Neuropharmacology最新文献

{"title":"Oxytocin significantly enhances GABAergic transmission in the central amygdala of alcohol-naïve and alcohol-dependent female rats","authors":"Emaya M. Moss ,&nbsp;Enkhzul Batsaikhan ,&nbsp;Bryan Cruz ,&nbsp;Michael Q. Steinman ,&nbsp;Marisa Roberto ,&nbsp;Dean Kirson","doi":"10.1016/j.neuropharm.2025.110628","DOIUrl":"10.1016/j.neuropharm.2025.110628","url":null,"abstract":"<div><div>Oxytocin is a promising treatment for alcohol use disorder (AUD) and has been shown to decrease alcohol consumption and withdrawal symptoms associated with alcohol dependence in animal models. Using a rat model of alcohol dependence to investigate oxytocin's effects on dependence-induced alcohol drinking and GABAergic transmission in the central amygdala (CeA), we previously reported that oxytocin blocked escalated alcohol drinking and the acute ethanol-induced enhanced GABA transmission in alcohol-dependent rats. However, these studies were performed only in male rats. We also previously reported sex differences in the effects of alcohol and stress related neuropeptides on CeA GABAergic transmission. Here we examined the effects of oxytocin on CeA GABAergic transmission in naïve and alcohol-dependent female rats, as well as examining sex differences in the expression of components of the oxytocin system. We found that oxytocin increased CeA GABAergic transmission in both naive and alcohol-dependent female rats and this increase was further elevated after the co-application of acute alcohol. We also found that females had fewer oxytocin-expressing neurons in the caudal paraventricular nucleus of the hypothalamus than males, and alcohol-dependent rats had fewer oxytocin-expressing neurons than naïve rats. Further, females had higher numbers of corticotropin releasing factor (<em>Crh</em>) neurons in the CeA, and higher expression levels of <em>Crh</em> and oxytocin receptor mRNA. This research highlights sex differences in pro- and anti-stress system functioning in the CeA in response to acute and chronic alcohol. Sex-specific neuroadaptations in oxytocin signaling may provide a target for more effective therapeutics in the treatment of AUD.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"279 ","pages":"Article 110628"},"PeriodicalIF":4.6,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144809973","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":"Gastrodin from the Gastrodia elata Blume alleviates neuronal inflammation and injury via regulates NOX2/Nrf2 balance","authors":"Ruijiao Zhou ,&nbsp;Yanlin Wang ,&nbsp;Xing Cao ,&nbsp;Xinzhu Yuan ,&nbsp;Lingqin Li ,&nbsp;Wei Zhang","doi":"10.1016/j.neuropharm.2025.110620","DOIUrl":"10.1016/j.neuropharm.2025.110620","url":null,"abstract":"<div><h3>Background</h3><div>Epilepsy is a serious recurrent neurological dysfunction, and its incidence is increasing sharply, often causing social dysfunction in patients and causing heavy economic and caregiving burdens to families and society. At present, most drugs used in the clinical treatment of epilepsy have serious side effects, such as liver and kidney function damage, psychological and physiological damage, and drug dependence.</div></div><div><h3>Methods</h3><div>The antiepileptic effect of gastrodin (GAS, a natural compound isolated from <em>Gastrodia elata</em> Blume) was studied in a PTZ-induced epilepsy rat model. The pharmacological effect of GAS was further clarified by combining animal behaviour and pathology detection experiments. H₂O₂ stimulation of the HT22 cell model was subsequently used to further explore the possible molecular mechanism of the antiepileptic effect of GAS. Molecular docking experiments and siRNA interference experiments were used to study the molecular mechanism of the antiepileptic effect of GAS.</div></div><div><h3>Results</h3><div>GAS can also improve the learning and memory ability of experimental animals. The antiepileptic effect of GAS was related to its obvious neuroprotective effects, including significantly reducing the apoptosis of hippocampal neurons in epileptic rats, reducing oxidative stress in neurons, and reducing the level of inflammation in the body. The experimental data revealed that GAS participated in the regulation of the NOX2/NRF2 balance, reduced the level of cellular oxidative stress, reduced the level of cellular inflammation, and protected against neuronal damage. In addition, we also showed that GAS has good affinity for NOX2, with a binding value of −5.12 kcal/mol. Knocking down NOX2 is expected to weaken the neuroprotective effect of GAS.