Molecular and Cellular Neuroscience最新文献

{"title":"Identifying potential genes driving ferroptosis in the substantia nigra and dopaminergic neurons in Parkinson's disease","authors":"Ardra Chakrabarti,&nbsp;Sonia Verma","doi":"10.1016/j.mcn.2025.103993","DOIUrl":"10.1016/j.mcn.2025.103993","url":null,"abstract":"<div><div>Parkinson's disease (PD) is a neurodegenerative disorder marked by dopaminergic (DA) neuron degeneration in the substantia nigra (SN). Conventional dopamine replacement therapies provide limited long-term efficacy and significant side effects. Emerging evidence suggests ferroptosis—a form of cell death driven by iron-dependent lipid peroxidation—contributes to PD pathology, though direct evidence linking dysregulation of ferroptosis-related genes in DA neuron loss in PD remains limited. This study explores the expression of ferroptosis-associated genes in the SN and DA neurons of PD patients, identifying potential therapeutic targets. We analyzed two independent RNA-seq datasets, GSE7621 and GSE8397 (GPL-96), from the GEO database to identify common differentially expressed ferroptosis-related genes in the SN of PD patients. We also conducted Gene Ontology and pathway enrichment analyses of these genes to explore the underlying mechanisms and constructed a protein-protein interaction network. The findings were further validated using an additional dataset, <span><span>GSE49036</span><svg><path></path></svg></span>. We further explored the dysregulation of these ferroptosis-related genes in DA neurons using RNA-seq data <span><span>GSE169755</span><svg><path></path></svg></span>, derived from DA neurons isolated from the SN of PD patients and controls. Lastly, the proposed hypothesis was experimentally validated in an in vitro PD model. This comprehensive multi-dataset analysis uncovers novel insights into the expression of ferroptosis-related genes in PD, suggesting potential biomarkers and therapeutic targets for mitigating DA neuron loss and PD progression.</div></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"132 ","pages":"Article 103993"},"PeriodicalIF":2.6,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143029142","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":"Sex-specific cognitive benefits and anti-inflammatory effects of coumestrol pretreatment in transient global cerebral ischemia","authors":"Cibele Canal Castro ,&nbsp;Adriana Vizuete ,&nbsp;Bruna Ferrary Deniz ,&nbsp;Angela Wyse ,&nbsp;Carlos Alexandre Netto","doi":"10.1016/j.mcn.2025.103991","DOIUrl":"10.1016/j.mcn.2025.103991","url":null,"abstract":"<div><div>Cerebral Global Ischemia (CGI) is a devastating neurological condition affecting millions globally each year, leading to significant inflammatory responses and long-term consequences, including delayed neuronal death and neurocognitive impairment. Following brain injury, resident microglial cells are activated, triggering pro-inflammatory cytokine expression and altering neuroimmune processes in a sex-dependent manner, particularly within the hippocampus. Coumestrol, a plant estrogen, is promoted as an alternative to post-menopausal hormone therapy due to its various mechanisms that enhance brain health, including its anti-inflammatory effects. This study aimed to investigate whether coumestrol pretreatment could attenuate the neuroinflammatory response following CGI by regulating pro-inflammatory pathways (GFAP, S100B, TNF-α, and IL-1β) and reversing CGI-induced memory loss.</div><div>Male and female rats underwent CGI for 10 min or a sham surgery and received an ICV infusion of 20 μg of coumestrol or vehicle 1 h before CGI induction. Our findings revealed intriguing sex-specific effects of coumestrol pretreatment on gliosis following CGI and reperfusion, suggesting modulation of glial responses after ischemic insults. Coumestrol pre-administration significantly reduced levels of pro-inflammatory cytokines TNF-α and IL-1β during both reperfusion periods in both sexes, thereby mitigating CGI-induced neuroinflammation. Moreover, coumestrol pretreatment effectively reduced stroke-induced cognitive impairment, alleviating ischemia-induced memory deficits in both male and female rats. These results demonstrate the coumestrol's ability to attenuate cognitive deficits induced by CGI and highlight its potential sex-specific effects on inflammatory pathways. This study suggests that coumestrol modulates the glial and microglial inflammatory response, offering a promising approach to mitigate memory deficits associated with cerebral global ischemia.