Neuropharmacology最新文献

{"title":"IP₃-mediated Ca²⁺ transfer from ER to mitochondria stimulates ATP synthesis in primary hippocampal neurons.","authors":"Ankit Dhoundiyal, Vanessa Goeschl, Stefan Boehm, Helmut Kubista, Matej Hotka","doi":"10.1016/j.neuropharm.2025.110626","DOIUrl":"10.1016/j.neuropharm.2025.110626","url":null,"abstract":"<p><p>During electrical activity, Ca²⁺ enhances mitochondrial ATP production, helping to replenish the energy consumed during this process. Most Ca²⁺ enters the cell via ligand- or voltage-gated channels on the neuronal membrane, where it stimulates the release of additional Ca²⁺ from the endoplasmic reticulum (ER). Although the influence of cytosolic Ca²⁺ on neuronal metabolism has been widely investigated, relatively few studies have explored the contribution of ER Ca²⁺ release in this context. Therefore, we investigated how activity-driven Ca²⁺ crosstalk between the ER and mitochondria influences the regulation of mitochondrial ATP production. We show that in primary hippocampal neurons derived from rat pups of either sex, depletion of ER Ca²⁺ led to a reduction in mitochondrial Ca²⁺ levels during both resting and stimulated states, while exerting only a minimal impact on cytosolic Ca²⁺ levels. Additionally, impaired ER-mitochondria Ca²⁺ transfer led to a reduction in mitochondrial ATP production. Similar effects were observed when inositol-3-phosphate receptors (IP₃Rs), but not ryanodine receptors (RyRs), were pharmacologically inhibited. Together, our findings show that, in hippocampal neurons, Ca²⁺ is transferred from the ER to mitochondria through IP₃ receptors, and this Ca²⁺ crosstalk in turn enhances mitochondrial ATP production in response to neuronal activity.</p>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":" ","pages":"110626"},"PeriodicalIF":4.6,"publicationDate":"2025-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144804464","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":"Increased NMDAR activity and GluN2A-NMDAR silent synapse expansion induced by chronic benzodiazepine treatment.","authors":"Caitlyn A Chapman, Nadya Povysheva, Jon W Johnson, Tija C Jacob","doi":"10.1016/j.neuropharm.2025.110624","DOIUrl":"10.1016/j.neuropharm.2025.110624","url":null,"abstract":"<p><p>Benzodiazepines (BZDs) are critical sedative, anticonvulsant, and anxiolytic drugs that potentiate inhibitory GABAergic neurotransmission. However, clinical utility is hampered by drug tolerance and a hyperexcitable withdrawal syndrome characterized by neuronal excitation/inhibition (E/I) imbalance. Although enhanced excitation is implicated in BZD tolerance, the homeostatic changes to glutamatergic receptors remain undefined. Here, we report the impact of chronic (7-day) BZD treatment on excitatory synapse and NMDA receptor (NMDAR) function, expression, and subcellular localization in cortical neurons. Chronic treatment with the BZD diazepam (DZP) resulted in an increase in NMDAR-mediated miniature excitatory postsynaptic currents (mEPSCs). Confocal imaging studies revealed a DZP-induced enrichment of GluN2B-containing NMDARs at functional synapses (expressing AMPA receptors, AMPARs) while GluN2B subunit expression was otherwise unaltered. Conversely, localization of GluN2A-containing NMDARs (GluN2A-NMDARs) to functional synapses was unchanged, while GluN2A-NMDAR total protein levels and surface accumulation were enhanced. Intriguingly, we demonstrate for the first time the BZD-induced enrichment and expansion of GluN2A-NMDAR coverage at silent (AMPAR-lacking) synapses. Finally, biochemical fractionation analysis of the translation elongation protein eEF2, known to control E/I balance, detected lower levels of deactivated, phosphorylated eEF2 in the synaptic fraction of DZP-treated neurons, indicative of enhanced local translation. Collectively, our findings suggest that chronic BZD treatment triggers compensatory mechanisms which 1) enhance NMDAR function via increased GluN2B-NMDARs at functional synapses, and 2) promote the expression, surface localization, and accumulation of GluN2A-NMDARs at silent synapses, augmenting the potential for further synaptic plasticity.