Molecular Neurobiology最新文献

{"title":"Pharmacogenetic Impact of CYP2C19 Variants on Diazepam Treatment Outcomes in Alcohol Withdrawal Syndrome.","authors":"Selin Özkan-Kotiloğlu, Kenan Can Tok, Mustafa Danışman, Mukaddes Asena Yıldırım, Ceren H Bozmaoğlu, Mehmet Gumustas, İnci Özgür-İlhan, Özlem Doğan, H Sinan Süzen, Dilek Kaya-Akyüzlü","doi":"10.1007/s12035-026-06282-0","DOIUrl":"10.1007/s12035-026-06282-0","url":null,"abstract":"<p><p>Diazepam (DZP) is widely accepted as an effective pharmaceutical intervention for treating Alcohol Withdrawal Syndrome (AWS), and its efficacy and metabolic profile are influenced by genetic variations in the CYP2C19 gene. The objective of the present study was to investigate the impact of the CYP2C19*2 and CYP2C19*17 phenotypes on DZP metabolism. Whole blood samples were collected from 114 patients with AWS following a 10-day course of oral DZP therapy. Genotyping was performed using PCR-RFLP. Plasma concentrations of DZP and nordiazepam (NDZP) were determined using HPLC-UV. The CYP2C19*17 TT genotype (1.597 ± 0.589) showed a significantly higher metabolic ratio (MR) compared to CC (1.159 ± 0.423) and CT (1.374 ± 0.368) genotypes (p = 0.015). Withdrawal severity after treatment was significantly lower in TT carriers than in CC and CT genotypes (p = 0.043). Pharmacokinetic and clinical parameters varied across CYP2C19 diplotypes, with ultrarapid (*17/*17) and rapid (*1/*17) metabolisers demonstrating higher MR and lower withdrawal severity compared to extensive metabolisers (*1/*1). The CYP2C19*2 haplotype was associated with higher dose-normalised DZP concentrations, whereas CYP2C19*17 was associated with a higher metabolic ratio. This study is the first to quantify plasma DZP and NDZP levels after 10-day oral administration and link them to CYP2C19*2 and CYP2C19*17 genotypes, haplotypes and diplotypes. The metabolic ratio (NDZP/DZP) emerged as a more integrative indicator of CYP2C19 activity than absolute levels, highlighting the complex genotype-phenotype relationship in DZP metabolism. Notably, the CYP2C19*17 gain-of-function allele significantly was associated with increased metabolic efficiency and improved clinical outcomes in AWS.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":"63 1","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149216469","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":"Caffeine and Exercise in Obesity-Associated Brain Aging and Neurodegeneration: Mechanistic Insights into AMPK/SIRT1/PGC-1α, BDNF/TrkB, and NLRP3 Inflammasome Signaling.","authors":"Xiao Yan, Jianying Li, Ting Wang","doi":"10.1007/s12035-026-06151-w","DOIUrl":"10.1007/s12035-026-06151-w","url":null,"abstract":"<p><p>Brain aging and neurodegenerative disorders are increasingly associated with metabolic dysfunction, chronic low-grade inflammation, and physical inactivity. Obesity may accelerate adverse brain aging through neuroinflammation, insulin resistance, mitochondrial dysfunction, altered metabolic flexibility, and impaired neuroplasticity. Physical exercise remains a cornerstone strategy for metabolic and brain health, although individual responses vary. Caffeine has emerged as a potential adjunct to exercise because of its ergogenic effects and its ability to modulate adenosine signaling, energy metabolism, inflammation, and neuroplasticity. This narrative review critically synthesizes human and preclinical evidence on caffeine, exercise, and their combination in relation to exercise performance, metabolic health, cognitive function, brain aging, and neurodegeneration, with particular emphasis on obesity. Acute caffeine ingestion may improve selected aspects of exercise performance, perceived exertion, alertness, and cognition, whereas chronic caffeine use combined with exercise may favor body composition, cardiometabolic health, and neuronal resilience. Responses depend on caffeine dose and timing, habitual intake, exercise modality and intensity, and individual characteristics. Mechanistic evidence indicates convergence on adenosine A1/A2A receptors, AMPK/SIRT1/PGC-1α, BDNF/TrkB, mitochondrial quality control, and NLRP3-related inflammatory signaling, providing a plausible basis for complementary effects on metabolic adaptation, neuroinflammation, mitochondrial homeostasis, and synaptic plasticity. However, direct evidence demonstrating true caffeine-exercise synergy, particularly for human brain aging or neurodegenerative outcomes, remains limited, with substantial reliance on indirect and preclinical findings. Caffeine should therefore be considered a context-dependent adjunct rather than a disease-modifying intervention. Future adequately powered, long-term randomized trials integrating cognitive outcomes, neuroimaging, and mechanistic biomarkers are needed to establish whether combined interventions exert additive, synergistic, or independent effects and to develop safe, personalized protocols.