CNS & neurological disorders drug targets最新文献

{"title":"Rational Design of (Oxadiazol-2-yl) Thiazolidin-4-one Derivatives for Parkinson's Disease: Insights from MD Simulations and Quantum Studies.","authors":"Asif Shaik, Krishna Shevate, Anik Sen, Shanish Antony A, Gomathy Subramanian","doi":"10.2174/0118715273437267251211144051","DOIUrl":"https://doi.org/10.2174/0118715273437267251211144051","url":null,"abstract":"<p><strong>Introduction: </strong>Parkinson's disease (PD) is a progressive neurodegenerative disorder primarily characterized by the loss of dopaminergic neurons in the substantia nigra. Sirtuin 3 (SIRT3), a mitochondrial NAD⁺-dependent deacetylase, has emerged as a promising therapeutic target due to its vital role in mitochondrial homeostasis and resistance to oxidative stress. However, existing SIRT3 modulators suffer from poor selectivity, suboptimal CNS penetration, and limited binding affinity. This study aimed to design and evaluate novel oxadiazole-thiazolidin-4-one hybrid compounds as potential SIRT3 modulators with improved neuroprotective profiles.</p><p><strong>Methods: </strong>A comprehensive computational workflow was carried out using the Schrödinger Suite 2025-1, including ADMET profiling, molecular docking, molecular dynamics (MD) simulations, Thermal MM/GBSA binding free energy estimation, and protein dynamics analyses (DCCM, PCA, FEL). Additionally, Density Functional Theory (DFT) and Fukui function analyses were conducted to elucidate electronic properties and reactive sites relevant to bioactivity.</p><p><strong>Results: </strong>The designed hybrids exhibited higher SIRT3 binding affinities than known modulators, with binding free energies ranging from -8.9 to -4.88 kcal/mol compared to resveratrol (-7.14 kcal/mol). Among them, TZOX04 [3-(5-benzyl-1,3,4-oxadiazol-2-yl)-2-(2,3,4-trihydroxyphenyl)thiazolidin-4- one] demonstrated the strongest binding energy (-8.94 kcal/mol), favorable drug-likeness, and optimal CNS permeability (logBB = 0.42).</p><p><strong>Discussion: </strong>Molecular dynamics confirmed the stability of the SIRT3-TZOX04 complex over 100 ns, while DFT and Fukui analyses identified key electron-rich regions contributing to reactivity and interaction potential. The oxadiazole-thiazolidinone hybridization approach provided a significant improvement in binding and pharmacokinetic behaviour over existing modulators.</p><p><strong>Conclusion: </strong>This work represents the first systematic investigation of oxadiazole-thiazolidin-4-one hybrids as SIRT3 modulators. TZOX04 emerged as a promising lead compound with enhanced binding affinity, stability, and pharmacokinetic characteristics for PD therapy. These findings warrant future synthetic and biochemical validation to confirm therapeutic efficacy.</p>","PeriodicalId":93947,"journal":{"name":"CNS & neurological disorders drug targets","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2026-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147847423","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Gut-Brain Connection: Exploring the Connection Between the Gastrointestinal System and Parkinson's Disease.","authors":"Ge YuXuan, Muhammad Khalid Iqbal, Bakhtawar Khan, Hamid Khan, Syed Shahab Ud Din Shah, Fawaz Al-Hussain, Mubin Mustafa Kiyani, Shahid Bashir","doi":"10.2174/0118715273419693251206130059","DOIUrl":"https://doi.org/10.2174/0118715273419693251206130059","url":null,"abstract":"<p><p>Parkinson's disease (PD) is a complex neurodegenerative disorder characterized by motor and non-motor symptoms. Recent studies indicate that the gut-brain axis contributes to both the initiation and progression of PD, a disorder that primarily affects the central nervous system. This article reviews current research on the interaction between the central nervous system and the gastrointestinal tract in PD. The vagus nerve, areas of the enteric nervous system (ENS), systemic inflammation, and the microbiome are all involved in this interaction. For example, recent studies have shown PD-related effects such as abnormal distribution of gut bacteria, increased gut barrier permeability, and α-synuclein transport from the gut to the brain. A comprehensive evaluation of motor and non-motor symptoms was conducted. Additionally, we explored drugs that specifically target the gastrointestinal system, the possible gastrointestinal symptoms of PD, and how these symptoms may serve as early indicators of the disease. Our article also discusses dietary modifications, probiotics, and fecal microbiota transplantation as potential treatments for PD. By reviewing clinical and basic scientific research as well as translational applications, this article highlights the relationship between the central nervous system and the digestive system in PD. A better understanding of this complex connection may lead to improved detection and treatment of this debilitating disease and offer new opportunities for prevention and therapy. Finally, this paper suggests directions for further research in this area.