</div></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"132 ","pages":"Article 103991"},"PeriodicalIF":2.6,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143008449","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":"Microglia-like cells from patient monocytes demonstrate increased phagocytic activity in probable Alzheimer's disease","authors":"Ceren Perihan Gonul ,&nbsp;Cagla Kiser ,&nbsp;Emis Cansu Yaka ,&nbsp;Didem Oz ,&nbsp;Duygu Hunerli ,&nbsp;Deniz Yerlikaya ,&nbsp;Melis Olcum ,&nbsp;Pembe Keskinoglu ,&nbsp;Gorsev Yener ,&nbsp;Sermin Genc","doi":"10.1016/j.mcn.2024.103990","DOIUrl":"10.1016/j.mcn.2024.103990","url":null,"abstract":"<div><div>Alzheimer's disease (AD) is a neurodegenerative disorder that is characterized by the accumulation of amyloid plaques, phosphorylated tau tangles and microglia toxicity, resulting in neuronal death and cognitive decline. Since microglia are recognized as one of the key players in the disease, it is crucial to understand how microglia operate in disease conditions and incorporate them into models. The studies on human microglia functions are thought to reflect the post-symptomatic stage of the disease. Recently developed methods involve induced microglia-like cells (iMGs) generated from patients' blood monocytes or induced pluripotent stem cells (iPSCs) as an alternative to studying the microglia cells <em>in vitro</em>. In this research, we aimed to investigate the phenotype and inflammatory responses of iMGs from AD patients. Monocytes derived from blood using density gradient centrifugation were differentiated into iMGs using a cytokine cocktail, including granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-34 (IL-34). After differentiation, cells were assessed by morphological analysis and a microglia surface marker, TMEM119. We used stimulants, lipopolysaccharide (LPS) and beta-amyloid, to examine iMGs' functions. Results showed that iMGs derived from AD patients exhibited increased secretion of pro-inflammatory cytokines upon LPS stimulation. Furthermore, their phagocytic ability was also heightened in stimulated and unstimulated conditions, with cells derived from patients showing increased phagocytic activity compared to healthy controls. Overall, these findings suggest that iMGs derived from patients using the direct conversion method possess characteristics of human microglia, making them an easy and promising model for studying microglia function in AD.</div></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"132 ","pages":"Article 103990"},"PeriodicalIF":2.6,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142896169","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":"Glutathione S-transferase: A keystone in Parkinson's disease pathogenesis and therapy","authors":"Pratyush Padhan ,&nbsp;Simran ,&nbsp;Neeraj Kumar ,&nbsp;Sonia Verma","doi":"10.1016/j.mcn.2024.103981","DOIUrl":"10.1016/j.mcn.2024.103981","url":null,"abstract":"<div><div>Parkinson's disease is a progressive neurodegenerative disorder that predominantly affects motor function due to the loss of dopaminergic neurons in the substantia nigra. It presents significant challenges, impacting millions worldwide with symptoms such as tremors, rigidity, bradykinesia, and postural instability, leading to decreased quality of life and increased morbidity. The pathogenesis of Parkinson's disease is multifaceted, involving complex interactions between genetic susceptibility, environmental factors, and aging, with oxidative stress playing a central role in neuronal degeneration. Glutathione S-Transferase enzymes are critical in the cellular defense mechanism against oxidative stress, catalysing the conjugation of the antioxidant glutathione to various toxic compounds, thereby facilitating their detoxification. Recent research underscores the importance of Glutathione S-Transferase in the pathophysiology of Parkinson's disease, revealing that genetic polymorphisms in Glutathione S-Transferase genes influence the risk and progression of the disease. These genetic variations can affect the enzymatic activity of Glutathione S-Transferase, thereby modulating an individual's capacity to detoxify reactive oxygen species and xenobiotics, which are implicated in Parkinson's disease