Metabolic brain disease最新文献

{"title":"Majoon-e-Boolis as a neurotherapeutic agent: cognitive and neuronal restoration in alzheimer's disease model.","authors":"Owais Hassan Wani, Prashant Dhaka, Pinky, Shahid Shah Choudhary, Asrar Ahmad Wani, Arsheed Iqbal, Suhel Parvez, Tanveer Ali Dar","doi":"10.1007/s11011-026-01952-3","DOIUrl":"10.1007/s11011-026-01952-3","url":null,"abstract":"<p><p>Majoon-e-Boolis (MB), a traditional Unani formulation, has been used for neurological conditions; however, its molecular mechanism remains largely unexplored. The current study was designed to explore the novel mechanistic insights between antioxidant activity, anti-inflammatory effects, dopaminergic support and anti-aggregation properties of the formulation for modulating the pathogenesis of Alzheimer's Disease (AD). Behavioral deficits were studied via Novel Object Recognition, Elevated Plus Maze and Open Field Test. In addition, the study looked at the immunohistochemistry of superoxide dismutase 2, tumor necrosis factor-alpha, tyrosine hydroxylase and α-synuclein (α-Syn) against Aβ1-42-induced AD model. Additionally, histopathological alterations were also performed against the AD model. The observed findings demonstrated that MB treatment in Aβ1-42-induced AD in rat models significantly improved their cognitive impairments and alleviated anti-anxiety behaviour with enhanced locomotor activity. Moreover, MB induced significant reduction in oxidative stress and neuroinflammation with enhanced dopaminergic neuronal activity. GC-MS analysis of MB revealed the presence of bioactive phytochemicals such as thiophene, guanidinopropionic acid, 5-hydroxymethylfurfural etc. The findings underscore the potential of MB as a promising therapeutic agent in mitigating the multifaceted pathology of Aβ1-42-induced AD in a rat model by exerting its neuroprotective effects, cognition restoration and overall maintenance of neuronal architecture through a combination of antioxidant, anti-inflammatory and anti-aggregation mechanisms, making it a multifaceted therapeutic candidate for AD.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"41 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148721321","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multi-omics analysis of untargeted metabolomics and gut microbiota study on the mechanism of Astragalus-Safflower to coordinate the regulation of energy metabolism pathways and gut microbiota remodeling to improve ischemic stroke.","authors":"Junmin Fu, Fuyu Liu, Yun Han, Yonggang Feng, Kaixin Shan, Mimi Wang, Xiang Meng, Haibo Zhang, Mingsan Miao, Suxiang Feng, Xiaoyan Fang","doi":"10.1007/s11011-026-01950-5","DOIUrl":"10.1007/s11011-026-01950-5","url":null,"abstract":"<p><p>Ischemic stroke (IS) is a detrimental neurological disorder with limited clinical therapeutic options. The Astragalus-Safflower herb pair (AS) shows therapeutic effects against IS, but its mechanism remains unclear. Herein, this study combined cerebral untargeted metabolomics, mitochondrial ultrastructural observation and 16 S rDNA gut microbiota profiling to systematically explore its neuroprotective mechanism. This study aimed to evaluate the efficacy of AS in alleviating IS, and investigate its mechanism of action. Rat models of middle cerebral artery occlusion (MCAO) were established using the intraluminal filament method. Behavioral tests confirmed that AS significantly improved neurological deficits and motor function. Untargeted metabolomics revealed that AS reversed nine IS-related energy metabolites in brain tissue. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment indicated involvement of nicotinamide metabolism and the TCA cycle. Molecular studies demonstrated that AS regulated mitochondrial energy metabolism via the AMPK/Sirt1/PGC-1α axis. Additionally, 16 S rDNA sequencing showed that AS restructured gut microbiota composition. Correlation analysis suggested a gut-brain axis mechanism linking microbial changes to cerebral energy metabolism. In conclusion, AS exerts neuroprotection against IS by activating the AMPK/Sirt1/PGC-1α pathway, thereby enhancing TCA cycle activity and maintaining energy homeostasis. Concurrently, AS reshapes the gut microbiota, contributing to its effects via the gut-brain axis. Taken together, this integrated multi-omics study systematically clarifies the multi-target pharmacological characteristics of AS. These findings provide a novel multi-target mechanistic basis for the clinical application of AS in the treatment of IS and enrich the understanding of its synergistic neuroprotective mechanism.