</div></div><div><h3>Conclusion</h3><div>GAS can reduce inflammation and apoptosis in nerve cells by affecting the NOX2/Nrf2 balance.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"279 ","pages":"Article 110620"},"PeriodicalIF":4.6,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144817224","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":"Perinatal and prenatal alcohol exposure impairs striatal cholinergic function and cognitive flexibility in adult offspring","authors":"William Purvines ,&nbsp;Himanshu Gangal ,&nbsp;Xueyi Xie ,&nbsp;Joseph Ramos ,&nbsp;Xuehua Wang ,&nbsp;Rajesh Miranda ,&nbsp;Jun Wang","doi":"10.1016/j.neuropharm.2025.110627","DOIUrl":"10.1016/j.neuropharm.2025.110627","url":null,"abstract":"<div><div>Fetal Alcohol Spectrum Disorder (FASD), caused by perinatal alcohol exposure (PeAE) and prenatal alcohol exposure (PAE), is characterized by significant cognitive impairments, including reduced cognitive flexibility. Despite the critical role of cholinergic interneurons (CINs) in the dorsomedial striatum (DMS) for cognitive and behavioral flexibility, their contribution to neurobehavioral deficits in FASD remains unclear. To address this gap, this research explored the impact of PeAE and PAE on CIN populations and activity, cognitive flexibility, and compulsive drinking behaviors in adult offspring. We first assessed CIN number by staining striatal sections for choline acetyltransferase (ChAT) and observed a significant reduction in CINs within the posterior striatum of adult PeAE offspring. Functional assessments revealed that PeAE and PAE markedly decreased CIN firing activity and reduced acetylcholine (ACh) release in the DMS, as measured by electrophysiology recordings and live-tissue confocal imaging using a genetically encoded ACh sensor. Behaviorally, PeAE offspring exhibited a significant deficit in adapting to reversed action-outcome contingencies despite intact initial learning capabilities. Moreover, PeAE mice exhibited compulsive alcohol drinking behavior, characterized by elevated consumption and preference for quinine-adulterated alcohol. These findings collectively highlight the critical role of impaired cholinergic signaling in the cognitive and behavioral deficits observed following PeAE and PAE. Understanding this cholinergic dysfunction provides valuable insights necessary for developing targeted interventions aimed at mitigating cognitive and behavioral consequences associated with FASD.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"279 ","pages":"Article 110627"},"PeriodicalIF":4.6,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144804442","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":"Zinc induces neuronal autophagy via HMGB1 nuclear translocation in acute cerebral ischemia","authors":"Mingqi Zhang ,&nbsp;Jian Yang ,&nbsp;Xuying Zhang ,&nbsp;Tingting Ma ,&nbsp;Peng Wang ,&nbsp;Jia Liang","doi":"10.1016/j.neuropharm.2025.110617","DOIUrl":"10.1016/j.neuropharm.2025.110617","url":null,"abstract":"<div><div>The process of autophagy following a stroke is a highly complex phenomenon. Damaged brain cells can produce multifactorial signals that may act as activators of autophagy. Zinc, which is abundantly present in the central nervous system, regulates numerous biological processes, including autophagy. Studies conducted on mammalian cells have consistently demonstrated that zinc promotes autophagy. However, the precise mediator of zinc-induced autophagy following acute ischemic stroke remains unclear. In this study, we investigated whether High Mobility Group Box 1 (HMGB1) is involved in the process of zinc-mediated neuronal autophagy after cerebral ischemia. We established a rat model of middle cerebral artery occlusion (MCAO), and our results indicated that chelating zinc significantly reduced infarct volume and improved neurological function after acute ischemic stroke. Additionally, chelating zinc diminished ischemia-induced neuronal autophagy and inhibited the translocation of HMGB1 from the nucleus to the cytoplasm during acute cerebral ischemia. In cellular experiments utilizing oxygen-glucose deprivation (OGD) treatment, we found that excessive intracellular zinc facilitates the translocation of HMGB1 from the nucleus to the cytoplasm, while HMGB1 regulates zinc-mediated autophagy. Furthermore, inhibiting HMGB1 in cultured neurons impeded the effects of zinc on autophagy. These findings provide evidence that zinc mediates neuronal autophagy by regulating the translocation of HMGB1 to the cytoplasm during acute ischemic stroke.