Ketoglutarate (α-KG), were discussed. We investigated succinate accumulation during ischemia and mitochondrial stress, which serves as an early alarm that drives inflammation through both intracellular and extracellular receptor-mediated mechanisms. Conversely, itaconate, an inducible metabolite produced by myeloid cells, exerts inhibitory effects and actively alleviates inflammation by covalently modifying proteins. Finally, we highlighted α-KG, a central metabolic hub that links metabolic status to cellular identity and aging by epigenetically regulating DNA and histone demethylase activity. By summarizing the functions of these metabolites across neurological disorders, including ischemic stroke, Alzheimer's disease, Parkinson's disease, and multiple sclerosis, we delineate a fundamental layer of biological regulation. Deciphering and therapeutic modulation of this metabolic language represent a frontier in neuroscience, offering novel targets for intractable neurological diseases.</p>","PeriodicalId":10905,"journal":{"name":"Current Neuropharmacology","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149105086","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":"Effect of L-carnitine and Mildronate on Cognitive Recovery after Traumatic Brain Injury: Assessment of the Role of Mitochondrial Function, Angiogenesis, and Neuroinflammation.","authors":"Veronika V Nesterova, Dianna S Adzhemian, Viktoria A Gribovskaya, Polina I Babenkova, Mikhail E Ivanov, Daria T Chursina, Sofya R Kononova, Artem P Gureev, Egor Yu Plotnikov, Denis N Silachev","doi":"10.2174/011570159X475297260924122654","DOIUrl":"https://doi.org/10.2174/011570159X475297260924122654","url":null,"abstract":"<p><p>Introduction/Introduction: Traumatic brain injury (TBI) frequently results in persistent cognitive deficits driven by secondary mechanisms including mitochondrial dysfunction, oxidative stress, and neuroinflammation. We compared the effects of L-carnitine and mildronate on spatial memory recovery after TBI and investigated the underlying cellular mechanisms.</p><p><strong>Methods: </strong>Male C57BL/6 mice were subjected to controlled cortical impact TBI and assigned to naïve, sham, TBI+saline, TBI+mildronate (100 mg/kg/day), or TBI+L-carnitine groups. Spatial working memory was evaluated using the Morris water maze over 21 days. At 24 days post-injury, we measured cortical and hippocampal malondialdehyde (MDA), mtDNA integrity and copy number, expression of genes related to mitochondrial biogenesis, glucose metabolism, angiogenesis, and neuroinflammation, and performed blood cytology.</p><p><strong>Results: </strong>TBI induced significant memory deficits, elevated MDA, and reduced mtDNA copy number without increased damage. Mildronate, but not L-carnitine, significantly improved cognitive performance. Mildronate upregulated Tfam, Glut4, Cd34, and Eng while downregulating Gfap in the hippocampus. Both compounds decreased MDA and circulating cell-free mtDNA.</p><p><strong>Discussion: </strong>Mildronate's superior neuroprotection appears to involve enhanced mitochondrial biogenesis, glucose transport, and angiogenesis, alongside suppression of astrogliosis. In contrast, L-carnitine showed limited cognitive benefit, possibly due to insufficient mitochondrial renewal and vascular repair.</p><p><strong>Conclusion: </strong>Mildronate exerts greater neuroprotective effects than L-carnitine after TBI, likely via coordinated restoration of mitochondrial quality control, glucose utilization, and vascular remodeling, offering a promising strategy to mitigate post-traumatic cognitive decline.</p>","PeriodicalId":10905,"journal":{"name":"Current Neuropharmacology","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149105036","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":"Research Hotspots and Trends of the PI3K/Akt Signaling Pathway in Spinal Cord Injury: A Bibliometric Analysis.","authors":"Guohua Jiang, Renkun Huang, Kewen Wang, Yuchang Gui, Guiyang Jiang, Yijun Liu, Jianwen Xu","doi":"10.2174/011570159X498134260915101216","DOIUrl":"https://doi.org/10.2174/011570159X498134260915101216","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Objective: &lt;/strong&gt;Poor neurological recovery after Spinal Cord Injury (SCI) remains a major clinical challenge. The Phosphoinositide 3-Kinase/Protein Kinase B (PI3K/Akt) signaling pathway plays a critical regulatory role in the pathological progression of SCI. This study aimed to systematically analyze the research status, hotspots, and developmental trends of the PI3K/Akt signaling pathway in SCI using bibliometric methods, thereby identifying research gaps and emerging frontiers to inform the development of more effective therapeutic strategies for SCI.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Publications related to SCI and the PI3K/Akt signaling pathway from January 1, 2005, to December 31, 2025 were retrieved from the Web of Science and Scopus databases. Following literature screening and data standardization, bibliometric and visualization analyses were performed using CiteSpace and VOSviewer to evaluate countries, institutions, authors, journals, keywords, and references associated with this research field.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;A total of 317 publications were included. The annual publication output demonstrated a phased increase, with rapid growth after 2014 and a peak in 2025. Thirty-four countries contributed to this field, with China identified as the leading contributor. China, the United States, and South Korea collectively accounted for more than 90% of the total publications. Wenzhou Medical University ranked as the most productive institution, and Xiao, Jian was among the most influential authors. The core journals were predominantly JCR Q1 journals in neuroscience and pharmacology, including Molecular Neurobiology. Research hotspots primarily focused on PI3K/Akt-mediated apoptosis and autophagy regulation, microglia-driven neuroinflammation, pyroptosis mechanisms, and translational strategies involving exosomes, hydrogels, and mesenchymal stem cells. Furthermore, the integration of network pharmacology and multi-omics bioinformatics approaches has substantially advanced mechanistic exploration in this field.