Molecular Neurobiology最新文献

{"title":"Mechanism of N6-Methyladenosine Modification in the Pathogenesis of Depression.","authors":"Zhuohang Xian, Liangjing Tian, Zhixuan Yao, Lei Cao, Zhilin Jia, Gangqin Li","doi":"10.1007/s12035-024-04614-6","DOIUrl":"10.1007/s12035-024-04614-6","url":null,"abstract":"<p><p>N6-methyladenosine (m6A) is one of the most common post-transcriptional RNA modifications, which plays a critical role in various bioprocesses such as immunological processes, stress response, cell self-renewal, and proliferation. The abnormal expression of m6A-related proteins may occur in the central nervous system, affecting neurogenesis, synapse formation, brain development, learning and memory, etc. Accumulating evidence is emerging that dysregulation of m6A contributes to the initiation and progression of psychiatric disorders including depression. Until now, the specific pathogenesis of depression has not been comprehensively clarified, and further investigations are warranted. Stress, inflammation, neurogenesis, and synaptic plasticity have been implicated as possible pathophysiological mechanisms underlying depression, in which m6A is extensively involved. Considering the extensive connections between depression and neurofunction and the critical role of m6A in regulating neurological function, it has been increasingly proposed that m6A may have an important role in the pathogenesis of depression; however, the results and the specific molecular mechanisms of how m6A methylation is involved in major depressive disorder (MDD) were varied and not fully understood. In this review, we describe the underlying molecular mechanisms between m6A and depression from several aspects including inflammation, stress, neuroplasticity including neurogenesis, and brain structure, which contain the interactions of m6A with cytokines, the HPA axis, BDNF, and other biological molecules or mechanisms in detail. Finally, we summarized the perspectives for the improved understanding of the pathogenesis of depression and the development of more effective treatment approaches for this disorder.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"5484-5500"},"PeriodicalIF":4.6,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142648353","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 Insights into Therapeutic Targets for Neuromyelitis Optica Spectrum Disorders: A Mendelian Randomization Study.","authors":"Yangyue Cao, Jingxiao Zhang, Jiawei Wang","doi":"10.1007/s12035-024-04612-8","DOIUrl":"10.1007/s12035-024-04612-8","url":null,"abstract":"<p><p>Neuromyelitis optica spectrum disorder (NMOSD) is a severe central nervous system disease primarily characterized by optic neuritis and myelitis, which can result in vision loss and limb paralysis. Current treatment options are limited in their ability to prevent relapses and mitigate disease progression, underscoring the urgent need for new drug targets to develop more effective therapies. The objective of this study is to identify potential drug targets associated with a reduced risk of NMOSD attacks or relapses through Mendelian randomization (MR) analysis, thereby addressing the limitations of existing treatment methods and providing better clinical options for patients. To identify therapeutic targets for NMOSD, a MR analysis was conducted. The cis-expression quantitative trait loci (cis-eQTL, exposure) data were sourced from the eQTLGen consortium, which included a sample size of 31,684. NMOSD (outcome) summary data were obtained from two of the largest independent cohorts: one cohort consisted of 86 NMOSD cases and 460 controls derived from whole-genome sequencing data, while the other cohort included 129 NMOSD patients and 784 controls. We performed a two-sample MR analysis to evaluate the association between single nucleotide polymorphisms (SNPs) and copy number variations with NMOSD. The MR analysis utilized the inverse variance weighted (IVW) method, supplemented by MR-Egger, weighted median, simple mode, and weighted mode methods. Sensitivity analyses were conducted to assess the presence of horizontal pleiotropy and heterogeneity. Colocalization analysis was employed to test whether NMOSD risk and gene expression are driven by common SNPs. Additionally, a phenome-wide association study (PheWAS) was performed to detect disease outcomes associated with NEU1. Supplementary analyses included single-nucleus RNA sequencing (snRNA-seq) data analysis, protein-protein interaction (PPI) networks, and drug feasibility assessments to prioritize potential therapeutic targets. Two drug targets, COL4A1 and NEU1, demonstrated significant MR results in two independent datasets. Notably, NEU1 showed substantial evidence of colocalization with NMOSD. Additionally, apart from the association between NEU1 and NMOSD, no other associations were observed between gene-proxied NEU1 inhibition and the increased risk of other NMOSD-related diseases. This study supports the potential of targeting NEU1 for drug inhibition to reduce the risk of NMOSD. Further preclinical research and drug development are warranted to validate the efficacy and safety of NEU1 as a therapeutic target and to explore its potential in NMOSD treatment.