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"279 ","pages":"Article 110617"},"PeriodicalIF":4.6,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144757525","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":"Serotonin 2A (5-HT2A) receptor as evolving biological target: function, structure, ligands and role in the therapy of neuropsychiatric diseases","authors":"Monika Fryc,&nbsp;Daria Kluzik,&nbsp;Anna Czopek,&nbsp;Jakub Jończyk,&nbsp;Agnieszka Zagórska","doi":"10.1016/j.neuropharm.2025.110622","DOIUrl":"10.1016/j.neuropharm.2025.110622","url":null,"abstract":"<div><div>The serotonin 5-HT_2A receptor is a G-protein-coupled receptor that plays a critical role in numerous physiological processes within the central nervous system. While it is essential for normal neurobiological function, dysregulation or aberrant signaling of the 5-HT_2A receptor has been implicated in the pathophysiology of various neuropsychiatric disorders. This review provides a comprehensive overview of the 5-HT_2A receptor, including its structure, function, ligand interactions, and therapeutic potential. Its molecular structure is detailed, with key binding domains highlighted that facilitate interactions with agonists, antagonists, and inverse agonists, influencing receptor activation and intracellular signaling pathways. The sites of 5-HT_2A receptor expression in both the central and peripheral nervous systems are also presented, and ligands are classified based on their interactions with the receptor. The receptor's role as a focal point in the treatment of psychiatric disorders such as schizophrenia and depression is examined, with emphasis placed on its modulation by atypical antipsychotics and emerging psychedelic-based therapies. Furthermore, its involvement in functional selectivity, biased agonism, and interactions with dopaminergic and glutamatergic systems is explored. Recent advancements in non-hallucinogenic 5-HT_2A receptor agonists and inverse agonists are also discussed, highlighting their potential for therapeutic intervention with improved safety profiles. The insights provided in this review contribute to a deeper understanding of 5-HT_2A receptors' role in neuropsychiatric disorders and support ongoing drug development efforts to optimize receptor-targeted therapies.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"279 ","pages":"Article 110622"},"PeriodicalIF":4.6,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144768807","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":"Age- and estrous-dependent effects of psilocybin in rats","authors":"A.L. Zylko ,&nbsp;R.J. Rakoczy ,&nbsp;B.F. Roberts ,&nbsp;M. Wilson ,&nbsp;A. Powell ,&nbsp;A. Page ,&nbsp;M. Heitkamp ,&nbsp;D. Feist ,&nbsp;J.A. Jones ,&nbsp;M.S. McMurray","doi":"10.1016/j.neuropharm.2025.110619","DOIUrl":"10.1016/j.neuropharm.2025.110619","url":null,"abstract":"<div><div>Psilocybin, a psychedelic compound in “magic” mushrooms, has promise as a novel treatment for psychiatric disorders, many of which are more prevalent in females and have onsets during adolescence. However, there is a lack of research about how factors such as sex and age affect responses to psilocybin, as well as potential safety concerns with developmental exposure. The primary objectives of this preclinical study were to determine if psilocybin-induced head twitch responses differ between adolescent and adult rats, and if estrous phase contributes to variation in female head twitch responses. Secondarily, this study sought to determine if treatment with psilocybin during adolescence has long-term effects on anxiety-associated behaviors and behavioral flexibility. Results showed that 1 mg/kg intragastric psilocybin failed to elicit head twitch responses in adolescents (P35 and P45) but elicited robust responses in adult rats. Further, adolescent psilocybin exposure did not cause long-term differences in performance on the elevated zero maze or probabilistic reversal learning tasks. Lastly, adult females in diestrus showed increased head twitch responses after 1 mg/kg psilocybin compared to females in proestrus. Collectively, these results highlight the existence of age- and sex-dependent differences in the effects of psychedelics, while finding no long-term effects on selected behaviors after adolescent exposure. These findings have implications on psychedelic study design, emphasizing the need for inclusive research considering age, sex, and hormonal status.