neuropathological processes. Moreover, biochemical studies have elucidated the role of Glutathione S-Transferase in not only maintaining cellular redox balance but also in modulating various cellular signalling pathways, highlighting its neuroprotective potential. From a therapeutic perspective, targeting Glutathione S-Transferase pathways offers promising avenues for the development of novel treatments aimed at enhancing neuroprotection and mitigating disease progression. This review explores the evident and hypothesized roles of Glutathione S-Transferase in Parkinson's disease, providing a comprehensive overview of its importance and potential as a target for therapeutic intervention.</div></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"132 ","pages":"Article 103981"},"PeriodicalIF":2.6,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142792063","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":"Microfluidics in neural extracellular vesicles characterization for early Alzheimer's disease diagnosis","authors":"Hossein Zare ,&nbsp;Michelle M. Kasdorf ,&nbsp;Amirala Bakhshian Nik","doi":"10.1016/j.mcn.2024.103982","DOIUrl":"10.1016/j.mcn.2024.103982","url":null,"abstract":"<div><div>Dementia is a general term for conditions impairing cognitive abilities including perception, reasoning, attention, judgment, memory, and daily brain function. Early diagnosis of Alzheimer's disease (AD), the most common form of dementia, using neural extracellular vesicles (nEVs) is the focus of the current study. These nEVs carry AD biomarkers including β-amyloid proteins and phosphorylated tau proteins. The novelty of this review lies in developing a microfluidic perspective by introducing the techniques using a microfluidic platform for early diagnosis of AD. A microfluidic device can detect small sample sizes with significantly low concentrations. These devices combine nEV isolation, enrichment, and detection, which makes them ideal candidates for early AD diagnosis.</div></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"132 ","pages":"Article 103982"},"PeriodicalIF":2.6,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142780528","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":"The mRNA expression profile of glycine receptor subunits alpha 1, alpha 2, alpha 4 and beta in female and male mice","authors":"Mikaela M. Ceder,&nbsp;Kajsa A. Magnusson,&nbsp;Hannah M. Weman,&nbsp;Katharina Henriksson,&nbsp;Linn Andréasson,&nbsp;Teresa Lindström,&nbsp;Oskar Wiggins,&nbsp;Malin C. Lagerström","doi":"10.1016/j.mcn.2024.103976","DOIUrl":"10.1016/j.mcn.2024.103976","url":null,"abstract":"<div><div>Glycine receptors are ligand-gated chloride-selective channels that control excitability in the central nervous system (CNS). Herein, we have investigated the mRNA expression of the glycine receptor alpha 1 (<em>Glra1</em>), alpha 2 (<em>Glra2</em>), alpha 4 (<em>Glra4</em>) and the beta (<em>Glrb</em>) subunits, in adult female and male mice.</div><div>Single-cell RNA sequencing data re-analysis of the <span><span>Zeisel et al. (2018)</span></span> dataset indicated widespread expression of <em>Glra1</em>, <em>Glra2</em> and <em>Glrb</em> in the CNS, while only a few cells in the cortex, striatum, thalamus, midbrain and the spinal cord expressed <em>Glra4</em>. Highest occurrence of <em>Glra1</em>, <em>Glra2</em> and <em>Glrb</em> were found in the brainstem. Moreover, <em>Glra1</em> and <em>Glrb</em> were revealed to have the highest occurrences in the spinal cord of the investigated subunits. However, both <em>Glra2</em> and <em>Glrb</em> had a more widespread expression in the CNS compared with <em>Glra1</em> and <em>Glra4</em>. Bulk quantitative real-time-PCR (qRT-PCR) analysis revealed <em>Glra1</em> expression in the hypothalamus, thalamus, brainstem and the spinal cord, and widespread, but low, <em>Glra2</em> and <em>Glrb</em> expression in the CNS. Moreover, <em>Glrb</em> could be detected in a few visceral organs. Additionally, females and males were found to express <em>Glra1</em>, <em>Glra2</em> and <em>Glrb</em> differently in certain brain areas such as the brainstem. Expression levels of <em>Glra4</em> were too low to be detected using qRT-PCR. Lastly, RNAscope spatially validated the expression of <em>Glra1</em>, <em>Glra2</em> and <em>Glrb</em> in the areas indicated by the single-cell and bulk analyses, and further revealed that <em>Glra4</em> can be detected in the cortex, amygdala, hypothalamus, thalamus, brainstem, especially the cochlear nucleus, and in the spinal cord.