</p>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":" ","pages":"110624"},"PeriodicalIF":4.6,"publicationDate":"2025-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144775877","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":"Methylphenidate triggers retinal oxidative stress and mitochondrial dysfunction under physiological conditions but has beneficial effects in inflammatory settings.","authors":"Eliane S Sanches, Ricardo A Leitão, Filipa I Baptista, Sandra I Mota, Margarida V Caldeira, Paulo J Oliveira, António F Ambrósio, Rosa Fernandes, Ana P Silva","doi":"10.1016/j.neuropharm.2025.110623","DOIUrl":"10.1016/j.neuropharm.2025.110623","url":null,"abstract":"<p><p>Methylphenidate (MPH) is widely used as the first-line pharmacological treatment for attention-deficit/hyperactivity disorder (ADHD). However, its misuse as a cognitive enhancer has been increasing worldwide. Despite the scientific advances in understanding the effects of MPH on the brain, its impact on the retina, which shares the same embryonic origin with the brain, remains poorly understood. In the present study, primary retinal neural cell cultures were exposed to MPH (0.1-1 mM) alone or to MPH after an inflammatory stimulus (lipopolysaccharide; LPS, 1 μg/ml). Additionally, male Wistar Kyoto rats (WKY, control rats) and Spontaneously Hypertensive rats (SHR, ADHD model) were orally treated with MPH (1.5 mg/kg/day, P28-57). MPH (0.1 mM) preserved retinal cell viability but induced oxidative stress through NOX2 and PI3K/AKT/DRP1 signaling activation and mitochondrial dysfunction. This was evidenced by a decrease in the mitochondria number, increased fragmentation, impaired membrane potential, reduced oxygen consumption rate, and shifted metabolism towards a glycolytic metabolic profile. Under an inflammatory environment, MPH enhanced antioxidant defenses, decreased oxidative stress and intracellular calcium levels, and improved mitochondrial structure and function. These contrasting effects were corroborated in animal studies, where MPH treatment reduced oxidative stress and improved mitochondrial function in the ADHD model, despite having detrimental effects in control rats. Our findings uncover a novel mechanism through which MPH affects retinal cells via NOX2/PI3K/AKT/DRP1 signaling and mitochondrial alterations. Moreover, MPH demonstrates a context-dependent effect, yielding detrimental outcomes under physiological conditions but beneficial effects in inflammatory settings. These results provide new insights into both MPH's therapeutic potential and misuse-associated risks.</p>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":" ","pages":"110623"},"PeriodicalIF":4.6,"publicationDate":"2025-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144768806","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":"Brain-invading monocytes promote seizure-associated cognitive deficits and neurodegeneration.","authors":"Soheila Pourkhodadad, Wenyi Wang, Raymond Dingledine, Nicholas H Varvel","doi":"10.1016/j.neuropharm.2025.110625","DOIUrl":"10.1016/j.neuropharm.2025.110625","url":null,"abstract":"<p><p>Seizure-associated cognitive comorbidities can substantially reduce the quality of life in people with epilepsy. Neuroinflammation is an invariant feature of all chronic neurologic diseases, including epilepsy, and acute brain insults, including status epilepticus (SE). The generalized seizures of SE trigger a robust inflammatory response involving astrocytosis, erosion of the blood-brain barrier (BBB), activation of brain-resident microglia, and recruitment of blood-borne C-C chemokine receptor type 2 positive (CCR2+) monocytes into the brain. We have demonstrated that blocking monocyte recruitment into the brain via global Ccr2 knockout or systemic CCR2 antagonism with a small molecule alleviates multiple deleterious pathologies induced by SE, including BBB damage, microgliosis, and neuronal damage, following pilocarpine-induced SE. This study aimed to determine if fleeting CCR2 antagonism improves SE-associated cognitive impairments in the long term. Here, we show that brief antagonism of CCR2 after SE prevents the working memory deficit in the Y-maze and retention memory in the novel object recognition test, but does not attenuate anxiety-like behavior in the open field arena. Notably, CCR2 antagonism was neuroprotective in the cortex and the CA1 region of the hippocampus. Neuronal numbers in the CA1 hippocampus, but not the cortex, correlated with retention memory. Our results indicate that blood-borne monocytes are a viable therapeutic cellular target for preventing cognitive comorbidities and neurodegeneration associated with seizures.