Pub Date : 2025-11-01Epub Date: 2025-09-08DOI: 10.1016/j.neuint.2025.106050
Jiali Li , Shangyao Qin , Hong Liu , Ziwei Dai , Zhida Lan , Yimin Yuan , Zhida Su
Traditionally, oligodendrocyte precursor cells (OPCs) were primarily regarded for their differentiation potential to mature oligodendrocytes that ensheath central nervous system (CNS) axons through myelin formation. Recent breakthroughs in single-cell sequencing and in vivo imaging technologies have revolutionized our understanding, revealing that OPCs engage in extensive dynamic interactions with diverse CNS cell populations during neurodevelopment, tissue homeostasis maintenance, and pathological microenvironment remodeling. Notably, while OPCs exhibit relatively conserved phenotypic signatures, their functional plasticity within heterogeneous microenvironments demonstrates significant spatial specificity and disease-context dependence. In this review, we will systematically sort out the molecular interaction mechanism between OPCs and neurons, astrocytes, microglia, and vascular endothelial cells, deeply analyze their dynamic functional profiles, and focus on discussing: (1) the fine-tuning regulatory model of neuronal circuits mediated by OPCs at the developmental stage (2) the bidirectional regulatory mechanism of OPCs involved in maintaining the metabolic-immune balance under homeostasis; (3) OPC functional reprogramming in the pathological process of multiple sclerosis, cerebral ischemia, etc. This review aims to consolidate current evidence into a cohesive perspective on OPC multimodal functions, evaluate non-myelinating contributions, and discuss promising therapeutic targets for neural regenerative medicine.
{"title":"Dynamic interaction of oligodendrocyte precursor cells with other cell types in the central nervous system","authors":"Jiali Li , Shangyao Qin , Hong Liu , Ziwei Dai , Zhida Lan , Yimin Yuan , Zhida Su","doi":"10.1016/j.neuint.2025.106050","DOIUrl":"10.1016/j.neuint.2025.106050","url":null,"abstract":"<div><div>Traditionally, oligodendrocyte precursor cells (OPCs) were primarily regarded for their differentiation potential to mature oligodendrocytes that ensheath central nervous system (CNS) axons through myelin formation. Recent breakthroughs in single-cell sequencing and <em>in vivo</em> imaging technologies have revolutionized our understanding, revealing that OPCs engage in extensive dynamic interactions with diverse CNS cell populations during neurodevelopment, tissue homeostasis maintenance, and pathological microenvironment remodeling. Notably, while OPCs exhibit relatively conserved phenotypic signatures, their functional plasticity within heterogeneous microenvironments demonstrates significant spatial specificity and disease-context dependence. In this review, we will systematically sort out the molecular interaction mechanism between OPCs and neurons, astrocytes, microglia, and vascular endothelial cells, deeply analyze their dynamic functional profiles, and focus on discussing: (1) the fine-tuning regulatory model of neuronal circuits mediated by OPCs at the developmental stage (2) the bidirectional regulatory mechanism of OPCs involved in maintaining the metabolic-immune balance under homeostasis; (3) OPC functional reprogramming in the pathological process of multiple sclerosis, cerebral ischemia, etc. This review aims to consolidate current evidence into a cohesive perspective on OPC multimodal functions, evaluate non-myelinating contributions, and discuss promising therapeutic targets for neural regenerative medicine.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"190 ","pages":"Article 106050"},"PeriodicalIF":4.0,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145026557","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}