</div></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"131 ","pages":"Article 103976"},"PeriodicalIF":2.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142695560","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":"Potential key pathophysiological participant and treatment target in autism spectrum disorder: Microglia","authors":"Zehua Tan ,&nbsp;Ruixin Xia ,&nbsp;Xin Zhao ,&nbsp;Zile Yang,&nbsp;Haiying Liu,&nbsp;Wenting Wang","doi":"10.1016/j.mcn.2024.103980","DOIUrl":"10.1016/j.mcn.2024.103980","url":null,"abstract":"<div><div>Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders characterized by social and communication deficits, as well as restricted or repetitive behaviors or interests. Although the etiology of ASD remains unclear, there is abundant evidence suggesting that microglial dysfunction is likely to be a significant factor in the pathophysiology of ASD. Microglia, the primary innate immune cells in the central nervous system (CNS), play a crucial role in brain development and homeostasis. Recently, numerous studies have shown that microglia in ASD models display various abnormalities including morphology, function, cellular interactions, genetic and epigenetic factors, as well as the expression of receptors, transcription factors, and cytokines. They impact normal neural development through various mechanisms contributing to ASD, such as neuroinflammation, and alterations in synaptic formation and pruning. The focus of this review is on recent studies regarding microglial abnormalities in ASD and their effects on the onset and progression of ASD at both cellular and molecular levels. It can provide insight into the specific contribution of microglia to ASD pathogenesis and help in designing potential therapeutic and preventative strategies targeting microglia.</div></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"131 ","pages":"Article 103980"},"PeriodicalIF":2.6,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142695557","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":"Sphingosine-1-phosphate receptor 3 promotes neuronal apoptosis via the TNF-α/caspase-3 signaling pathway after acute intracerebral hemorrhage","authors":"Dengpan Song ,&nbsp;Mengyuan Li ,&nbsp;Longxiao Zhang ,&nbsp;Kaiyuan Zhang ,&nbsp;Yuan An ,&nbsp;Mengzhao Feng ,&nbsp;Fang Wang ,&nbsp;Chi-Tai Yeh ,&nbsp;Jian Wang ,&nbsp;Fuyou Guo","doi":"10.1016/j.mcn.2024.103979","DOIUrl":"10.1016/j.mcn.2024.103979","url":null,"abstract":"<div><h3>Background</h3><div>Intracerebral hemorrhage (ICH) has a high incidence and mortality rate among cerebrovascular diseases, and effective treatments are lacking. Sphingosine-1-phosphate receptor 3 (S1PR3) is associated with secondary immune inflammatory injury following ICH. However, its relationship with neuronal apoptosis and the specific underlying mechanism are not clear.</div></div><div><h3>Methods</h3><div>We observed the effect of S1PR3 on neuronal apoptosis by assessing neurobehavioral scores, performing Western blot (WB) analysis, and performing TUNEL staining in a mouse model of ICH. Moreover, WBs and flow cytometry were used to study the specific mechanism and signaling pathways in HT22 cells in vitro.</div></div><div><h3>Results</h3><div>The expression of S1PR3, CCL2, TNF-α, and cleaved-caspase-3 (c-caspase-3) and neuronal apoptosis were significantly increased after ICH, accompanied by neurobehavioral deterioration. These effects were significantly improved by treatment with CAY10444, a specific S1PR3 antagonist. After S1P stimulation of HT22 cells, the expression of S1PR3, CCL2, TNF-α and c-caspase-3 increased, and neuronal apoptosis increased by activating caspase-3 through the downstream PI3K/AKT apoptosis signaling pathway. After CAY10444 treatment, the expression of CCL2, TNF-α and c-caspase-3 was significantly reduced, and the PI3K/AKT apoptotic signaling pathway was regulated to reduce neuronal apoptosis.</div></div><div><h3>Conclusion</h3><div>An increase in S1P/S1PR3 after ICH may induce neuronal apoptosis by increasing TNF-α expression and activating the PI3K/AKT signaling pathway and the expression of caspase-3 effector proteins. CAY10444 can reduce neuronal apoptosis, improve symptoms and play a neuroprotective role by antagonizing S1PR3. S1PR3 may be a promising therapeutic target.