</p>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":" ","pages":"110625"},"PeriodicalIF":4.6,"publicationDate":"2025-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12360420/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144794960","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":"5-Lipoxygenase triggers depressive-like behaviors via activating NLRP3-induced pyroptosis in CUMS-exposed mice.","authors":"Yani Zhang, Zheng Yang, Ting Xu, Qian Wang, Tingting Sang, Xuan Sheng, Yan Fang, Lisheng Chu","doi":"10.1016/j.neuropharm.2025.110704","DOIUrl":"https://doi.org/10.1016/j.neuropharm.2025.110704","url":null,"abstract":"<p><p>5-Lipoxygenase (5-LOX) is implicated the pathogenesis of depression, yet the underlying molecular mechanism remains unclear. In our study, we investigated the dynamic changes of 5-LOX expression after chronic unpredictable mild stress (CUMS) stimulation. The results demonstrated that 5-LOX expression was significantly upregulated in the prefrontal cortex (PFC) after CUMS stimulation for 2 weeks, 4 weeks and 8 weeks. CUMS stimulation activated 5-LOX on neurons, and induced neuronal loss in the PFC. Moreover, the expression levels of pyroptosis-related proteins showed a gradual increase with prolongation of CUMS stimulation. Notably, inhibiting 5-LOX with zileuton effectively alleviated depressive-like behaviors, increased the expression of monoamine neurotransmitters and exerted neuroprotective effects in CUMS-exposed mice. 5-LOX inhibition also markedly reduced the expression levels of pyroptosis-related proteins. We further explored the role of 5-LOX in NLRP3-mediated cell pyroptosis in vitro. 5-LOX knockdown significantly suppressed LPS/ATP-induced pyroptosis in PC12 cells. 5-LOX overexpression enhanced the pyroptosis induced by LPS/ATP, while NLRP3 inhibitors reversed the aggravation. These findings indicate that 5-LOX contributes to the pathogenesis of depression via promoting NLRP3-mediated cell pyroptosis. Thus, 5-LOX inhibition could be applied as a clinic intervention for the treatment of depression.</p>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":" ","pages":"110704"},"PeriodicalIF":4.6,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145258604","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":"Astrocytic Connexin43 in Alzheimer's disease: mechanisms, interaction with P2 receptors, and therapeutic potential.","authors":"Weijie Xiong, Yixun Su, Alexei Verkhratsky, Chenju Yi","doi":"10.1016/j.neuropharm.2025.110705","DOIUrl":"https://doi.org/10.1016/j.neuropharm.2025.110705","url":null,"abstract":"<p><p>Pathogenesis of Alzheimer's disease (AD) is closely linked to functional abnormalities of the gap junction protein Connexin43 (Cx43) in astrocytes. Cx43 mediates ion homeostasis, metabolic support, and glial network signalling through formation of gap junctions and hemichannels. However, in AD, aberrant activation of Cx43 hemichannels exacerbates disrupted calcium signalling, promotes the release of ATP and glutamate, and amplifies neuroinflammation, ultimately contributing to a self-perpetuating pathological loop. This review provides a comprehensive summary of the pathophysiological roles of Cx43 in AD, with emphasis on its hemichannel function, and the interaction between Cx43 hemichannel and P2 receptors in AD pathogenesis. We further illustrate the potential contribution of non-channel function of Cx43 to reactive astrogliosis, and discuss recent preclinical advances in therapeutic strategies targeting Cx43, such as connexin-mimetic peptides and small-molecule inhibitors.