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Discussion: &lt;/strong&gt;This bibliometric analysis revealed that the PI3K/Akt pathway is a central regulatory hub in the pathological microenvironment of SCI, with the research focus gradually shifting from basic mechanistic exploration (apoptosis, autophagy, inflammation) to translational intervention strategies. The global research landscape is dominated by Chinese institutions and scholars, indicating strong academic momentum in this field. Moreover, the rapid development of network pharmacology and bioinformatics provides a new paradigm for multi-target and systematic research, which helps bridge basic research and clinical translation more effectively. These findings highlight the importance of PI3K/Akt-targeted regulation in neuroprotection and functional recovery after SCI and highlight key directions for future mechanistic research and therapeutic development.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/stro","PeriodicalId":10905,"journal":{"name":"Current Neuropharmacology","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149105071","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":"Transcutaneous Auricular Vagus Nerve Stimulation for Chronic Pain Management: A Narrative Review.","authors":"Mingyan Li, Hongan Yang, Baijintao Sun, Yuxi Song, Bing Li, Hanfeng Yang, Chuan Zhang","doi":"10.2174/011570159X503412260915114332","DOIUrl":"https://doi.org/10.2174/011570159X503412260915114332","url":null,"abstract":"<p><p>Chronic pain represents a global public health challenge; current therapeutic interventions remain limited and are frequently accompanied by adverse effects. Transcutaneous auricular Vagus Nerve Stimulation (taVNS) has emerged in recent years as a potential non-invasive neuromodulation therapy, providing novel possibilities for chronic pain management. Preliminary research indicates that taVNS demonstrates preliminary therapeutic potential in conditions such as migraine, fibromyalgia, and chronic low back pain, with initial exploratory applications also conducted in trigeminal neuralgia, diabetic peripheral neuropathy, and persistent abdominal pain. Multiple studies suggest that this modality can effectively attenuate pain intensity and enhance patients' quality of life. The underlying analgesic mechanisms are likely associated with modulation of the locus coeruleus-noradrenergic system, the prefrontal cortex-dopaminergic system, and autonomic nervous system function, as well as the suppression of inflammatory responses. Although current evidence suggests that taVNS may be a safe and effective adjunctive therapy, future high-quality, large-scale, and longitudinal studies are imperative to establish standardized stimulation parameters and confirm long-term clinical benefits.</p>","PeriodicalId":10905,"journal":{"name":"Current Neuropharmacology","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149105217","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 Implications of Cell Death Pathways Across the Course of Amyotrophic Lateral Sclerosis.","authors":"Jiayang Yu, Dong Xie, Xinyu Zeng, Shuaipan Zhang, Bin Xiao, Jing Zhang, Min Fang, Qingguang Zhu, Chongjie Yao","doi":"10.2174/011570159X500937260908042834","DOIUrl":"https://doi.org/10.2174/011570159X500937260908042834","url":null,"abstract":"<p><p>Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron loss, resulting in paralysis and limited survival. Multiple regulated cell death pathways, including apoptosis, necroptosis, ferroptosis, pyroptosis, lysosomal cell death, autophagy-dependent cell death, NETosis, and other emerging cell death modalities, have been implicated in ALS, but their mechanistic interactions and relative contributions remain poorly understood. This knowledge gap has hindered the development of effective therapies. Better experimental models are needed to dissect these pathways. This review summarizes current knowledge on the roles of cell death pathways in ALS. A tiered framework (M1-M4) is applied to critically evaluate data from human postmortem tissue, patient-derived cells, and animal models, ranking studies according to their relevance to human disease. Potential crosstalk among these pathways is further examined. It is also proposed that the relative contribution of specific cell death pathways may shift with disease progression, although this hypothesis requires longitudinal validation. To integrate this dynamic perspective, cell death pathway activities are hypothetically aligned with the King's clinical staging system. This stage-informed framework is presented as a conceptual model intended to generate hypotheses rather than to serve as a validated clinical algorithm. The model distinguishes established therapies from preclinical and exploratory strategies. Future research should prioritize the development of human-relevant model systems, the identification of longitudinal biomarkers of cell death, and the implementation of rigorously designed combination trials. These efforts may ultimately enable more precise, stage-appropriate therapeutic strategies for ALS.</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":"149036720","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}