Ferroptosis constitutes a critical pathological mechanism in cerebral ischemia-reperfusion injury (CI/RI), significantly influencing neurological outcomes. While dual specificity phosphatase 1 (DUSP1) demonstrates neuroprotective effects against CI/RI, its regulatory role in ferroptosis remains to be elucidated. This study systematically investigated the therapeutic potential of DUSP1 through ferroptosis modulation in both in vitro and in vivo models. Using oxygen-glucose deprivation/reoxygenation (OGD/R)-treated PC12 cells with either DUSP1 overexpression or knockdown, we comprehensively assessed ferroptosis parameters including cell viability, malondialdehyde content, glutathione levels, intracellular iron concentration, reactive oxygen species accumulation, and expression of key ferroptosis-related proteins. In middle cerebral artery occlusion/reperfusion (MCAO/R) rat models, pharmacological inhibition of DUSP1 was employed to evaluate its impact on cerebral infarction volume, neurological deficits, histopathological changes, and ferroptosis biomarkers. Mechanistic studies incorporated the p38 mitogen-activated protein kinase pathway inhibitor adezmapimod. Our results demonstrated that (1) ferroptosis was significantly induced in both the OGD/R and MCAO/R models, accompanied by upregulated DUSP1 expression; (2) DUSP1 overexpression attenuated ferroptosis and ameliorated CI/RI, whereas genetic knockdown exacerbated these pathological processes; (3) pharmacological inhibition of DUSP1 aggravated cerebral injury and ferroptosis markers in MCAO/R rats; and (4) adezmapimod treatment effectively rescued ferroptosis progression in DUSP1-deficient cells by restoring glutathione peroxidase 4 and ferroportin expression while downregulating transferrin receptor and Ferritin Heavy Chain levels. These findings establish that DUSP1 confers neuroprotection against CI/RI through p38-mediated ferroptosis regulation, suggesting its promise as a novel therapeutic target for ischemic stroke.
{"title":"DUSP1-mediated suppression of p38 MAPK signaling pathway reduces ferroptosis in cerebral ischemia-reperfusion injury.","authors":"Shuyin Ma, Xiaodong Zhang, Jiaxin Fan, Mengying Chen, Qingling Yao, Nan Zhang, Kaili Shi, Minyu Duan, Han Yang, Tiantian Gao, Xiaodong Ma, Jingyi Wang, Weina Li, Chuxiao Zhou, Shuqin Zhan","doi":"10.1016/j.neuint.2025.106024","DOIUrl":"10.1016/j.neuint.2025.106024","url":null,"abstract":"<p><p>Ferroptosis constitutes a critical pathological mechanism in cerebral ischemia-reperfusion injury (CI/RI), significantly influencing neurological outcomes. While dual specificity phosphatase 1 (DUSP1) demonstrates neuroprotective effects against CI/RI, its regulatory role in ferroptosis remains to be elucidated. This study systematically investigated the therapeutic potential of DUSP1 through ferroptosis modulation in both in vitro and in vivo models. Using oxygen-glucose deprivation/reoxygenation (OGD/R)-treated PC12 cells with either DUSP1 overexpression or knockdown, we comprehensively assessed ferroptosis parameters including cell viability, malondialdehyde content, glutathione levels, intracellular iron concentration, reactive oxygen species accumulation, and expression of key ferroptosis-related proteins. In middle cerebral artery occlusion/reperfusion (MCAO/R) rat models, pharmacological inhibition of DUSP1 was employed to evaluate its impact on cerebral infarction volume, neurological deficits, histopathological changes, and ferroptosis biomarkers. Mechanistic studies incorporated the p38 mitogen-activated protein kinase pathway inhibitor adezmapimod. Our results demonstrated that (1) ferroptosis was significantly induced in both the OGD/R and MCAO/R models, accompanied by upregulated DUSP1 expression; (2) DUSP1 overexpression attenuated ferroptosis and ameliorated CI/RI, whereas genetic knockdown exacerbated these pathological processes; (3) pharmacological inhibition of DUSP1 aggravated cerebral injury and ferroptosis markers in MCAO/R rats; and (4) adezmapimod treatment effectively rescued ferroptosis progression in DUSP1-deficient cells by restoring glutathione peroxidase 4 and ferroportin expression while downregulating transferrin receptor and Ferritin Heavy Chain levels. These findings establish that DUSP1 confers neuroprotection against CI/RI through p38-mediated ferroptosis regulation, suggesting its promise as a novel therapeutic target for ischemic stroke.</p>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":" ","pages":"106024"},"PeriodicalIF":4.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144768181","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}