</p>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":" ","pages":"110705"},"PeriodicalIF":4.6,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145252264","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":"Exploring the Effects of Microdosing on Health Behaviour Change.","authors":"Luisa Prochazkova, Laura C Carvalho, Natasza Marrouch, Jorge Encantado, Pedro J Teixeira","doi":"10.1016/j.neuropharm.2025.110688","DOIUrl":"https://doi.org/10.1016/j.neuropharm.2025.110688","url":null,"abstract":"<p><strong>Objective: </strong>While microdosing psychedelics is increasingly popular for enhancing well-being, its effects on health behavior change (HBC) remain poorly understood. This study investigated self-reported health-related behavior changes and putative underlying psychological mechanisms associated with psychedelic microdosing in a naturalistic setting.</p><p><strong>Methods: </strong>A retrospective mixed-method survey was conducted with 365 participants who had experience with psychedelic microdosing. Participants completed quantitative and qualitative items assessing changes in health behaviors (e.g., sleep, physical activity, diet) and psychological mechanisms (e.g., self-efficacy, emotional regulation) as a result of microdosing. Qualitative responses were analyzed thematically, and logistic regressions explored associations between behavioral change and individual/contextual predictors.</p><p><strong>Results: </strong>Microdosing was associated with positive changes across several health behaviors, most commonly in sleep, contemplative practices, physical activity, and work-life balance. Intention to change emerged as the strongest predictor of behavioral change, while dose, protocol, and psychiatric status were not significant predictors. Thematic analysis identified potential psychological mechanisms such as improved mental health, cognitive clarity, self-awareness, self-determination, and relatedness.</p><p><strong>Discussion: </strong>This study provides an initial exploration into the health-related behavior changes in microdosing. Future controlled studies should explore how microdosing might best support intentional health-promoting interventions.</p>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":" ","pages":"110688"},"PeriodicalIF":4.6,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145232766","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":"Genetic deletion of NAPE-PLD alters stress responsiveness and HPA-axis functionality in a context-dependent manner in mice.","authors":"Taylor J Woodward, Diana Dimen, Emily Fender Sizemore, Sarah Stockman, Fezaan Kazi, Serge Luquet, Ken Mackie, Istvan Katona, Andrea G Hohmann","doi":"10.1016/j.neuropharm.2025.110702","DOIUrl":"10.1016/j.neuropharm.2025.110702","url":null,"abstract":"<p><p>The endocannabinoid (eCB) system regulates stress responsiveness and hypothalamic-pituitary-adrenal (HPA) axis activity. The enzyme N-acyl phosphatidylethanolamine phospholipase-D (NAPE-PLD) is primarily responsible for the synthesis of the endocannabinoid signaling molecule anandamide (AEA) and other structurally related lipid signaling molecules known as N-acylethanolamines (NAEs). However, little is known about how activity of this enzyme affects behavior. As AEA plays a regulatory role in stress adaptation, we hypothesized that reducing synthesis of AEA and other NAEs would dysregulate stress reactivity. To test this hypothesis, we evaluated wild type (WT) and NAPE-PLD knockout (KO) mice in behavioral assays that assess stress responsiveness and anxiety-like behavior. NAPE-PLD KO mice exhibited anxiety-like behaviors in the open field test after a period of single housing. NAPE-PLD KO mice exhibited an exaggerated freezing response at baseline but blunted response 2,3,5-trimethyl-3-thiazoline (TMT) predator odor when compared to WT mice. NAPE-PLD KO mice also exhibited a context-dependent dysregulation of HPA axis in response to TMT in the paraventricular hypothalamic nucleus at a neuronal level, as measured by c-Fos immunohistochemstry. Male, but not female, NAPE-PLD knockout mice showed higher levels of circulating corticosterone relative to same-sex wildtype mice in response to TMT exposure, suggesting a sexually dimorphic dysregulation of the HPA axis at the hormonal level. Sex specific findings observed here mirror the sexually dimorphic drug response we recently identified in NAPE-PLD KO mice (Woodward et al., 2025). Together, these findings suggest that the enzymatic activity of NAPE-PLD regulates emotional resilience and recovery from both acute and sustained stress.