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"41 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148722022","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrative transcriptomic and genetic analysis implicates fatty acid metabolic reprogramming in perivascular macrophages in Alzheimer's disease.","authors":"Fan Wang, Xiangyang Wang, Yuhui Chen, Qing Li, Shuo Wang, Min Cai, Jianhua Zhao","doi":"10.1007/s11011-026-01949-y","DOIUrl":"10.1007/s11011-026-01949-y","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Dysregulated lipid metabolism and neuroinflammation are increasingly recognized as interacting contributors to Alzheimer's disease (AD), but the cell-type-specific genetic links between fatty acid metabolism and AD remain incompletely defined. This study aimed to identify fatty acid metabolism-related genes associated with AD risk and to characterize their relevance to perivascular macrophage (PVM) states. Single-cell RNA-sequencing data from GSE160936 and bulk transcriptomic data from GSE270454 were integrated to evaluate cell-type-specific fatty acid metabolism activity in AD and control samples.The primary data sources, fatty acid metabolism gene set, AUCell scoring strategy, CellChat workflow, GSEA resources, and MR software settings were specified to improve reproducibility. PVMs were further analyzed for differential expression, ligand-receptor communication, pathway enrichment, transcription factor regulation, and pseudotime-associated transcriptional changes. Cis-eQTL-based two-sample Mendelian randomization was performed using eQTLGen exposure data and AD GWAS summary statistics, followed by sensitivity analyses, reverse MR, and Bayesian colocalization.The analyses were interpreted across three distinct evidence levels: cell-type-resolved transcriptional association, systemic genetic expression prioritization, and tissue-level protein expression. Nominal MR findings were interpreted alongside multiple-testing considerations and colocalization support.Candidate protein expression was examined in hippocampal tissue from APP/PS1 and wild-type mice by Western blotting. Single-cell analysis identified eight major cell populations and showed increased fatty acid metabolism activity in PVMs from AD samples. Mendelian randomization prioritized ten fatty acid metabolism-related genes associated with AD risk, among which ACSL1, EPM2AIP1, MALT1, and RASGRP3 showed strong colocalization support (PP.H4 &gt; 0.9). Pathway analyses linked these genes to lipid metabolic regulation, inflammatory signaling, phagocytosis, and mitochondrial/peroxisomal fatty acid metabolism. Co-expression analysis suggested associations between MALT1 and fatty acid oxidation-related genes, including ACADM and ACOX1. Western blotting in whole hippocampal lysates from APP/PS1 mice provided exploratory tissue-level protein evidence, showing increased ACSL1 and MALT1 and decreased RASGRP3 expression; these findings should not be interpreted as confirmatory PVM-specific validation. This integrative analysis prioritizes ACSL1, EPM2AIP1, MALT1, and RASGRP3 as candidate genes connecting fatty acid metabolic dysregulation with AD-associated neuroinflammatory processes. Because the genetic instruments were blood-derived and the protein assays used whole hippocampal lysates, the findings should be interpreted as candidate-gene prioritization and hypothesis generation rather than proof of direct PVM-specific causality.Accordingly, the study supports a prioritized candidate framework","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"41 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148706912","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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 