</p>","PeriodicalId":93947,"journal":{"name":"CNS & neurological disorders drug targets","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147847413","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tetrandrine Attenuates Cerebral Ischemia/Reperfusion Injury by Regulating Th17/Treg Balance and Mediating PI3K/Akt Pathway in Mice, Based on Network Pharmacology Analysis.","authors":"Huanyu Gou, Feng Li, Zishan Huang, Jiarui Zheng, Yuzhen Guo, Mingjiang Yao","doi":"10.2174/0118715273428782260117040032","DOIUrl":"https://doi.org/10.2174/0118715273428782260117040032","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Introduction: &lt;/strong&gt;Stroke has found to be the second leading cause of death in China. Research indicates that the immune imbalance of Th17/Treg is an important pathophysiological alteration and the cause of poor prognosis after ischemic stroke, the most common type of stroke. Tetrandrine (Tet), a bisbenzyl isoquinoline alkaloid and potential immunoregulator, has been reported to possess therapeutic effect on ischemic stroke; however, the specific mechanism remains to be clarified. This research aims to explore the molecular mechanisms underlying Tet's effects on cerebral ischemiareperfusion injury (CIRI) through bioinformatics methods and experimental validation.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Using public databases, we predicted potential therapeutic targets of Tet against CIRI. Common targets were then used to build a protein-protein interaction (PPI) network, from which key gene targets were identified. Functional and pathway enrichment analyses were conducted via Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). Afterwards, molecular docking and experimental validation were performed to confirm the predictions. The middle cerebral artery occlusion and reperfusion (MCAO/R) mice model was established. Twenty-four hours after Tet injection (intraperitoneally, 25 and 50 mg/kg), behavior index evaluation, cerebral blood flow, and tetrazolium chloride (TTC) staining were performed. Pathological changes on cortex, striatum, and hippocampus were observed using hematoxylin-eosin (HE) staining. Percentages of Th17 cells and Treg cells were determined by flow cytometry analysis. The expressions of mRNAs of Th17/Treg markers were measured by quantitative real-time polymerase chain reaction (qPCR). And the expressions of proteins PI3K/Akt Signaling Pathway were measured by Western blot analysis.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Our study identified 52 potential therapeutic targets of Tet for CIRI, with 10 key gene targets selected from PPI network analysis. GO and KEGG enrichment analyses indicated that these targets were primarily associated with the PI3K/Akt signaling pathway and Th17 cell differentiation. Molecular docking suggested potential interactions between Tet and Trp53, Cdk4, and Pik3ca. Experimental validation demonstrated that Tet ameliorated neurological deficits and reduced cerebral ischemic damage. Flow cytometry revealed that, compared to the model group, Tet treatment increased Treg cells while decreasing Th17 cells. Additionally, Tet downregulated RORγt and upregulated FoxP3 at the mRNA level. Western blot analysis further confirmed that Tet reduced the p-Akt/Akt and p-PI3K/PI3K protein expression ratios.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Discussion: &lt;/strong&gt;Our integrated approach demonstrates that tetrandrine alleviates CIRI by restoring Th17/Treg balance via PI3K/Akt signaling - a mechanism previously unreported for this alkaloid. The downregulation of RORγt and upregulation of FOXP3 confirm Tet's immunomodulatory sp","PeriodicalId":93947,"journal":{"name":"CNS & neurological disorders drug targets","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2026-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147847444","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Vindeburnol Induces Neuroprotection in Rat Traumatic Brain Injury via Adrenergic Receptor Antagonism.","authors":"Mikhail Ivanov, Lyudmila Borets, Elmira Yakupova, Olga Riabova, Alexander Yurin, Denis Silachev, Vadim Makarov","doi":"10.2174/0118715273454662260416105842","DOIUrl":"https://doi.org/10.2174/0118715273454662260416105842","url":null,"abstract":"<p><strong>Introduction/objective: </strong>Traumatic Brain Injury (TBI) causes substantial neurological deficits and remains a major therapeutic challenge. This study aimed to evaluate the neuroprotective properties of Vindeburnol (VIND), a semi-synthetic derivative of vincamine, and to identify its potential molecular targets and optimal dosing regimen for post-traumatic treatment.