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":"63 1","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149194540","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":"Tissue Dissociation Workflows Influence Reactive Astrocyte Recovery in Single-Cell Transcriptomics.","authors":"Dominika Dostalova, Pavel Abaffy, Zuzana Matusova, Jan Kriska, Tomas Knotek, Denisa Kirdajova, Jana Tureckova, Martin Pavlicek, Pavla Jendelova, Miroslava Anderova, Lukas Valihrach","doi":"10.1007/s12035-026-06278-w","DOIUrl":"10.1007/s12035-026-06278-w","url":null,"abstract":"<p><p>Single-cell RNA sequencing has advanced our understanding of glial diversity, yet tissue dissociation remains an important technical variable. We revealed that a widely used commercial dissociation protocol can underrepresent reactive astrocytes in an acute ischemic stroke model, with preliminary observations indicating a comparable trend in a chronic tauopathy model. Benchmarking against an optimized, low-shear workflow demonstrates that different tissue dissociation workflows can substantially alter the recovery and apparent transcriptomic profile of disease-associated astrocytes, selectively losing signatures of morphological remodeling. Our findings indicate that workflow-dependent recovery biases affecting reactive astrocytes may be more prevalent than recognized, underscoring the need for pathology-tailored, gentle isolation workflows to avoid distortions in downstream neuropathological interpretations and the prioritization of therapeutic targets.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":"63 1","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13675257/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149207363","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Latent HIV Infection of BBB Pericytes Enhances Gap Junction-mediated Crosstalk with Endothelial Cells.","authors":"Sarah Schmidlin, Oandy Naranjo, Silvia Torices, Nikolai Fattakhov, Monika Gilicinska, Masha Minevich, Kyra A Schindler, Destiny Tiburcio, Olivia M Osborne, Arpan Acharya, Minseon Park, Mario Stevenson, Siddappa N Byrareddy, Michal Toborek","doi":"10.1007/s12035-026-06266-0","DOIUrl":"10.1007/s12035-026-06266-0","url":null,"abstract":"<p><p>HIV-Associated Neurocognitive Impairments persist, with over 50% of patients experiencing cognitive decline. Blood-brain barrier (BBB) impairment is a consistent feature of this comorbidity, which is remarkable, because BBB endothelial cells are not productively infected by HIV-1. Conversely, pericytes can be productively infected with HIV-1 and are essential for cerebrovascular homeostasis. Given this, we hypothesized that HIV-1 infection of pericytes disrupts BBB endothelial cell integrity through dysfunctional gap junction and hemichannel signaling, impairing pericyte-endothelial intercellular communication. Using a co-culture model with primary human BBB pericytes and brain microvascular endothelial cells, pericytes were infected with HIV-1 for 3 or 7 days, exhibiting active and latent viral phenotypes. Findings revealed enhanced gap junction communication between HIV-infected pericytes and endothelial cells under both conditions, and blocking gap junctions modulated endothelial inflammatory responses. Overall, this study advances our understanding of the molecular mechanisms underlying HIV-associated BBB dysfunction and may inform the development of targeted therapeutic strategies.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":"63 1","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13675307/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149207338","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Restoring Neural Homeostasis via Class II HDAC Modulation: Mechanistic Insights and Therapeutic Opportunities.","authors":"Rohan Gupta, Reetesh Kumar, Bhargav Shreevatsa K S, Deepak Kumar Modi, Smita Kumari, Naveen Kumar, Pallavi Singh, Karthikeyan Ravi, Mosleh Mohammad Abomughaid","doi":"10.1007/s12035-026-06265-1","DOIUrl":"10.1007/s12035-026-06265-1","url":null,"abstract":"<p><p>Class II histone deacetylases (HDACs) comprise class IIa enzymes HDAC4, HDAC5, HDAC7, and HDAC9 and class IIb enzymes HDAC6 and HDAC10, which differ substantially in structure, catalytic activity, subcellular localization, and neural function. Class IIa HDACs exhibit weak intrinsic deacetylase activity and function predominantly as signal-responsive scaffolds that couple calcium and kinase signaling to