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"279 ","pages":"Article 110619"},"PeriodicalIF":4.6,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144760603","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":"Sinapic acid attenuates PERK-dependent ER stress signaling and resolves α-synuclein pathology in rotenone-induced Parkinson's disease rat model","authors":"Moutaz Bellah Yasser ,&nbsp;Radwa S. Hagag ,&nbsp;Norhan M. El-Sayed ,&nbsp;Reem M. Hazem","doi":"10.1016/j.neuropharm.2025.110621","DOIUrl":"10.1016/j.neuropharm.2025.110621","url":null,"abstract":"<div><div>The current study aimed to evaluate the neuroprotective potential of sinapic acid (SA) administration in alleviating Parkinson's disease (PD) features, focusing on its effects in amelioration of endoplasmic reticulum (ER) stress-mediated unfolded protein response (UPR) signaling, oxidative stress, and alpha-synucleinopathy in chronic ROT-induced PD rats.</div><div>PD was induced using 11 ROT injections (1.5 mg/kg/48h; s.c.). One day following the fifth ROT dose, rats started treatment with SA (10 mg/kg), SA (20 mg/kg), SA (40 mg/kg), or L-dopa/carbidopa (100/10 mg/kg) daily via oral gavage for 21 consecutive days, followed by assessment of neurobehavioral parameters and subsequent histopathological and neurochemical analyses.</div><div>Treatment with a high dose of SA amended ROT-induced locomotor deficits with significantly improved open-field ambulation, grooming, and rearing behavior, as well as increased cylinder wall forelimb placements, and prolonged rotarod fall-off latency. Additionally, SA treatment protected nigral dopaminergic neurons from ROT-induced neurodegeneration and dose-dependently preserved nigral tyrosine hydroxylase (TH) immunoexpression. Furthermore, SA treated rats showed markedly improved striatal dopamine (DA) content and diminished striatal alpha synuclein (α-Syn) overexpression. Additionally, SA treatment provided antioxidant properties as evidenced by improved striatal GSH/SOD/Catalase and suppressed MDA levels. Notably, SA administration resulted in significant, dose-dependent attenuation of ER stress sensors PERK, eIF2α, CHOP/GADD135, IRE1α, and ATF6 signaling.</div><div>These findings provide novel <em>in vivo</em> insights into SA's beneficial neuroprotective properties in amelioration of ROT-induced ER stress via modulation of all three UPR branches, particularly the PERK/eIF2α/CHOP signaling axis, and establishes SA as a promising neurotherapeutic candidate for possible management of PD.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"279 ","pages":"Article 110621"},"PeriodicalIF":4.6,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144749514","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":"Low-molecular weight protamine enhances neuroprotection and remyelination by mitigating chondroitin sulfate proteoglycan inhibition in models of demyelination","authors":"Tapani K. Koppinen ,&nbsp;Carolina R. Reyes ,&nbsp;Liam Beckett ,&nbsp;Jinhan Nam ,&nbsp;Tuomas A.E. Kallionpää ,&nbsp;Saila Medina Leskinen ,&nbsp;Nadine Huber ,&nbsp;Annakaisa Haapasalo ,&nbsp;Francisco J. Rivera ,&nbsp;Merja H. Voutilainen ,&nbsp;Heikki Rauvala","doi":"10.1016/j.neuropharm.2025.110618","DOIUrl":"10.1016/j.neuropharm.2025.110618","url":null,"abstract":"<div><div>Chondroitin sulfate proteoglycans (CSPGs) are inhibitory molecules deposited in the extracellular matrix of lesions in multiple sclerosis (MS). CSPGs maintain ongoing inflammatory processes and prevent oligodendrocyte progenitor cell (OPC) differentiation, resulting in impaired remyelination and chronic pathology in MS. Here, we profile low-molecular weight protamine (LMWP) as a small, positively charged peptide that binds to the negatively charged inhibitory sections of CSPGs. We show that LMWP overcomes CSPG inhibition of OPC differentiation and increases remyelination following toxin-based focal demyelination. Moreover, LMWP ameliorates disease progression in experimental autoimmune encephalomyelitis (EAE) model. LMWP is blood brain barrier-penetrant, and peripheral administration in EAE mice results in significantly lowered concentrations of serum neurofilament light-chain. Additionally, tissue analyses show increased myelin thickness and a reduction in axonal degeneration with LMWP treatment in EAE mice, supporting its role as a neuroprotective compound. Finally, LMWP reduces microgliosis and fibrosis in EAE, most likely, favoring tissue repair. Thus, LMWP supports remyelination as well as neuroprotection resulting in a promising strategy for the treatment of demyelinating disease, such as MS.