</p><p><strong>Methods: </strong>Radioligand binding assays were used to determine VIND affinity for 22 CNS receptors, 7 ion channels, and 1 enzyme at a concentration of 10 μM. The in vivo neuroprotective effect was studied in a rat model of TBI induced by controlled cortical impact. VIND was administered intraperitoneally at doses of 10 or 20 mg/kg daily or every other day for 10 days. Neurological recovery was assessed using the beam-walking and limb-placement tests, and brain lesion volume was quantified by MRI on day 14.</p><p><strong>Results: </strong>VIND showed strong inhibition of radioligand binding at α1- and α2-adrenergic receptors (74% and 84.1%, respectively). In vivo, the most pronounced neuroprotective effect was observed at 20 mg/kg every other day, resulting in approximately a twofold reduction in lesion volume (88.7 ± 6.5 mm3 vs 179.4 ± 19.3 mm3 in saline-treated TBI rats, p < 0.001) and a significant improvement in neurological outcomes. The 10 mg/kg dose showed a non-significant trend towards neuroprotection.</p><p><strong>Discussion: </strong>The neuroprotective effect of VIND is likely mediated by the inhibition of excessive adrenergic receptor activation, resulting in improved neuronal survival and functional recovery. These findings highlight adrenergic modulation as a promising therapeutic mechanism for mitigating post-traumatic brain damage.</p><p><strong>Conclusion: </strong>Vindeburnol demonstrated significant neuroprotective efficacy in a rat model of TBI and may represent a promising pharmacological candidate for post-traumatic neuroprotection.</p>","PeriodicalId":93947,"journal":{"name":"CNS & neurological disorders drug targets","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2026-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147725034","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mendelian Randomization Reveals Potential Drug Targets for Multiple Sclerosis Targeting Ferroptosis.","authors":"Tao Wu, Yuze Cao, Lihua Wang, Zhaoxia Wang, Hongjun Hao, Huixue Zhang","doi":"10.2174/0118715273445879260111145647","DOIUrl":"https://doi.org/10.2174/0118715273445879260111145647","url":null,"abstract":"<p><strong>Introduction: </strong>Multiple sclerosis (MS) is a multifactorial autoimmune condition, and existing medications offer limited efficacy, especially regarding the control of disease progression. Our previous research has suggested a significant role for ferroptosis in the mechanism of MS, making it a promising therapeutic target.</p><p><strong>Methods: </strong>To identify potential treatment targets related to ferroptosis, we conducted Mendelian randomization analysis. We used transcription and proteomic data for 511 ferroptosis-related proteins extracted from 49 tissues in GTEx v8 and deCODE data to derive genetic instruments. We conducted Mendelian randomization based on summary-level data from the International MS Genetics Consortium (47,429 cases and 68,374 controls). Reverse Mendelian randomization, Steiger filtering, Bayesian colocalization, constrained maximum likelihood, and model averaging-based (cML-MA) method, and phenomewide scanning were performed to strengthen findings. Additionally, we explored protein-protein interaction networks to uncover possible links between target proteins and approved MS therapeutics.</p><p><strong>Results: </strong>Under Bonferroni significance (P < 1.52 × 10-4), Mendelian randomization using cisexpression quantitative trait locus instruments revealed nine ferroptosis-related proteins (STAT3, MAPK1, MAPK3, MAP3K11, CISD2, KEAP1, ZEB1, PVT1, PARP1) with significant results in at least one tissue. Bayesian colocalization indicated that four of them (STAT3, PP.H4=0.97; MAPK1, PP.H4=0.95; MAPK3, PP.H4=0.99; ZEB1, PP.H4=0.96) share variation with MS. Under Bonferroni significance (P < 1.11 × 10-3), two proteins also obtained significant proteomic results (STAT3, P = 1.18 × 10-13, MAPK3, P = 3.25 × 10-8). Regional association analysis and phenomewide Scanning suggest a potential involvement of STAT3 in MS. STAT3 and MAPK3 interact with target proteins of current MS drugs, particularly STAT3.