</div></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"131 ","pages":"Article 103979"},"PeriodicalIF":2.6,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142702763","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":"TAT-PPA1 protects against oxidative stress-induced loss of dopaminergic neurons","authors":"Hyun Jung Kwon ,&nbsp;Hyo Young Jung ,&nbsp;Soo Young Choi ,&nbsp;In Koo Hwang ,&nbsp;Dae Won Kim ,&nbsp;Min Jea Shin","doi":"10.1016/j.mcn.2024.103978","DOIUrl":"10.1016/j.mcn.2024.103978","url":null,"abstract":"<div><div>Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra (SN) of the midbrain, resulting in severe motor impairments. Inorganic pyrophosphatase 1 (PPA1) plays a key role in various biological processes, and this study introduces a cell-penetrating PPA1 fusion protein (TAT-PPA1) to explore its transduction into cells and brain tissues. TAT-PPA1 effectively penetrates SH-SY5Y cells and the SN region of PD animal models without toxicity, exhibiting protective effects against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP-)-induced cell death. TAT-PPA1 revealed an inhibitory influence on the MAPK signaling pathway and MPTP-induced reactive oxygen species (ROS) production. TAT-PPA1 suppresses JNK, AKT, p53, ERK, and p38 phosphorylation, showcasing its multifaceted role in cell survival pathways. In the MPTP-induced PD animal model, TAT-PPA1 prevents dopaminergic cell death and enhances motor function. This study shows that TAT-PPA1 protects against oxidative stress and cell death in neurodegenerative diseases, suggesting potential as a PD treatment.</div></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"131 ","pages":"Article 103978"},"PeriodicalIF":2.6,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142564710","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":"Inhibition of phosphodiesterase 10A mitigates neuronal injury by modulating apoptotic pathways in cold-induced traumatic brain injury","authors":"Mustafa C. Beker ,&nbsp;Mehmet O. Altintas ,&nbsp;Enes Dogan ,&nbsp;Cigdem Bayraktaroglu ,&nbsp;Buse Balaban ,&nbsp;Aysenur Ozpinar ,&nbsp;Nursena Sengun ,&nbsp;Serdar Altunay ,&nbsp;Ertugrul Kilic","doi":"10.1016/j.mcn.2024.103977","DOIUrl":"10.1016/j.mcn.2024.103977","url":null,"abstract":"<div><div>Brain injury develops from a complex series of pathophysiological phases, resulting in acute necrotic or delayed apoptotic cell death after traumatic brain injury (TBI). Inhibition of apoptotic cell death is critical for the treatment of acute neurodegenerative disorders, such as TBI. Here, we investigated the role of phosphodiesterase 10A (PDE10A) in the development of neuronal injury, particularly in apoptotic cell death. Using the PDE10A inhibitor TAK-063, we found that PDE10A inhibition is associated with decreased brain injury, brain swelling, and blood brain barrier disruption 48 h after cold-induced TBI. Furthermore, a particularly notable result was observed with 3 mg/kg TAK-063, which reduced disseminated neuronal injury. Protein abundance analysis revealed that PDE10A inhibition activates survival kinases AKT and ERK-1/-2, which were associated with the decreased activation of MMP-9 and PTEN. Additionally, iNOS and nNOS levels significantly reduced in the TAK-063 group, playing roles in inflammation and apoptosis. A planar surface immunoassay was performed for in-depth analyses of the apoptotic signaling pathways. We observed that inhibition of PDE10A resulted in the decreased expression of TNFRSF1A, TNFRSF10B, and TNFRSF6 receptors, particularly inducing apoptotic cell death. Moreover, these findings correlated with reduced levels of pro-apoptotic proteins, including PTEN, p27, Cytochrome-c, cleaved Caspase-3, Bad, and p53. Interestingly, TAK-063 treatment reduced levels of anti-apoptotic proteins or enzymes, including XIAP, Claspin, and HIF1α, without affecting Bcl-x, MCL-1, SMAC, HO-1, HO-2, HSP27, HSP60, and HSP70. The findings suggest that PDE10A regulates cellular signaling predominantly pro-apoptotic pathways, and inhibition of this protein is a promising approach for the treatment of acute brain injury.</div></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"131 ","pages":"Article 103977"},"PeriodicalIF":2.6,"publicationDate":"2024-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142504325","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}