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"5518-5530"},"PeriodicalIF":4.6,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142676372","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":"Unraveling Spatiotemporal Metabolic Perturbation of Amino Acids Associated with Ischemia-Reperfusion Injury by MALDI MS Imaging.","authors":"Kening Li, Yingying Gong, Wenqiao Chang, Jieping Yan, Ying Hu, Zongfu Pan, Ping Huang","doi":"10.1007/s12035-024-04649-9","DOIUrl":"10.1007/s12035-024-04649-9","url":null,"abstract":"<p><p>Various complex metabolic perturbations are involved in cerebral ischemia-reperfusion (I/R) injury. However, limited data have been reported on dynamic spatiotemporal metabolic perturbations of amino acids (AAs) in I/R injured rat brains. In this work, a combination of laser-assisted chemical transfer (LACT) and hexafluoroisopropanol (HFIP) was applied to the enhancement of on-tissue derivatization of AAs for matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI) of their dynamic spatiotemporal changes during I/R injury. The spatiotemporal distribution patterns of 15 derivatized AAs in the rat subjected to middle cerebral artery occlusion (MCAO) followed by different periods of reperfusion were unraveled by using MALDI MSI, including excitatory amino acids (e.g., Glu, Asp), inhibitory amino acids (e.g., GABA, Gly) and the other amino acids (e.g., Val, Pro, Gln, Phe). The metabolic perturbations of AAs showed similarities and differences in cerebral cortex (CTX) and striatum (STR) of MCAO rat brains at different periods of I/R injury. Generally, in 0.5-1.5 h of ischemia followed by 1-6 h of reperfusion, I/R triggered a dramatic increase in the levels of some AAs such as Glu, Asp, Gly, GABA, Gln, and Phe in both CTX and STR. After 6 h of reperfusion, AA levels gradually decreased. Immunohistochemistry (IHC) assay further showed that the immunoreactivities of selected enzymes related to Glu and GABA metabolism increased at the later stage of reperfusion. This present work provided spatiotemporal metabolic perturbations of AAs, which will further help us understand the mechanisms of I/R injury and also have great significance in developing region-specific therapeutic drugs and diagnostic markers.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"5744-5757"},"PeriodicalIF":4.6,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142770579","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":"Rutin Attenuates Distraction Spinal Cord Injury by Inhibiting Microglial Inflammation Through Downregulation of P38 MAPK/NF-κB/STAT3 Pathway.","authors":"Junrui Jonathan Hai, Weishi Liang, Duan Sun, Peng Yin, Bo Han, Xianjun Qu","doi":"10.1007/s12035-024-04659-7","DOIUrl":"10.1007/s12035-024-04659-7","url":null,"abstract":"<p><p>Distraction spinal cord injury (DSCI) is a severe complication following scoliosis correction surgery, for which there are currently no effective clinical treatments. This study aims to evaluate the inhibitory effects of rutin, a natural product, on inflammation in DSCI and to investigate the underlying mechanisms. In vitro, microglial cells were exposed directly to rutin to assess its ability to inhibit lipopolysaccharide (LPS)-induced inflammation. In rats with DSCI, the inhibitory effect of rutin on DSCI was evaluated using behavioral tests. mRNA sequencing was performed on spinal cord tissues to elucidate the mechanism of rutin's action. Rutin significantly suppressed the LPS-induced increase in inflammatory factors in microglial cells. In DSCI rats treated with rutin, scores in the Basso-Beattie-Bresnahan (BBB) were significantly improved. The mechanism of rutin's action was found to be related to its ability to reduce inflammatory infiltration in spinal cord tissue, protecting neurons from apoptosis and microstructural demyelination. Through assays of transcriptomic differentially expressed genes (DEGs), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, and RT-qPCR validation of the top DEGs, MAPK13 (also known as P38 MAPK) was finally identified as the key target gene in promoting DSCI development. Further molecular docking analysis indicated an interaction between rutin and P38 MAPK, supporting the rutin's action and the underlying mechanism in anti-inflammation. In conclusion, rutin effectively inhibited the development of DSCI in rats. The mechanism of rutin's action was associated with its activity in blocking the P38 MAPK/NF-κB/STAT3 pathway in the microglial cells of spinal cord. Rutin could be developed as a potential anti-DSCI drug for clinical applications.