</p><p><strong>Discussion: </strong>These findings highlight the causal involvement of ferroptosis pathways in MS pathogenesis, emphasizing STAT3 and MAPK3 as promising therapeutic candidates. This work broadens current understanding of MS biology and suggests new directions for targeted drug development focused on ferroptosis regulation.</p><p><strong>Conclusion: </strong>Our analysis indicates that genetically predicted ferroptosis-related protein levels of STAT3, MAPK1, MAPK3, and ZEB1 are associated with MS risk. Among them, STAT3 and MAPK3 emerge as potential therapeutic candidates, with STAT3 warranting particular clinical investigation.</p>","PeriodicalId":93947,"journal":{"name":"CNS & neurological disorders drug targets","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2026-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147724949","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Zebrafish (Danio rerio) as a Model for Neurodegenerative Disease Research: Mechanisms, Biomarkers, and Translational Promise.","authors":"Nikhat Khan, Gaurav Doshi","doi":"10.2174/0118715273442688260330060220","DOIUrl":"https://doi.org/10.2174/0118715273442688260330060220","url":null,"abstract":"<p><p>Zebrafish (Danio rerio) have gained prominence as a versatile vertebrate model for studying neurodegenerative disorders due to their genetic similarity to humans, rapid development, transparency, and suitability for high-throughput drug screening. The usefulness of zebrafish in modelling human neurological disorders is supported by the similarity of their brains' anatomical and neurochemical characteristics, including comparable divisions of the forebrain, midbrain, and hindbrain, as well as dopaminergic, serotonergic, glutamatergic, and GABAergic pathways. Zebrafish have been used to successfully model several neurodegenerative diseases, including Alzheimer's disease (via tau phosphorylation and amyloid-beta aggregation), Parkinson's disease (via dopaminergic neuronal loss and alpha-synuclein pathology), Huntington's disease (via polyglutamine-expanded huntingtin), and amyotrophic lateral sclerosis (via mutant SOD1 and TDP- 43 transgenes). They have also been used to study multiple sclerosis, spinocerebellar ataxias, and Rett syndrome, enabling mechanistic exploration and preclinical drug discovery. This review crucially depicts how zebrafish models provide an affordable, morally acceptable, and scalable platform for early-stage neurodegeneration research. These models complement, rather than replace, rodent- and human-derived systems. Additionally, we will review how to bridge the gap between therapeutic screening and basic mechanistic findings, highlighting their increasing significance in the neuroscience research continuum.</p>","PeriodicalId":93947,"journal":{"name":"CNS & neurological disorders drug targets","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2026-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147792200","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bibliometric Analysis of Neutrophil Extracellular Traps in Stroke: Research Trends and Hotspots.","authors":"Kexin Zhong, Biao Tang","doi":"10.2174/0118715273417315251128141230","DOIUrl":"https://doi.org/10.2174/0118715273417315251128141230","url":null,"abstract":"<p><p>Stroke is the second leading cause of death in the world, requiring innovation in therapeutic methods. Neutrophil Extracellular Traps (NETs), networks released by neutrophils, are associated with stroke. This study explores the trends and hotspots of NETs in stroke through bibliometric analysis. The literature on \"NETs in stroke\" was obtained from the Web of Science Core Collection (WoSCC), published from January 1, 2015, to August 31, 2025. This study displays the collaboration of authors, the influence of different journals and references, and the hotspots of keywords, using visualization tools such as Citespace, VOSviewer, Bibliometric, Bibliometrix, and Excel. A total of 370 available studies in the field of \"NETs in stroke\" were selected. The number of publications in this field has been increasing year by year, with China and the United States leading, indicating that the field has attracted widespread attention in these two countries. Institutional collaborations are primarily limited within the country, and international exchanges are necessary to advance research. De Meyer Simon F. and Frontiers in Immunology are the most productive author and journal, while Tobias A. Fuchs and Blood are the most cited author and journal in the field, respectively. Volker Brinkmann's pioneering work, Extracellular Traps Kill Bacteria, is the most cited reference. Through keyword analysis, it was found that studies on \"NETs in stroke\" primarily focused on ischemic stroke and thrombosis, with tissue factor being a key topic and myocardial ischemia emerging as a potential research trend. This study analyzes trends and hotspots of \"NETs in stroke\" visually, providing data support and a theoretical basis for researchers to identify appropriate collaborators and research directions.