transcription through nucleocytoplasmic shuttling, recruitment of HDAC3-containing NCoR/SMRT corepressor complexes, and interactions with MEF2, CREB, and FOXO. Conversely, HDAC6 is a predominantly cytoplasmic deacetylase that regulates α-tubulin acetylation, cytoskeletal dynamics, axonal transport, autophagy, and proteostasis. Dysregulated class II HDAC signaling contributes to neurodegenerative diseases through convergent mechanisms involving synaptic dysfunction, maladaptive transcriptional repression, mitochondrial impairment, oxidative stress, neuroinflammation, blood-brain barrier disruption, and defective clearance of pathological proteins. Disease-associated substrates include amyloid-β and tau in Alzheimer's disease, α-synuclein in Parkinson's disease, mutant huntingtin in Huntington's disease, and TDP-43/SOD1 in amyotrophic lateral sclerosis. Emerging evidence additionally links aberrant HDAC4/5 signaling to neurodevelopmental disorders through altered synaptic maturation, excitation-inhibition balance, and circuit development. This review integrates the structural and mechanistic biology of class II HDACs with their disease-specific roles and evaluates therapeutic approaches to restore neural homeostasis. Particular emphasis is placed on selective HDAC6 inhibitors, modulation of class IIa protein-protein interactions and subcellular trafficking, natural compounds, and RNA-based strategies. Finally, we discuss major translational challenges, including isoform specificity, brain penetration, context-dependent functions, and the need to distinguish catalytic from non-enzymic mechanisms when developing disease-modifying interventions for neurological disorders while preserving normal essential HDAC functions and minimizing off-target toxicity.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":"63 1","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149182568","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":"C/EBPβ Drives Ischemia-Induced Microglial Inflammatory Reprogramming Through Transcriptional Activation of ATF3 and Exacerbates Brain Injury.","authors":"Zhongkai Zhang, Feinan Zhuo, Houqian Ouyang, Chuang Chi, Fu Zhang, Yiye Chi, Zhongxiao Lin","doi":"10.1007/s12035-026-06256-2","DOIUrl":"10.1007/s12035-026-06256-2","url":null,"abstract":"<p><p>Microglial activation contributes substantially to secondary brain injury after ischemic stroke, but the transcriptional mechanisms governing this response remain poorly defined. Here, we identified CCAAT/enhancer-binding protein β (C/EBPβ) as a key regulator of ischemia-induced microglial inflammation. RNA sequencing of microglia isolated from mice subjected to transient middle cerebral artery occlusion (tMCAO) revealed extensive transcriptional reprogramming, characterized by activation of inflammatory pathways, including chemokine, TNF, IL-17, and efferocytosis signaling, as well as cell-cycle programs, together with suppression of homeostatic processes involved in synaptic regulation and neuronal support. Network analysis identified Cebpb as a highly connected hub across multiple inflammatory pathways. C/EBPβ expression was markedly increased in peri-infarct microglia after tMCAO and in primary microglia exposed to oxygen-glucose deprivation/reoxygenation. Microglia-selective Cebpb knockdown reduced TNF-α, IL-1β, CCL2, and CD16 expression, increased IL-4, IL-13, and ARG1 expression, and attenuated ischemia-induced morphological remodeling. Consistent effects were observed in primary microglia and BV2 cells, supporting a central role for C/EBPβ in microglial pro-inflammatory activation under ischemic conditions. Mechanistically, C/EBPβ directly bound the Atf3 promoter and activated its transcription, while ATF3 partially mediated C/EBPβ-dependent Il1b induction. In vivo, microglial Cebpb knockdown reduced acute ischemic lesion volume, neuronal apoptosis in the striatum and cortex, and long-term cerebral atrophy. These histopathological improvements were accompanied by sustained recovery of neurological function, somatosensory performance, motor coordination, recognition memory, and spatial learning and memory. Collectively, these findings establish the C/EBPβ-ATF3 axis as a transcriptional pathway that promotes microglial inflammation and secondary neuronal injury after cerebral ischemia. Targeting microglial C/EBPβ may therefore limit ischemic brain damage and improve long-term neurological recovery after stroke.