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"6027-6040"},"PeriodicalIF":4.6,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142854787","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":"Therapeutic Potential of MCC950 in Restoring Autophagy and Cognitive Function in STZ-Induced Rat Model of Alzheimer's Disease.","authors":"Abdul Naeem, Arshi Waseem, Mohsin Ali Khan, Avril Ab Robertson, Syed Shadab Raza","doi":"10.1007/s12035-024-04662-y","DOIUrl":"10.1007/s12035-024-04662-y","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is currently the seventh leading cause of death worldwide. In this study, we explored the critical role of autophagy in AD pathology using a streptozotocin (STZ)-induced AD model in Wistar rats. The experimental groups included sham, STZ-induced AD, and STZ + MCC950-treated animals. Our findings revealed that administering two doses of STZ (3 mg/kg) intracerebroventricular at the interval of 48 h (on days 0 and 2), triggered autophagy, as evidenced by elevated levels of autophagy markers such as LC3II, ULK1, Beclin1, Ambra1, Cathepsin B, and a reduction in p62 levels. Behavioral assessments, including the water maze and novel object recognition tests, confirmed cognitive deficits and memory impairment, while the open-field test indicated increased anxiety in STZ-induced AD rats. In particular, treating the STZ-induced AD group with MCC950 (50 mg/kg) decreased the overexpression of autophagy-related proteins, which was consistent with better behavioral outcomes and lower anxiety. Overall, this study highlights new insights into AD pathophysiology and suggests potential therapeutic avenues.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"6041-6058"},"PeriodicalIF":4.6,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142864852","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":"Revisiting the Emerging Role of Light-Based Therapies in the Management of Spinal Cord Injuries.","authors":"Santimoy Sen, Nidhi Parihar, Prathamesh Mahadev Patil, Suryanarayana Murty Upadhyayula, Deepak B Pemmaraju","doi":"10.1007/s12035-024-04658-8","DOIUrl":"10.1007/s12035-024-04658-8","url":null,"abstract":"<p><p>The surge in spinal cord injuries (SCI) attracted many neurobiologists to explore the underlying complex pathophysiology and to offer better therapeutic outcomes. The multimodal approaches to therapy in SCI have proven to be effective but to a limited extent. The clinical basics involve invasive procedures and limited therapeutic interventions, and most preclinical studies and formulations are yet to be translated due to numerous factors. In recent years, photobiomodulation therapy (PBMT) has found many applications in various medical fields. In most PBMT, studies on SCI have employed laser sources in experimental animal models as a non-invasive source. PBMT has been applied in numerous facets of SCI pathophysiology, especially attenuation of neuroinflammatory cascades, enhanced neuronal regeneration, reduced apoptosis and gliosis, and increased behavioral recovery within a short span. Although PBMT is specific in modulating mitochondrial bioenergetics, innumerous molecular pathways such as JAK-STAT, PI3K-AKT, NF-κB, MAPK, JNK/TLR/MYD88, ERK/CREB, TGF-β/SMAD, GSK3β-AKT-β-catenin, and AMPK/PGC-1α/TFAM signaling pathways have been or are yet to be exploited. PMBT has been effective not only in cell-specific actions in SCI such as astrocyte activation or microglial polarization or alterations in neuronal pathology but also modulated overall pathobiology in SCI animals such as rapid behavioral recovery. The goal of this review is to summarize research that has used PBMT for various models of SCI in different animals, including clarifying its mechanisms and prospective molecular pathways that may be utilized for better therapeutic outcomes.