TLR4-NF-κB-FDX1 cuproptosis axis in mediating cognitive impairment associated with type 1 diabetes in children: an exploratory mechanistic study.","authors":"Jiao Wang, Li-Hai Zhang, Xiang-Yu Meng, Yu-Ming Kang","doi":"10.1007/s11011-026-01913-w","DOIUrl":"10.1007/s11011-026-01913-w","url":null,"abstract":"<p><p>This study explored how the TLR4-NF-κB-FDX1 cuproptosis axis contributes to type 1 diabetes (T1DM)-related cognitive impairment, seeking to uncover novel intervention targets. Key genes were screened from T1DM datasets via bioinformatics analysis. Primary hippocampal neurons, HBMECs, and a Transwell co-culture BBB model were established under high glucose plus copper overload. Cells received TLR4 inhibitor TAK-242 or FDX1 knockdown. A streptozotocin-induced T1DM mouse model was generated, followed by stereotaxic injection of TLR4-shRNA or FDX1-shRNA adenovirus. Cell viability, cuproptosis markers, BBB permeability, cognitive behaviors, and underlying mechanisms were assessed by CCK-8, ICP-MS, TEER, behavioral tests, Western blot, immunofluorescence, and ChIP-qPCR. FDX1 was markedly upregulated in T1DM and strongly correlated with TLR4/NF-κB. In vitro, high glucose plus copper overload activated the TLR4-NF-κB-FDX1 axis, induced DLAT lipoylation aggregation and cuproptosis, and caused neuronal synaptic injury along with disruption of endothelial tight junctions. Blocking TLR4 or knocking down FDX1 significantly attenuated these damages. In vivo, T1DM mice showed cognitive deficits and BBB disruption, both rescued by TLR4 or FDX1 knockdown. ChIP-qPCR confirmed that NF-κB bound directly to the FDX1 promoter to enhance its transcription. This study demonstrated for the first time that the TLR4-NF-κB-FDX1 cuproptosis axis plays a key pathological role in T1DM-related cognitive impairment, offering a new avenue for targeted therapy.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"41 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148679374","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oleuropein regulates neuronal survival and Histone acetylation in Parkinson's disease: cellular and epigenetic insights.","authors":"Richa Singh, Aaina Singh Rathore, Arunim Shah, Priyanka Kumari Keshri, Hagera Dilnashin, Nitesh Kumar Gupta, Singh Ankit Satyaprakash, Shekhar Singh, Chandra Prakash Chaturvedi, Surya Pratap Singh","doi":"10.1007/s11011-026-01945-2","DOIUrl":"10.1007/s11011-026-01945-2","url":null,"abstract":"<p><p>The complex physiology of Parkinson's disease (PD) and its limited response to conventional therapies make it a challenging condition to manage. Evidence suggests that both environmental and genetic variables play essential roles in the progression of PD. However, the possible interplay between environment and genetics in PD etiology remains mostly unresolved. Brain-derived neurotrophic factor (BDNF) is a neurotrophin widely distributed and intensively investigated in the mammalian brain. BDNF modulates dopaminergic neurotransmission via neuronal differentiation regulation. BDNF communicates with the Tropomyosin receptor kinase B (TrkB) and activates Extracellular Signal-Regulated Kinase 1/2 (ERK1/2) which can subsequently phosphorylate downstream CREB protein at ser133 residue. Research suggests that numerous health advantages, including significant protections for PD, have been linked to olives, a specific component of the Mediterranean diet. OLE is effective in the treatment of a variety of neurological conditions, including PD. Changes in gene expression patterns induced by aberrant histone acetylation can also aid in the causes of PD. Thus, in the context of neurological diseases, comprehending the epigenetic regulation of the neuronal survival gene is thought to be essential. OLE was first administered intraperitoneally as a pretreatment for seven days. Thereafter, OLE was administered one hour after the rotenone injection for 5 weeks. Herein, we have observed the neuroprotective role of OLE in the cellular signalling cascade associated with neuronal survival through the BDNF/ERK/CREB pathway. Subsequently, we examined the effect of OLE on the enrichment of histone acetylation AcH3K9 in the neuro-survival gene promoter region in PD cases. The data suggest that OLE regulates at both cellular and epigenomic levels by promoting the enrichment of acetylated H3K9 on the neuro-survival gene promoter region in the nigrostriatal region of PD mice.