Journal of Neurochemistry最新文献

{"title":"Unveiling the Therapeutic Potential of D2AAK1 and Its Derivatives: Mechanistic Insights and Applications in Neurodegenerative Disease Treatment","authors":"Michał K. Jastrzębski,&nbsp;Piotr Wójcik,&nbsp;Akanksha Mudgal,&nbsp;Sylwia Woźniak,&nbsp;Katarzyna M. Targowska-Duda,&nbsp;Olga Wronikowska-Denysiuk,&nbsp;Agnieszka Michalak,&nbsp;Witold Jeleniewicz,&nbsp;Tadeusz Karcz,&nbsp;Jan Raczek,&nbsp;Andrzej Stepulak,&nbsp;Agnieszka A. Kaczor","doi":"10.1111/jnc.70232","DOIUrl":"https://doi.org/10.1111/jnc.70232","url":null,"abstract":"<div>\u0000 \u0000 <p>The global rise in life expectancy has been accompanied by a growing prevalence of neurodegenerative diseases, such as Alzheimer's disease (AD). These complex disorders arise from multiple pathogenic factors and biological pathways, necessitating the development of multi-target therapeutic strategies. D2AAK1, discovered by our group, has emerged as a promising candidate due to its cytoprotective, antioxidant, and procognitive properties. This study aimed to further elucidate the mechanisms underlying the action of D2AAK1 and its derivatives, with a focus on their potential for neuroprotection and cognitive enhancement. The effect of D2AAK1 on cell viability was evaluated under normal conditions and during H₂O₂-induced oxidative stress using the resazurin assay. p38 MAPK activity was measured through cell-based ELISA. mRNA expression was analyzed using a two-step quantitative PCR method, and enzymatic effects were assessed via photometric, fluorescence, and luminescence techniques. Behavioral studies in murine models were performed to investigate the influence of the compounds on memory processes. It was found that D2AAK1 and its derivatives significantly enhanced cell viability, with some derivatives exhibiting greater potency than D2AAK1. In vivo, one derivative notably improved memory performance and reversed scopolamine-induced memory impairment in the novel object recognition test in male Swiss mice. Mechanistic studies revealed that D2AAK1 increased the expression of cytoprotective proteins such as Bcl-2 and HO-1, while concurrently reducing the expression and activity of pro-apoptotic factors, including caspase-3, p38 MAPK, and MAO-B. These dual actions culminated in enhanced cellular resilience and viability, translating into improved cognitive outcomes. The findings suggest that D2AAK1 and its derivatives, through their multi-factor mechanism of action, hold promise as therapeutic agents for the treatment of neurodegenerative diseases.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>\u0000 </div>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 10","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145146586","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":"Neural-Specific Expression and Membrane Localization of FAM163B Regulates SAP97 Expression","authors":"Xiaoyu Zhang,&nbsp;Shanshan Sun,&nbsp;Wei Zhao,&nbsp;Yan Jiang,&nbsp;Yuting Weng,&nbsp;Ilgiz Gareev,&nbsp;Xuemin Ge,&nbsp;Xinrong Li,&nbsp;Jiaqi Wang,&nbsp;Qiongqiong Hu,&nbsp;Dechun Cheng,&nbsp;Lili Mu,&nbsp;Jinghua Wang","doi":"10.1111/jnc.70244","DOIUrl":"https://doi.org/10.1111/jnc.70244","url":null,"abstract":"<div>\u0000 \u0000 <p>The cell membrane plays a significant role in the development and functional maintenance of neurons. However, the functions of many neuronal membrane proteins remain unclear, posing a challenge to the treatment of brain diseases. Family with sequence similarity 163 member B (FAM163B) is a single-transmembrane protein, and <i>FAM163B</i> is a neuroregulatory gene with unknown functions. In this study, we aimed to elucidate the function of FAM163B in neurons of the mouse brain. FAM163B was exclusively expressed in the mouse brain among various tissues analyzed. Immunoblotting, real-time PCR, and cellular immunofluorescence confirmed high expression of FAM163B in mouse neurons, which were mainly located in the cell membrane. Overexpression of FAM163B in SH-SY5Y cells and primary mouse cortical neurons resulted in downregulated expression of SAP97, and knockdown of FAM163B increased the expression level of SAP97. SAP97 is an important transporter that plays a part in synaptic function and neuroplasticity. Besides, an interaction was found between FAM163B and VAPA. VAPA is involved in the intracellular vesicle transport and membrane fusion processes. By staining with FM4-64FX, overexpression of FAM163B weakened the endocytosis ability of neurons, while knockdown enhanced it. The study provides for an understanding of the roles of FAM163B in neurons.