</p>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":" ","pages":"110702"},"PeriodicalIF":4.6,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145232967","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":"Excessive calpain impairs offspring cognition via BDNF/TrkB dysregulation after maternal non-obstetric surgery during pregnancy","authors":"Nannan Zhang ,&nbsp;Mengdie Wang ,&nbsp;Jia Qin ,&nbsp;Wei Zeng ,&nbsp;Jiafeng Fu ,&nbsp;Yanfei Lu ,&nbsp;Hongfa Wang ,&nbsp;Qiang Ma ,&nbsp;Foquan Luo","doi":"10.1016/j.neuropharm.2025.110701","DOIUrl":"10.1016/j.neuropharm.2025.110701","url":null,"abstract":"<div><div>Maternal non-obstetric surgery during pregnancy has been linked to adverse neurodevelopmental outcomes in offspring, but the underlying mechanisms remain poorly understood. This study investigated how excessive calpain activity disrupts hippocampal development and impairs cognition by suppressing the BDNF/TrkB signaling pathway in a Sprague-Dawley pregnant rat model. We revealed that maternal surgery impaired spatial learning and contextual fear memory in offspring, whereas propofol alone had no such effect. These deficits were accompanied by reduced hippocampal dendritic spine density, decreased NeuN expression, and downregulation of PSD95, BDNF, TrkB, and phosphorylated TrkB proteins. Notably, calpain activity was significantly increased following surgery. Postnatal administration of calpain inhibitor MDL 28170 or TrkB agonist 7,8-DHF partially restored protein expression levels, alleviated dendritic and neuronal structure, and improved cognitive performance. These findings indicate that excessive calpain activation impairs offspring cognition by disrupting BDNF/TrkB-mediated synaptic plasticity and neuronal integrity. Pharmacological inhibition of calpain or activation of TrkB may serve as potential therapeutic strategies to mitigate neurodevelopmental damage caused by maternal surgery during pregnancy.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"281 ","pages":"Article 110701"},"PeriodicalIF":4.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145222232","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":"AMPK activation mitigates α-synuclein pathology and dopaminergic degeneration in cellular and mouse models of Parkinson's disease","authors":"Yoonha Kim,&nbsp;Jong Sam Lee,&nbsp;Sumin Son,&nbsp;Seobin Park,&nbsp;Hyungkeun Oh,&nbsp;Yoon Kyung Choi,&nbsp;Dong-Eun Kim","doi":"10.1016/j.neuropharm.2025.110700","DOIUrl":"10.1016/j.neuropharm.2025.110700","url":null,"abstract":"<div><div>Parkinson's disease (PD) is characterized by oxidative stress, mitochondrial dysfunction, and pathological accumulation of p-α-Synuclein (p-α-Syn). AMP-activated protein kinase (AMPK) has emerged as a regulator of cellular energy homeostasis, yet its role in PD pathology remains unclear. Here, we examined the effects of AMPK activation in SH-SY5Y neuroblastoma cells and in an MPTP-induced PD mouse model. In both undifferentiated and retinoic acid-differentiated SH-SY5Y cells exposed to 6-hydroxydopamine (6-OHDA), pharmacological AMPK activation with AICAR reduced reactive oxygen species (ROS) production and p-α-Syn aggregation. These effects were associated with enhanced mitophagy, increased lysosomal degradation, and stimulation of mitochondrial biogenesis, collectively restoring mitochondrial integrity and improving dopaminergic features. <em>In vivo</em>, AICAR treatment attenuated nigrostriatal dopaminergic degeneration in MPTP-exposed mice, reduced p-α-Syn accumulation, and preserved tyrosine hydroxylase expression. Moreover, systemic cytokine analysis revealed that AMPK activation suppressed IL-6–mediated inflammation, while modulating IL-1β levels in a context-dependent manner. These results demonstrate that AMPK activation mitigates α-synuclein pathology, preserves mitochondrial function, and protects dopaminergic neurons in both cellular and animal PD models. Our findings support AMPK as a potential therapeutic target for disease modification in PD.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"281 ","pages":"Article 110700"},"PeriodicalIF":4.6,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145186546","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}