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"41 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148630950","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Polysaccharide-driven gut microbial metabolism in neurodegenerative brain diseases: from SCFAs and tryptophan catabolites to neuroinflammatory regulation.","authors":"Chengqi Peng, Lingxiao Chen, Zongyao Wu, Cizhen Danzeng, Xiaorui Cheng","doi":"10.1007/s11011-026-01946-1","DOIUrl":"10.1007/s11011-026-01946-1","url":null,"abstract":"<p><p>The gastrointestinal tract constitutes the principal anatomical interface of the microbiota-gut-brain axis (MGBA), orchestrating neuroimmune and metabolic crosstalk. Dysregulation within this network drives neurodegenerative pathogenesis through altered microbial metabolism, peripheral immune activation, and subsequent aggregation of pathological proteins in the central nervous system (CNS). Natural bioactive polysaccharides modulate this axis primarily via indirect, microbiota-dependent mechanisms-acting as fermentable prebiotics that reshape gut ecology and metabolite profiles-rather than through direct CNS penetration of intact macromolecules. These macromolecules promote neuroprotective short-chain fatty acids (SCFAs) that reinforce mucosal and blood-brain barrier (BBB) integrity. At the molecular level, polysaccharide interventions attenuate the TLR4/NF-κB/NLRP3 inflammatory cascade and upregulate Nrf2/BDNF neurotrophic signaling, effects predominantly mediated by microbiota-derived metabolites and peripheral-to-central signaling, with limited evidence for direct CNS entry of low-molecular-weight fractions. This review evaluates the pharmacological mechanisms of natural polysaccharides in neurodegenerative disorders, focusing on microbe-derived metabolic regulation, immune homeostasis, and clearance of neuropathological aggregates. While preclinical efficacy is promising, clinical translation demands rigorous structure-activity relationship mapping and specialized targeted delivery platforms.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"41 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148630983","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"T₃ and curcumin regulates collagen-IV and collagen-VI expression: role in suppression of amyloid-β via TGFβ1-Sp1 signaling in hypothyroid mice brain.","authors":"Sulata Kumari Sahu, Madhusmita Nayak, Achyutananda Samal, Sarita Jena, Jyotsnarani Pradhan, Jagneshwar Dandapat, Luna Samanta, Srikanta Jena","doi":"10.1007/s11011-026-01937-2","DOIUrl":"10.1007/s11011-026-01937-2","url":null,"abstract":"<p><p>Hypothyroidism has been associated with cognitive disorders and high risk of neurodegenerative disorders like Alzheimer's disease (AD), which is caused by amyloid-β (Aβ) accumulation in brain. The aim of the study is to examine the therapeutic ability of triiodothyronine (T₃) and curcumin in regulating two key extracellular matrix proteins (ECM), collagen IV and collagen VI in brain since both drugs have neuroprotective and anti-fibrotic effects. The study further explored the possible role of signaling molecules such as transforming growth factor β1 (TGFβ1) and specificity protein 1 (Sp1) in regulating the effects of T₃ and curcumin on Aβ accumulation and ECM protein expression. Experiment was carried on Balb/c mouse model by inducing hypothyroidism with 0.05% PTU followed by treatment of T₃, curcumin and a combination of both. The study revealed a significant increase in the expression of collagen IV and VI, along with elevated levels of TGFβ1 and Sp1 signalling proteins, in hypothyroid conditions in response to increased Aβ expression in both the cortex and hippocampus. Western blot and RT-PCR analysis showed that T₃ and curcumin treatment downregulate the levels of ECM proteins, the APP gene, Aβ protein, and