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"279 ","pages":"Article 110618"},"PeriodicalIF":4.6,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144749513","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":"Striatal GluN2A gene suppression reduces L-DOPA-induced abnormal involuntary movements in parkinsonian rats","authors":"Taiki Yabumoto ,&nbsp;Brik A. Kochoian ,&nbsp;Stefano Coletta ,&nbsp;Oskar Laur ,&nbsp;Xinping Huang ,&nbsp;Cassandra A. Bure ,&nbsp;Christopher Ware ,&nbsp;Peng Jin ,&nbsp;Stephen F. Traynelis ,&nbsp;Stella M. Papa","doi":"10.1016/j.neuropharm.2025.110616","DOIUrl":"10.1016/j.neuropharm.2025.110616","url":null,"abstract":"<div><div>L-DOPA-induced dyskinesia (LID) is a common disabling complication of long-term L-DOPA therapy in Parkinson's disease (PD). LID development is associated with maladaptive plasticity mechanisms in striatal circuits contributed by dysregulated dopamine and glutamate signaling. Upregulation of the NMDAR subunit 2A (GluN2A) over chronic L-DOPA treatment is thought to play a role in corticostriatal synaptic changes. We investigated the motor effects of selective GluN2A gene silencing by injecting a shRNA vector in the striatum of hemiparkinsonian rats. Striatal GluN2A knockdown significantly reduced abnormal involuntary movements (AIMs) while sustaining the therapeutic benefit of L-DOPA. These findings suggest that targeted adjustments of striatal NMDAR subunit composition may be a promising strategy for managing the long-term therapy of PD.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"279 ","pages":"Article 110616"},"PeriodicalIF":4.6,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144760604","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":"Comparative effectiveness of moderate treadmill training and venlafaxine treatment on long-lasting brain changes induced by prenatal dexamethasone exposure","authors":"Katarzyna Głombik ,&nbsp;Magdalena Kukla-Bartoszek ,&nbsp;Maciej Suski ,&nbsp;Katarzyna Curzytek ,&nbsp;Beata Grygier ,&nbsp;Agnieszka Basta-Kaim","doi":"10.1016/j.neuropharm.2025.110604","DOIUrl":"10.1016/j.neuropharm.2025.110604","url":null,"abstract":"<div><div>Prenatal exposure to dexamethasone (DEX) is known to induce long-term behavioral and molecular impairments. This research investigated whether moderate physical exercise (treadmill running) and venlafaxine administration, or their combination, applied in early adulthood, could modulate the behavioral and brain molecular alterations induced by prenatal DEX exposure in Sprague-Dawley male rats. It was demonstrated that both exercise and venlafaxine treatment ameliorated deficits in memory, depressive-like behavior, and anxiety-like behavior. Subsequent proteomic analysis of the frontal cortex revealed significant modulation in the proteome following each intervention. Analysis disclosed convergent effects of all three interventions, notably the upregulation of LYAR and downregulation of KLHL36. Increased LYAR expression may counteract DEX-induced ribosomal inhibition, while reduced KLHL36 aligns with potential stress resilience modulation. Shared protein changes between exercise and venlafaxine implicated pathways governing learning, regulation of neurotransmitter levels and their metabolism, and cell-cell organization. Combined treatment uniquely impacted 164 proteins involved in 44 distinct biological pathways, which suggests that joint use of training and venlafaxine has a pleiotropic effect. Among the altered pathways besides behavior, cognition, and memory were glycerophospholipid and arachidonic acid metabolism, which potentially influence neuronal membrane integrity and synaptic function, as well as exocytosis and MAPK signaling pathways. Notably, among the investigated mitochondrial proteins, HIGD1a exhibited a consistent pattern of upregulated expression across all three experimental treatment groups, suggesting altered mitochondrial function and antioxidant defense by the treatments used.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"279 ","pages":"Article 110604"},"PeriodicalIF":4.6,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144739663","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}