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>\u0000 </div>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 10","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145135579","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":"Clinical and MRI Correlates of β-Amyloid Load Inconsistent With Its Presumed Neurotoxicity in Cognitively Healthy Ageing","authors":"Pavel Filip,&nbsp;J. Riley McCarten,&nbsp;Laura Hemmy,&nbsp;Jillian Crocker,&nbsp;Michael Wolf,&nbsp;Jeromy Thotland,&nbsp;Zuzan Cayci,&nbsp;Todd Kes,&nbsp;Shalom Michaeli,&nbsp;Melissa Terpstra,&nbsp;Silvia Mangia","doi":"10.1111/jnc.70241","DOIUrl":"10.1111/jnc.70241","url":null,"abstract":"<p>Cognitively healthy ageing and its conceptual counterpart, dementia, have long garnered much interest in the research community, the broader public and regulatory bodies alike. Although β-amyloid deposition is widely regarded as the principal neuropathological hallmark of Alzheimer's disease, its precise role in the causal chain of cognitive decline remains under debate. Applying strict criteria to define neurocognitive health, a selection of 35 participants aged over 60 years was drawn from the Human Connectome Project—Ageing. The evaluation of both cognitive and physical fitness, and comprehensive magnetic resonance imaging (MRI) protocol, encompassing diffusion-weighted imaging, T1w/T2w ratio, resting-state functional MRI and arterial spin labelling, were combined with an additional 18F-florbetaben scan to evaluate β-amyloid load. Strikingly, β-amyloid load failed to adhere to the transcription patterns of amyloid precursor protein in all surveyed areas but the entorhinal cortex. Moreover, it was associated with either higher cognitive performance, general fitness, cerebral tissue integrity and cerebral perfusion, or had no discernible impact. This pilot study adds to the growing body of evidence that questions the significance attributed to β-amyloid build-up and the mechanisms of its accumulation in the ageing brain. The results invite a re-evaluation of established theories on β-amyloid build-up neurotoxicity at low concentrations as observed in this cohort. Future investigations should focus on recruiting larger populations to ascertain whether a specific threshold of β-amyloid build-up precipitates cognitive decline or whether β-amyloid accumulation, in fact, serves as a protective mechanism that ultimately fails.</p><p>\u0000 \u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure>\u0000 </p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 9","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12455269/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145124794","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neurotransmitter Transporters—Unraveling Molecular Mechanisms and Therapeutic Opportunities","authors":"Harald H. Sitte,&nbsp;Ulrik Gether,&nbsp;Eurico Cabrita,&nbsp;Thomas Stockner","doi":"10.1111/jnc.70240","DOIUrl":"https://doi.org/10.1111/jnc.70240","url":null,"abstract":"<p>Neurotransmitter transporters are essential regulators of synaptic neurotransmission, maintaining the delicate balance of neurotransmitters in the central and peripheral nervous systems. Dysfunction of these transporters is linked to a wide range of neurological and psychiatric disorders, including depression, Parkinson's disease, epilepsy, and substance use disorders. This special issue of <i>The Journal of Neurochemistry</i> brings together cutting-edge research that advances our understanding of the molecular mechanisms, structural dynamics, and physiological roles of neurotransmitter transporters. The contributions highlight key themes, including the regulation of transporter trafficking and surface expression through post-translational modifications, the structural dynamics underlying transporter function, and the role of glutamate transporters in excitotoxicity and stress resilience. Additionally, the issue explores pharmacological innovations, such as optopharmacological tools and bioisosteric analogs, that offer new avenues for therapeutic intervention. By integrating insights from structural biology, electrophysiology, genetic models, and computational approaches, this collection underscores the interdisciplinary nature of transporter research and its potential to inform the development of novel therapies for neurological and psychiatric conditions. The articles collectively emphasize the progress and challenges in the field while pointing toward future directions for translational research and precision medicine.