</p>","PeriodicalId":93947,"journal":{"name":"CNS & neurological disorders drug targets","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2026-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147792226","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Therapeutic Innovations in Parkinson's and Alzheimer's Disease: Molecular Mechanisms and Emerging Strategies.","authors":"S Kasthuri, S Padmavathi, M Jeevitha, Jayaraman Rajangam","doi":"10.2174/0118715273445849260403045802","DOIUrl":"https://doi.org/10.2174/0118715273445849260403045802","url":null,"abstract":"<p><p>Parkinson's Disease (PD) and Alzheimer's Disease (AD) are still significant neurodegenerative disorders that have few disease-modifying therapies. In this review, recent advances are assessed based on the strength of evidence for major molecular targets and the therapeutic approaches that have been developed around those targets. Alpha-synuclein is a key target in PD, as indicated by genetic correlations, pathological distribution, and experimental evidence supporting its involvement in neuronal injury. Initial trials of alpha-synuclein antibodies and vaccines show evidence of target engagement, with yet-to-be-determined clinical outcomes. Interventions targeting gene-based dopamine synthesis restoration using AADC or multi-enzyme vectors have shown consistent biological effects, with clinical variability, and determining optimized delivery and patient selection is necessary. In AD, amyloid-beta- and tau-directed interventions have produced measurable changes in biomarkers, and some agents have demonstrated a slight deceleration of deterioration at an early stage of the disease. The experience with previous BACE inhibitors also demonstrates that excellent mechanistic rationale does not always translate into clinical efficacy in the case of interference with critical physiological processes by target modulation. Regenerative methods, such as stem-cell-based neuronal grafts in PD and neurotrophic factor gene delivery in AD, show potential to repair network function, but still pose issues regarding long-term stability, integration, and the complexity of the procedures. Lifestyle-driven interventions, control of the gut microbiome, and neuromodulation methods also remain of interest and can be included in the list of supportive strategies offered to complement molecular therapies. AI-based analytics and digital tools are helpful in the earlier detection, monitoring, and trial stratification. Taken together, existing evidence suggests that authenticated protein targets, neurotransmitter-targeted remedial strategies, and technology-enabled accuracy methods are the most promising approaches for the development of disease-modifying therapies in PD and AD.</p>","PeriodicalId":93947,"journal":{"name":"CNS & neurological disorders drug targets","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2026-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147792251","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Focused Ultrasound-activated Extracellular Vesicles-nanoparticle Hybrids for Targeted Brain Drug Delivery: Engineering Strategies and Translational Outlook.","authors":"Yash Kalra, Shikha Baghel Chauhan, Indu Singh, Chirag Jain","doi":"10.2174/0118715273460963260314133640","DOIUrl":"https://doi.org/10.2174/0118715273460963260314133640","url":null,"abstract":"<p><p>A revolutionary method for targeted neurotherapeutics is focused ultrasound (FUS)-mediated blood-brain barrier (BBB) regulation. In order to enable controlled and targeted intracerebral drug delivery, recent developments in hybrid extracellular vessssicle-nanoparticle (EV-NP) platforms combine the biological compatibility of natural vesicles with the adjustable characteristics of synthetic nanocarriers. The engineering approaches, translational difficulties, and molecular underpinnings of FUS-activated EV-NP hybrids are all thoroughly