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"5891-5916"},"PeriodicalIF":4.6,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142807599","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":"Inhibition of Vascular Endothelial Growth Factor Reduces Photoreceptor Death in Retinal Neovascular Disease via Neurotrophic Modulation in Müller Glia.","authors":"Shuang Gao, Sha Gao, Yanuo Wang, Lu Xiang, Hanwei Peng, Gong Chen, Jianmin Xu, Qiong Zhang, Caihong Zhu, Yingming Zhou, Na Li, Xi Shen","doi":"10.1007/s12035-025-04689-9","DOIUrl":"10.1007/s12035-025-04689-9","url":null,"abstract":"<p><p>VEGF is not only the most potent angiogenic factor, but also an important neurotrophic factor. In this study, vitreous expression of six neurotrophic factors were examined in proliferative diabetic retinopathy (PDR) patients with prior anti-VEGF therapy (n = 48) or without anti-VEGF treatment (n = 41) via ELISA. Potential source, variation and impact of these factors were further investigated in a mouse model of oxygen-induced retinopathy (OIR), as well as primary Müller cells and 661W photoreceptor cell line under hypoxic condition. Results showed that vitreous levels of NGF, NT-3, NT-4, BDNF, GDNF and CNTF were significantly higher in eyes undergoing anti-VEGF therapy compared with PDR controls. Statistical correlation between vitreous VEGF and each trophic factor was found. Hypoxia significantly induced the expressions of these neurotrophic factors, whereas application of anti-VEGF agent in OIR model could further upregulate retinal NGF, NT-3, NT-4, together with downregulation of BDNF, GDNF, CNTF, especially in Müller glia. Inhibition of Müller cell-derived VEGF would result in similar neurotrophic changes under hypoxia. With changes of corresponding neurotrophic receptors in the cocultured photoreceptor cells, their synergic effect could protect hypoxic photoreceptor from apoptosis when VEGF inhibition was present. These findings demonstrated that regulation of Müller cell-derived neurotrophic factors might be one of the possible mechanisms by which anti-VEGF therapy produced neuroprotective effects on PDR. These results provided new evidence for the therapeutic strategy of PDR.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"6352-6368"},"PeriodicalIF":4.6,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142951886","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":"Identification of Potential Intervention Targets Involved in Prior Exercise that Attenuates Peripheral Neuropathic Pain by Integrating Transcriptome and Whole-genome Bisulfite Sequencing Analyses.","authors":"BingLin Chen, Ting Wang, ChenChen Zhu, Chan Gong, JieWen Zheng, YiLi Zheng, JiaBao Guo","doi":"10.1007/s12035-025-04696-w","DOIUrl":"10.1007/s12035-025-04696-w","url":null,"abstract":"<p><p>Changes in DNA methylation and subsequent alterations in gene expression have opened a new direction in research related to the pathogenesis of peripheral neuropathic pain (PNP). This study aimed to reveal epigenetic perturbations underlying DNA methylation in the dorsal root ganglion (DRG) of rats with peripheral nerve injury in response to prior exercise and identify potential target genes involved. Male Sprague-Dawley rats were divided into three groups, namely, chronic constriction injury (CCI) of the sciatic nerve, CCI with prior 6-week swimming training (CCI_Ex), and sham operated (Sham). Mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) were used as the main observation indicators to evaluate behavioral changes associated with pain. In this study, 6-week swimming training before CCI prevented later chronic pain. In particular, CCI rats with prior exercise showed a significant increase in the MWT and TWL of the injured lateral hind paw compared with CCI rats without exercise on days 14, 21, and 28 after CCI. Whole-genome bisulfite sequencing from the injured lumbar (L4-L6) DRGs on the 28th day after surgery was detected. We also generated DNA methylation maps of the two comparisons (sham group vs. CCI and CCI groups vs. CCI_Ex group), and 396 overlapping differentially methylated region-related genes were found between the two comparisons. Moreover, we integrated RNA sequencing to understand the mechanism by which differential DNA methylation after CCI may influence gene expression. Finally, Ryr1 and Xirp2 were identified through association analysis of two omics and quantitative reverse-transcription polymerase chain reaction, respectively. The methylation levels of Ryr1 and Xirp2 were upregulated with a corresponding increase in their mRNA expression in the DRGs of CCI rats, whereas prior exercise downregulated Ryr1 methylation and restore its expression level. Functional enrichment analysis of both omics found that the calcium signaling pathway was significantly enriched. Therefore, the potential intervention targets (Ryr1 and Xirp2) in L4-L6 DRGs may be involved in prior exercise that attenuates PNP induced by CCI. This study provides crucial insights into the epigenetic regulation of PNP responses to prior exercise.