</p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 9","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70240","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145110641","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Effects of Early Life Social Isolation Are Sex-Specific","authors":"E. A. Rybnikova,&nbsp;N. N. Nalivaeva","doi":"10.1111/jnc.70239","DOIUrl":"10.1111/jnc.70239","url":null,"abstract":"<p>Early life social isolation (ESI) is a severe stress that disrupts brain development, contributing to susceptibility to various stressors and predisposition to neurological and other diseases in later life. In rats, ESI can be modeled by maternal separation of pups, allowing for the study of its after-effects at different stages of animal development. This editorial highlights an article in the current issue of the Journal of Neurochemistry that reports the long-lasting behavioral effects of mild ESI (brief repetitive episodes of pup separation during the third week of postnatal development of rats) and the changes in the BDNF system of the nucleus accumbens. In particular, this study focused on ESI effects dependent on animal sex. This allowed the authors to show that mild ESI impaired social reward processing only in male rats and that this effect was accompanied by persistent downregulation of BDNF/TrkB signaling in the nucleus accumbens. In contrast, ESI in females had no behavioral consequences in the studied paradigm, although it led to increased BDNF/TrkB signaling. These findings indicate that male rats are more susceptible to maternal separation stress than females and highlight the important role of the BDNF system in the formation of this vulnerability.</p><p>\u0000 \u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure>\u0000 </p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 9","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70239","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145092084","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Embracing Scientific Debate in Brain Metabolism","authors":"Jens V. Andersen,&nbsp;Blanca I. Aldana,&nbsp;Lasse K. Bak,&nbsp;Kevin L. Behar,&nbsp;Karin Borges,&nbsp;Anthony Carruthers,&nbsp;Paul Cumming,&nbsp;Amin Derouiche,&nbsp;Carlos M. Díaz-García,&nbsp;Kelly L. Drew,&nbsp;João M. N. Duarte,&nbsp;Gustavo C. Ferreira,&nbsp;Federico Giove,&nbsp;Albert Gjedde,&nbsp;Fahmeed Hyder,&nbsp;Maria S. Ioannou,&nbsp;Oliver Kann,&nbsp;Tibor Kristian,&nbsp;James C. K. Lai,&nbsp;Graeme F. Mason,&nbsp;Ewan C. McNay,&nbsp;Maiken Nedergaard,&nbsp;Thaddeus S. Nowak Jr,&nbsp;Anant B. Patel,&nbsp;Caroline D. Rae,&nbsp;Timothy A. Ryan,&nbsp;Patricia F. Schuck,&nbsp;Ian A. Simpson,&nbsp;Susan J. Vannucci,&nbsp;Helle S. Waagepetersen,&nbsp;Gary Yellen,&nbsp;Mary C. McKenna","doi":"10.1111/jnc.70230","DOIUrl":"10.1111/jnc.70230","url":null,"abstract":"<div>\u0000 \u0000 <p>Brain metabolism is a fascinating and exciting research topic. Many new metabolic features of the brain continue to be unveiled and much remains to be discovered. To truly enable scientific progress, it is imperative that discoveries and theories are continually challenged through scholarly discussion. Here we address an earlier editorial by Bolaños et al. 2025 to underline the importance of embracing and respectfully engaging in scientific debate.</p>\u0000 <p>\u0000 \u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure>\u0000 </p>\u0000 </div>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 9","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145086354","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":"Ospemifene, a Selective Estrogen Receptor Modulator, Enhances Oligodendrocyte Myelination and Preserves Neurofunctions Against Injuries","authors":"Wei Liu,&nbsp;Hong Ren,&nbsp;Junda Wang,&nbsp;Xu Huang,&nbsp;Shuangling Wu,&nbsp;Xing Gao,&nbsp;Tao Li,&nbsp;Zhou Zhang,&nbsp;Feng Mei,&nbsp;Bin Yu,&nbsp;Fei Wang","doi":"10.1111/jnc.70235","DOIUrl":"10.1111/jnc.70235","url":null,"abstract":"<div>\u0000 \u0000 <p>Insufficient myelinogenesis following central nervous system (CNS) injuries is a well-documented pathological feature in various diseases, such as white matter injury (WMI) and multiple sclerosis (MS). Repurposing FDA-approved drugs capable of promoting oligodendrocytes (OLs) differentiation represents a realistic and feasible approach for myelin repair and functional