examined in this paper. Mechanistically, FUS uses acoustic cavitation to provide a temporary and reversible opening of the blood-brain barrier, which allows therapeutic medicines to pass through selectively while reducing side effects. Thermosensitive lipid and perfluorocarbon inclusion, ligand-mediated targeting, and stimuli-responsive surface design are examples of engineering advancements that improve biodistribution and release accuracy. When compared to traditional systems, preclinical models show higher therapeutic indices, prolonged drug retention, and brain penetration efficiencies of up to 90%. Large-scale production, standardization, and regulatory validation still face difficulties, nevertheless, especially with regard to long-term safety and reproducibility. New developments have a strong emphasis on combining synthetic biology, microfluidics, and artificial intelligence to improve design parameters and guarantee clinical scalability. All things considered, FUS-activated EV-NP hybrids offer a potential new avenue for precision neuropharmacology, bridging the gap between next-generation tailored therapies and non-invasive delivery methods.</p>","PeriodicalId":93947,"journal":{"name":"CNS & neurological disorders drug targets","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2026-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147619090","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting Vascular Dementia: Pharmacological Mechanisms and Therapeutic Strategies.","authors":"Saloni Sharma, Devkant Sharma, Anjali Sharma","doi":"10.2174/0118715273440657260226125023","DOIUrl":"https://doi.org/10.2174/0118715273440657260226125023","url":null,"abstract":"<p><strong>Introduction: </strong>Vascular dementia is a leading cause of cognitive deterioration worldwide, caused by a complex interplay of pathological mechanisms such as disrupted cerebral blood flow, oxidative stress, neuroinflammation, and endothelial dysfunction. A clear knowledge of these mechanisms is crucial for developing efficient treatment strategies. Various drug classes, including statins, cholinesterase inhibitors, anti-diabetic drugs, leukotriene antagonists, and nootropics, offer promising approaches by addressing different facets of this multifaceted condition. This review's objective is to offer a comprehensive analysis of the functional mechanisms of diverse pharmacological agents in curing vascular dementia. It further aims to identify their therapeutic potential, limitations, and areas requiring future research.</p><p><strong>Methodology: </strong>A review of the literature was conducted to examine evidence from preclinical and clinical research. Pharmacological chemicals were evaluated for their effects on key pathological pathways, including oxidative stress, inflammation, endothelial dysfunction, and impaired neurotransmission.</p><p><strong>Result and discussion: </strong>Each class of drugs reviewed demonstrates distinct benefits in addressing specific aspects of vascular dementia. Statins primarily mitigate vascular risk factors and neuroinflammation, while cholinesterase inhibitors enhance neurotransmitter availability to support cognitive function. Anti-diabetic drugs exhibit neuroprotective properties through metabolic regulation and antiinflammatory effects, and leukotriene antagonists show potential in reducing oxidative damage and inflammation. Nootropics, on the other hand, focus on enhancing synaptic plasticity and memory. Despite these promising mechanisms, limitations such as inconsistent clinical outcomes, potential adverse effects, and the absence of individualized treatment protocols remain significant challenges.</p><p><strong>Conclusion: </strong>This review emphasizes the need for developing integrated therapeutic strategies that target the diverse pathological mechanisms underlying vascular dementia. While current pharmacological approaches show considerable potential, there is a desperate need for long-term clinical validation and the development of personalized medicine frameworks. Advances in diagnostic tools, biomarkers, and imaging technologies will be crucial for early diagnosis and effective disease monitoring, paving the way for improved patient results and a more profound understanding of vascular dementia's complexity.</p>","PeriodicalId":93947,"journal":{"name":"CNS & neurological disorders drug targets","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2026-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147596845","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}