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":"63 1","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149195353","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":"Molecular Pathogenesis of Cerebral Amyloid Angiopathy in Alzheimer's Disease: The Role of the Central Fibrinolytic Cascade at the Neurovascular Unit.","authors":"Sachin Kumar, Shravan Kumar Paswan, Pritt Verma, Saurabh Chaturvedi, Vishal Kumar Vishwakarma, Harlokesh Narayan Yadav","doi":"10.1007/s12035-026-06263-3","DOIUrl":"10.1007/s12035-026-06263-3","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is increasingly recognized as a multifactorial neurodegenerative disorder involving complex neurovascular pathology. Departing from classic neurocentric paradigms, this review provides a conceptually novel perspective on how vascular inflammation and dysfunction actively drive AD progression through the lens of cerebral amyloid angiopathy (CAA) pathology. We evaluate the bidirectional cascade between amyloid-β pathology and the neurovascular unit, highlighted by cerebrovascular alterations and blood-brain barrier disruption. Crucial for cerebral homeostasis, the central nervous system's fibrinolytic pathway plays a dual role in this cascade, where the dysregulation of tissue plasminogen activator (tPA), plasminogen activator inhibitor 1 (PAI-1), and plasminogen accelerates CAA. We posit that suppressed fibrinolytic activity impedes amyloid-β clearance, while aberrant plasminogen-amyloid-β interactions paradoxically trigger localized inflammatory and thrombotic cascades that exacerbate vascular injury. By looking beyond traditional, neuron-centered models of Alzheimer's, fibrinolytic regulation and vascular repair offer a powerful new way to intervene. Bringing these discoveries to the clinic means finding a way to clear amyloid-β without tipping the scale toward bleeding risks. If we can map these complex vascular-fibrinolytic links, we can open the door to early intervention to design targeted therapies that prevent vascular damage and fundamentally change the trajectory of CAA and Alzheimer's disease.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":"63 1","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149194763","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":"Gut Microbiota Modulation in CNS Disorders: Therapeutic Strategies and Implications for Drug Efficacy.","authors":"Lamiaa A Ahmed, Khaled F Al-Massri","doi":"10.1007/s12035-026-06192-1","DOIUrl":"10.1007/s12035-026-06192-1","url":null,"abstract":"<p><p>Various central nervous system (CNS) disorders, including neurodegenerative diseases, depression, schizophrenia, epilepsy, and anxiety, present significant obstacles to public health because of their intricate causes and the scarcity of effective treatments. Recent studies have shown that gut microbiota (GM) and CNS communicate bidirectionally. Modulation of immune system, neurotransmitters, and neuroactive metabolites are only a few examples of how GM can significantly influence CNS. Dysbiosis or changes in composition and function of gut microbes play a contributing role in various CNS disorders. In these disorders, probiotics, prebiotics, fecal microbiota transplantation, antibiotics use, and interventions based on microbial metabolites have demonstrated beneficial effects in animal models and some clinical studies. By restoring microbial equilibrium, increasing microbial diversity, and promoting the generation of beneficial metabolites, these approaches can improve the efficacy of traditional medications while minimizing their side effects and the disease itself, based on preclinical evidence and emerging clinical studies. Nevertheless, several obstacles should be overcome before the clinical translation of these approaches, such as using of standardized methods for modulating GM, identifying specific microbial signatures linked to various CNS illnesses, and understanding the exact mechanisms of gut-brain communication. This review provides a novel integrated perspective by comprehensively clarifying the bidirectional interactions between CNS pharmacological agents and microbiota-based therapeutic strategies in different neurological and psychiatric disorders, offering a unified framework to improve traditional pharmacological therapies. Importantly, future studies should concentrate on exploring the mechanisms and the exact interconnections between GM and CNS problems to elaborate targeted therapies for these disorders.