recovery. In this study, we report that ospemifene, an FDA-approved selective estrogen receptor modulator (SERM), significantly promotes the differentiation of purified mouse oligodendrocyte precursor cells (OPCs) both in cultures and on nanofibers. In neonatal mice subjected to hypoxia, ospemifene prevented hypoxia-induced myelin deficits in the developing central nervous system (CNS) and preserved neurofunctions in young adolescents, likely due to its promyelination potency. To assess the impact in demyelination models, we utilized the experimental autoimmune encephalomyelitis (EAE) mouse model, and ospemifene treatment alleviated functional deterioration in a dose-dependent manner and benefited myelin regeneration. To confirm the effect on remyelination, toxin-induced demyelination mice, injected with lysophosphatidylcholine into the corpus callosum, were treated with ospemifene. This treatment increased newly generated myelin sheaths in the lesions, confirming its promyelinogenesis effect. Together, our findings suggest that ospemifene is a promising treatment option for demyelinating diseases.</p>\u0000 <p>\u0000 \u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure>\u0000 </p>\u0000 </div>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 9","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145075415","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":"Botulinum Neurotoxin A Signaling in Pain Modulation Within Human Sensory Neurons","authors":"Katherin A. Gabriel,&nbsp;Kali Hankerd,&nbsp;Paulino Barragan-Iglesias,&nbsp;Amy D. Brideau-Andersen,&nbsp;Lance E. Steward,&nbsp;Steve McGaraughty,&nbsp;Edwin Vazquez-Cintron,&nbsp;Theodore J. Price","doi":"10.1111/jnc.70236","DOIUrl":"10.1111/jnc.70236","url":null,"abstract":"<div>\u0000 \u0000 <p>OnabotulinumtoxinA (onabotA), a Botulinum neurotoxin type A (BoNT/A), is an effective treatment for chronic migraine, but its direct mechanism of action on human sensory neurons has not been fully elucidated. While rodent studies on dorsal root ganglion (DRG) and trigeminal ganglion (TG) show that BoNT/A inhibits neurotransmission, including calcitonin gene-related peptide (CGRP/<i>CALCA</i>) release, by cleaving synaptosomal-associated protein 25 (SNAP-25), only one previous study has assessed its effect on human DRG neurons. The objective of this study was to understand the mechanism of action of BoNT/A in cultured human sensory neurons and assess, using RNA sequencing, the transcriptomic consequences of BoNT/A treatment. Using DRGs obtained from organ donors, the expression of key targets, including synaptic vesicle glycoprotein 2C (<i>SV2C</i>), <i>SNAP25</i>, &amp; <i>CALCA</i>, was validated by mining existing transcriptomic datasets as well as immunohistochemistry. Cultured dissociated human DRG neurons treated with BoNT/A were used to examine cleavage of SNAP25, release of CGRP, and transcriptomic changes after BoNT/A treatment. SV2C was found to be widely expressed in human DRG neurons in a pattern that completely overlapped with CGRP expression. Consistent with this finding, BoNT/A disrupted soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein complexes in human DRG neurons as demonstrated by SNAP-25 cleavage in most somatosensory neurons and a reduction in capsaicin-evoked CGRP release, indicating impaired vesicle fusion. Moreover, bulk RNA sequencing experiments revealed downregulated expression of a large subset of genes responsible for neurotransmitter and neuropeptide release from neurons, suggesting a novel mechanism through which BoNT/A regulates neurotransmission. These results provide new insight into the molecular mechanisms by which BoNT/A may exert its pain-relieving effects in humans.</p>\u0000 <p>\u0000 \u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure>\u0000 </p>\u0000 </div>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 9","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145069814","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":"Connexin and Pannexin Hemichannels: Broad-Spectrum Players in Neuroinflammatory Signaling","authors":"Juan C. Sáez,&nbsp;Francisco J. Ocaranza,&nbsp;Juan Prieto-Villalobos,&nbsp;Juan A. Orellana","doi":"10.1111/jnc.70237","DOIUrl":"10.1111/jnc.70237","url":null,"abstract":"<p>Connexin- and pannexin-formed hemichannels have emerged as pivotal, upstream amplifiers of neuroinflammation. Under physiological stressors—depolarization, Ca²⁺ overload, redox shift, or cytokine exposure—these large pores release adenosine