the signaling factors. The study found that T₃ and curcumin treatment downregulates the collagen IV and VI expression by negatively regulating TGFβ1 and Sp1 when expression of APP and Aβ are low. T₃ and coadministration of T₃ with curcumin more effectively regulate thyroid function and ECM protein expression in both the cortex and hippocampus. Whereas curcumin alone exhibits limited impacts under the experimental conditions in our study, this may due to bioavailability, dosage or treatment duration which need to further investigation. Our results indicate a novel therapeutic approach for understanding Aβ pathology associated with hypothyroidism, emphasizing the potential association between thyroid hormone and nature-based compounds, such as curcumin, in modulating ECM dynamics and neuroprotection.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"41 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148579378","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Blockade of the SP/NK1 receptor axis: multimodal neuroprotection via inflammatory suppression, hypoxic modulation, and lympho-vascular remodeling in global cerebral ischemia.","authors":"Mehmet Öz, Erdem Arslan","doi":"10.1007/s11011-026-01943-4","DOIUrl":"10.1007/s11011-026-01943-4","url":null,"abstract":"<p><p>Transient global cerebral ischemia (tGCI), often precipitated by cardiac arrest, triggers severe neuroinflammation, oxidative stress, and hypoxia, culminating in diffuse delayed neuronal death and debilitating cognitive-affective dysfunctions. Substance P (SP) and its neurokinin-1 (NK1) receptor act as critical upstream mediators in this pathological cascade. To interrogate this biological pathway and rescue acute stroke-induced behavioral deficits, this study investigated the multifaceted neuroprotective efficacy of the NK1 receptor antagonist maropitant, utilizing a rat two-vessel occlusion (2VO) model as a translational platform. Male Wistar rats were divided into Sham (CON), Ischemia-Reperfusion (I/R), and I/R + Maropitant (I/R + MAR; 10 mg/kg, i.p., immediately post-ischemia) groups. Following a 60-minute occlusion and 24-hour reperfusion, behavioral paradigms (Open Field, Elevated Plus Maze, Forced Swim, Novel Object Recognition) were conducted. Subsequent biochemical (TNF-α, MPO, Caspase-3, HIF-1α, VEGF, BDNF) and histopathological/immunohistochemical (H&E, CD34, LCA, D2-40) analyses were performed on serum and hippocampal/cortical tissues. Maropitant administration significantly ameliorated I/R-induced memory impairment and mitigated anxiety- and depressive-like behaviors without altering general locomotion. Biochemically, targeted NK1 receptor blockade markedly attenuated central and systemic levels of TNF-α, MPO, Caspase-3, HIF-1α, and VEGF, while modulating stress-induced BDNF surges. Histopathologically, maropitant preserved cytoarchitecture by significantly reducing necrotic and degenerative cell counts across the cerebral cortex, CA3, and dentate gyrus. Crucially, immunohistochemical evaluation revealed that while maropitant suppressed post-ischemic leukocyte infiltration (LCA), it distinctly promoted functional neovascularization (CD34) and robust lymphatic vessel expansion (D2-40), facilitating tissue clearance. Targeted pharmacological blockade of the SP/NK1 receptor axis provides robust neuroprotection by dampening neuroinflammatory and apoptotic cascades while driving constructive lympho-vascular remodeling. These findings highlight NK1 receptor antagonism as a highly promising therapeutic strategy for mitigating acute ischemic brain injury and associated functional deficits.