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":"63 1","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13672476/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149194606","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"β-Cyclodextrin-Complexed 1,8-Cineole Attenuates Motor Deficits and Preserves Tyrosine Hydroxylase Immunoreactivity in a Reserpine-Induced Mouse Model of Parkinsonism.","authors":"Luan Araújo-Monteiro, Beatriz Soares-Silva, Patrícia Santos Carvalhinho-Lopes, Valéria Cunha Moreira, Barbara Vitória de Campos Cruz Binatto, Ellen Games Jacob Pereira, Ana Paula Nascimento de Lima, Lucindo José Quintans-Junior, José Ronaldo Dos Santos, Alessandra Mussi Ribeiro","doi":"10.1007/s12035-026-06262-4","DOIUrl":"10.1007/s12035-026-06262-4","url":null,"abstract":"<p><p>Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by dopaminergic dysfunction and motor impairment. Natural compounds have emerged as promising candidates for neuroprotection and symptomatic relief in experimental models of PD. This study investigated the effects of β-cyclodextrin-complexed 1,8-cineole (CIN) in a reserpine (RES)-induced mouse model of parkinsonism. Male mice were treated with RES (0.1 mg/kg, s.c., every 48 h) and/or CIN (5 mg/kg, p.o., once daily) for 30 days. Behavioral assessments evaluated motor, sensorimotor, and locomotor function. Tyrosine hydroxylase (TH) and α-synuclein immunoreactivity were assessed by immunohistochemistry. Repeated RES administration induced progressive motor and sensorimotor impairments and reduced TH immunoreactivity in mesencephalic dopaminergic nuclei. CIN treatment significantly reduced catalepsy, vacuous chewing movements, and chin tremors and improved sensorimotor performance in the adhesive removal test. These behavioral effects were accompanied by preservation of TH immunoreactivity in the substantia nigra pars compacta (SNpc) and ventral tegmental area (VTA). However, CIN did not significantly alter hippocampal α-synuclein immunoreactivity. These findings indicate that β-cyclodextrin-complexed CIN attenuates motor and sensorimotor deficits and is associated with preservation of dopaminergic markers in a RES-induced mouse model of parkinsonism. These results support further investigation of CIN as a neuroactive compound in experimental models of PD.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":"63 1","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13672656/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149194761","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Omega-3 Fatty Acid Pretreatment Modulates Mitochondrial Quality-Control and PINK1/PARKIN-Related Gene Expression in Acute LPS-Induced Neuroinflammation.","authors":"Serpil Demirci, Sanem Asci, Halil Asci, Melike Dogan Unlu, Abdurrahman Gulal, Ilter Ilhan","doi":"10.1007/s12035-026-06236-6","DOIUrl":"10.1007/s12035-026-06236-6","url":null,"abstract":"<p><p>Neuroinflammation contributes to central nervous system injury through interconnected oxidative, glial, apoptotic, and mitochondrial responses. Omega-3 (OM-3) fatty acids are neuroprotective, but their association with mitochondrial quality-control pathways during acute neuroinflammation remains incompletely defined. This study examined the preventive effects of OM-3 pretreatment in a lipopolysaccharide (LPS)-induced neuroinflammation model. Adult female Wistar albino rats (n = 8/group) were randomly assigned to Control, LPS (5 mg/kg, intraperitoneal), LPS + OM-3 (OM-3, 0.5 g/kg/day intraperitoneally for 3 days before LPS), and OM-3 groups. Six hours after LPS administration, brain and cerebellar tissues were evaluated by histopathology, immunohistochemistry (8-OHdG, Cas-3, and GFAP), qRT-PCR for apoptosis-, antioxidant-, mitochondrial biogenesis-, and mitophagy-related transcripts, and biochemical assessment of total antioxidant status (TAS), total oxidant status (TOS), and oxidative stress index (OSI). LPS increased histopathological injury and 8-OHdG, Cas-3, and GFAP immunoreactivity; increased BAX/BCL-2, PINK1, PARKIN, and SNCA transcript levels; reduced PGC-1alpha and NRF2-related antioxidant responses; decreased TAS; and increased OSI. OM-3 pretreatment attenuated many of these changes relative to LPS alone. However, several outcomes remained significantly different from Control, indicating partial rather than complete reversal. Because PINK1 and PARKIN were measured only at the mRNA level, the findings demonstrate modulation of the transcriptional response of mitophagy-related genes and do not establish functional mitophagic flux. In this 6-h acute preventive model, OM-3 pretreatment was associated with partial neuroprotection and modulation of transcriptional markers linked to antioxidant defense and mitochondrial quality Control. Protein-level and flux assays, later time points, and post-injury treatment designs are required before functional restoration of mitophagy or therapeutic efficacy can be concluded.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":"63 1","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149194756","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}