triphosphate, glutamate, and other danger signals that activate P2X/P2Y and N-methyl-D-aspartate receptors, ignite NLR family pyrin domain containing (NLRP) 3 inflammasome, and propagate Ca²⁺/reactive oxygen species waves between mast cells, microglia, astrocytes, oligodendrocytes, neurons, and brain endothelium. Evidence across acute (e.g., stroke, trauma, seizure, and sepsis) and chronic (e.g., Alzheimer's, and multiple sclerosis) models shows that genetic ablation or pharmacological blockade of hemichannels shrinks lesions, preserves synaptic plasticity, restores blood–brain barrier integrity, and rescues cognition, often without altering the primary pathogenic trigger. Translational leads include mimetic peptides (e.g., Gap19, ¹⁰panx1), the nanomolar, gap junction–sparing small-molecule D4, and the pleiotropic alkaloid boldine, all of which curb epileptiform activity, neurodegeneration, and depressive-like behavior. Yet key gaps persist, such as the long-term safety of chronic inhibition, which remains poorly defined and will be critical to translate these “gatekeeper” channels into next-generation neuro–anti-inflammatory therapeutics.</p><p>\u0000 \u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure>\u0000 </p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 9","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70237","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145069826","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clozapine's Molecular Signature: Selective 5-HT2A Receptor Downregulation and Signalling in Rat Brain Cortical Regions","authors":"Sylwia Kedracka-Krok,&nbsp;Jakub Nowak,&nbsp;Ewelina Fic,&nbsp;Joanna Solich,&nbsp;Piotr Rybczynski,&nbsp;Weronika Romanska,&nbsp;Patrycja Sarga,&nbsp;Katarzyna Pustelny,&nbsp;Marta Dziedzicka-Wasylewska","doi":"10.1111/jnc.70229","DOIUrl":"https://doi.org/10.1111/jnc.70229","url":null,"abstract":"<div>\u0000 \u0000 <p>The superior clinical efficacy of clozapine (CLO) in treatment-resistant schizophrenia remains incompletely understood. To elucidate these mechanisms, we employed a multi-platform proteomic strategy—combining data-dependent acquisition (DDA) with fractionation, data-independent acquisition (DIA) and targeted parallel reaction monitoring (PRM)—to analyse chronic drug-induced proteomic changes in the prefrontal cortex (PFC) and remaining cerebral cortex (CX) of rats. This approach enabled unbiased analysis of over 6300 proteins per group in DDA and over 8700 in DIA. Consistent across all analytical methods, chronic CLO administration induced robust downregulation of the serotonin 5-HT2A receptor (5HTR2A) in both PFC and CX, whereas risperidone (RIS) exhibited no significant effect on 5-HTR2A levels at clinically relevant doses. Despite sharing high affinity for this receptor, CLO and RIS elicited markedly distinct signalling profiles. In the PFC, CLO inhibited serotonergic, G-protein (Gαq and Gβγ), calcium, and cytoskeletal signalling pathways, accompanied by strong downregulation of phospholipase C delta 4 (PLCδ4), an isoform implicated in suicidal behaviour. Concurrently, CLO upregulated calcium-independent phospholipase A2γ (iPLA2γ) and guanylyl cyclase C (GUCY2C), suggesting potential modulation of docosahexaenoic acid (DHA) signalling and cGMP-driven synaptic plasticity. In contrast, RIS predominantly activated Gαi, Gαz, and Gβγ signalling in the CX and enhanced mitochondrial function. RIS also upregulated GUCY2C. Both drugs differentially modulated protein networks associated with potential heteromeric complexes involving 5HTR2As, including interactions with 5-HT1A, 5-HT2C, dopamine D2, oxytocin and cannabinoid CB1 receptors, highlighting their impact on complex serotonergic modulation. Notably, despite CLO's suppression of Gαq signalling, compensatory upregulation of Gαi was not observed, indicating a net attenuation of 5HTR2A-mediated output rather than a simple G-protein coupling switch. These findings advance our understanding of serotonergic, metabolic and receptor-level adaptations induced by atypical antipsychotics and suggest that CLO's superior efficacy may derive from its unique ability to downregulate 5HTR2A and remodel signalling networks beyond classical dopaminergic mechanisms.</p>\u0000 <p>\u0000 \u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure>\u0000 </p>\u0000 </div>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 9","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145062436","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}