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"6562-6575"},"PeriodicalIF":4.6,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143008583","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":"Identification, Clinical Values, and Prospective Pathway Signaling of Lipid Metabolism Genes in Epilepsy and AED Treatment.","authors":"Hong Wei, Biao Jin, Kangren Zhao, Dandan Liu, Jing Ran, Fuling Yan","doi":"10.1007/s12035-025-04688-w","DOIUrl":"10.1007/s12035-025-04688-w","url":null,"abstract":"<p><p>The dysregulation of lipid metabolism has been associated with the etiology and progression of the neurological pathology. However, the roles of lipid metabolism and the molecular mechanism in epilepsy and the use of antiepileptic drugs (AEDs) are relatively understudied. Gene expression profiles of GSE143272 from blood samples were included for differential analysis, and the lipid metabolism-related differentially expressed genes (DEGs) were identified. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed. The STRING database and Cytoscape software were used to establish and visualize protein-protein interaction (PPI) networks. RT-PCR and western blotting were used to verify the expression levels of lipid metabolism-related DEGs in serum and cerebrospinal fluid (CSF). Eleven lipid metabolism-related DEGs were identified including CXCL8, PTGS2, FOSB, G0S2, HLA-C, CLEC12A, ARG1, ELANE, RSAD2, CTSG, and DEFA1. And among them, five lipid metabolism-related Hub DEGs including CXCL8, PTGS2, ELANE, CTSG, and ARG1 were finally verified in serum samples of epilepsy patients. Moreover, CXCL8 was selected and validated in the epilepsy without AEDs and epilepsy with AEDs. G0S2 was significantly decreased in serum and CSF in epilepsy with AEDs compared to epilepsy without AEDs. Collectively, these findings suggest that lipid metabolism is closely related to epilepsy. This revelation opens up opportunities to further investigate the associated molecular mechanisms and possible therapeutic targets for epilepsy.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"6478-6489"},"PeriodicalIF":4.6,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142984183","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":"EAAT2 Activation Regulates Glutamate Excitotoxicity and Reduces Impulsivity in a Rodent Model of Parkinson's Disease.","authors":"Sanjay Das, Kyle Mccloskey, Binod Nepal, Sandhya Kortagere","doi":"10.1007/s12035-024-04644-0","DOIUrl":"10.1007/s12035-024-04644-0","url":null,"abstract":"<p><p>Parkinson's disease (PD) is a systemic disease characterized by motor and nonmotor impairments. Loss of dopaminergic neurons in the substantia nigra pars compacta region in PD disrupts dopamine-glutamate homeostasis in the corticostriatal circuit, contributing to cognitive impairment. In addition, excitatory amino acid transporter-2 (EAAT2), localized predominantly to astrocytes and responsible for > 80% of synaptic glutamate clearance, is downregulated in PD, causing glutamate spillover and excitotoxicity. This altered dopamine-glutamate homeostasis and excitotoxicity may affect reward-mediated decision-making behaviors and promote impulsive behaviors in PD. In this study, we hypothesized that GTS467, a small-molecule activator of EAAT2, could effectively reduce excitotoxicity and treat cognitive impairment without promoting impulsive behavior in PD. Rats that were unilaterally lesioned with the 6-OHDA toxin to produce Parkinsonian symptoms were referred to as lesioned rats. Lesioned rats were trained to meet baseline criteria in a 5-choice serial reaction time task, and the chronic effects of GTS467 were assessed after 3 weeks of treatment. The results showed that chronic treatment with GTS467 significantly improved correct responses and reduced premature impulsive responses and omissions compared with saline treatment. This improvement in performance correlated with a reduction in glutamate levels, an increase in EAAT2 expression, and normalization of NMDA receptor subunit expression and signaling. Furthermore, transcriptomic studies on the prefrontal cortex tissue have shown the differential expression of genes involved in neuroprotection, neuroinflammation, learning, and memory. These results validate the role of glutamate excitotoxicity in promoting impulsive behaviors and suggest that GTS467 can be developed as a therapeutic agent to reduce cognitive impairment and impulsive behaviors in PD.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"5787-5803"},"PeriodicalIF":4.6,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11953204/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142770536","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}