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"41 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148579373","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pentoxifylline targets TLR4/MyD88/NF-κB signaling to ameliorate neuroinflammation and metabolic dysfunction in a rat model of chronic hypoperfusion-induced vascular cognitive impairment.","authors":"Xiaohan Wang, Bingchuan Xie, Xiaoyang Yuan, Jiaying Rong, Xiaojing Lv, Qingying Ma, Li Shen, Bing Han","doi":"10.1007/s11011-026-01934-5","DOIUrl":"10.1007/s11011-026-01934-5","url":null,"abstract":"<p><p>Vascular cognitive impairment (VCI) driven by chronic cerebral hypoperfusion lacks disease-modifying therapy. We tested whether pentoxifylline (PTX), a methylxanthine phosphodiesterase inhibitor with dual hemorheological and anti-inflammatory properties, attenuates VCI-like cognitive and inflammatory abnormalities in a rat model. Three-month-old male Sprague-Dawley rats underwent bilateral common carotid artery occlusion (BCCAO) or sham surgery. PTX (60 mg kg⁻1 day⁻1, gavage) or vehicle was administered for 28 days starting 24 h post-operation. Spatial cognition was assessed with the Morris water maze; neuronal injury, microglial activation, and glucose metabolism were evaluated by histology, immunofluorescence, 1⁸F-FDG PET/CT, and western blotting. Systemic and hippocampal cytokines were quantified by multiplex immunoassay; TLR4/MyD88/NF-κB signaling was profiled by RNA-seq and western blotting. BCCAO induced progressive cognitive deficits without sustained weight loss, paralleled by CA1 neuronal damage, microglial proliferation, and marked elevations of IL-1β, IL-2, IL-17, and TNF-α in plasma and hippocampus. PTX shortened escape latency, restored probe-trial platform crossings, preserved neuronal morphology, suppressed microglial Iba-1⁺/Ki67⁺ expansion, and reduced all four cytokines. Mechanistically, PTX down-regulated TLR4, MyD88, and NF-κB p65 mRNA and protein, reduced nuclear translocation of NF-κB p65, and partially reversed frontal and hippocampal glucose hypometabolism. Peripheral IL-1β and IL-17 levels correlated positively with cognitive impairment. Pentoxifylline concurrently mitigates hypoperfusion-associated neuroinflammation, neuronal injury, and glucose hypometabolism via inhibition of the TLR4/MyD88/NF-κB axis, supporting PTX as a readily translatable candidate for early VCI intervention.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"41 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148562468","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"From synaptic development to degeneration: a narrative review of small molecule strategies targeting alpha-synuclein in Parkinson's disease.","authors":"Leanne Khoo, Khuen Yen Ng, Cien Leong Chye, Yi Ko, Jia Yee Lee, Yian Koh, Min Tze Tsen, Soi Moi Chye","doi":"10.1007/s11011-026-01911-y","DOIUrl":"10.1007/s11011-026-01911-y","url":null,"abstract":"<p><p>Aggregation of α-synuclein (α-Syn) is a defining pathological feature of Parkinson's disease (PD), contributing to progressive neuronal dysfunction and death. Unlike prior reviews focused predominantly on aggregation as an isolated endpoint, this review proposes a neurodevelopmental-neurodegenerative continuum as an interpretive framework, suggesting that α-Syn's physiological roles in synaptic development and circuit maturation may be linked to its later pathological behaviour. Within this context, we discuss recent advances in small-molecule strategies targeting key stages of α-Syn pathology, including synthesis, misfolding, aggregation, post-translational modification, and clearance. These include translation and misfolding inhibitors, aggregation modulators such as minzasolmin (UCB0599), epigallocatechin gallate and anle138b, as well as compounds that enhance α-Syn degradation through autophagy-lysosomal and ubiquitin-proteasome pathways. Additional strategies targeting proteostasis and mitochondrial dysfunction are also considered. Beyond its pathogenic role, α-Syn contributes to synaptic vesicle trafficking, neurotransmitter release, and neuronal maturation, and disruption of these functions may increase vulnerability to later neurodegeneration. In conclusion, small-molecule-based therapies represent a promising multi-targeted strategy for PD; however, key translational challenges and unresolved questions remain, including optimisation of pharmacokinetics, target specificity, and blood-brain barrier (BBB) penetration and validation in clinical settings.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"41 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148562437","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}