Pub Date : 2025-10-01Epub Date: 2025-07-26DOI: 10.1016/j.neuint.2025.106023
Xiangli Tong , Zhen Tong , Weijia Wu , Jialun Yang , Juan Wang , Yang Wang , Dandan Chen , Yiyang Wang , Fanqi Zeng , Qiyan Du , Yishan Chen , Wenfeng Liu
Cognitive dysfunction in early-stage Alzheimer's disease (AD) involves significant impairments in synaptic plasticity and dendritic spines integrity. Intriguingly, exercise interventions have demonstrated efficacy in enhancing cognitive function. However, the precise molecular mechanisms, particularly the upstream endogenous regulators (such as miRNAs) through which exercise mediates this synaptic improvement, remain unclear. Our findings indicated that 12 weeks of aerobic exercise effectively increased learning and memory, promoted amyloid beta (Aβ) and cerebral amyloid angiopathy (CAA) clearance in early-stage AD. Furthermore, aerobic exercise markedly enhanced dendritic spines density of pyramidal neurons in cortical layers II/III and the hippocampal CA1 region, as well as the expression of synapse-associated proteins such as cAMP response element-binding protein (CREB), synaptophysin (SYN), and postsynaptic density protein 95 (PSD95). Whole genome RNA sequencing (RNA-Seq) and bioinformatics analysis was performed to identify miR-3473e, a target closely related to AD and also a response factor that serves as a key mediator of aerobic exercise benefits. Subsequent findings revealed that miR-3473e was overexpressed in the brains of APP/PS1 mice, whereas aerobic exercise led to a decrease in its expression. Moreover, aerobic exercise enhanced its downstream targets, EPH receptor B2 (EphB2) and solute carrier family 1 member 1 gene (Slc1a1) as well as increased downstream GluN1, GRIA1 and p-GluN2B/GluN2B protein expression levels. In summary, we demonstrate that aerobic exercise can improve synaptic plasticity, and these effects are mediated via suppression of miR-3473e and regulation EphB2-NMDA/AMPA receptor signaling pathway, underscoring the potential of aerobic exercise to enhance cognitive function in early-stage of AD.
{"title":"Aerobic exercise rescues synaptic plasticity in early-stage Alzheimer's disease by suppressing miR-3473e to activate EphB2-dependent NMDA/AMPA receptor signaling","authors":"Xiangli Tong , Zhen Tong , Weijia Wu , Jialun Yang , Juan Wang , Yang Wang , Dandan Chen , Yiyang Wang , Fanqi Zeng , Qiyan Du , Yishan Chen , Wenfeng Liu","doi":"10.1016/j.neuint.2025.106023","DOIUrl":"10.1016/j.neuint.2025.106023","url":null,"abstract":"<div><div>Cognitive dysfunction in early-stage Alzheimer's disease (AD) involves significant impairments in synaptic plasticity and dendritic spines integrity. Intriguingly, exercise interventions have demonstrated efficacy in enhancing cognitive function. However, the precise molecular mechanisms, particularly the upstream endogenous regulators (such as miRNAs) through which exercise mediates this synaptic improvement, remain unclear. Our findings indicated that 12 weeks of aerobic exercise effectively increased learning and memory, promoted amyloid beta (Aβ) and cerebral amyloid angiopathy (CAA) clearance in early-stage AD. Furthermore, aerobic exercise markedly enhanced dendritic spines density of pyramidal neurons in cortical layers II/III and the hippocampal CA1 region, as well as the expression of synapse-associated proteins such as cAMP response element-binding protein (CREB), synaptophysin (SYN), and postsynaptic density protein 95 (PSD95). Whole genome RNA sequencing (RNA-Seq) and bioinformatics analysis was performed to identify miR-3473e, a target closely related to AD and also a response factor that serves as a key mediator of aerobic exercise benefits. Subsequent findings revealed that miR-3473e was overexpressed in the brains of APP/PS1 mice, whereas aerobic exercise led to a decrease in its expression. Moreover, aerobic exercise enhanced its downstream targets, EPH receptor B2 (EphB2) and solute carrier family 1 member 1 gene (Slc1a1) as well as increased downstream GluN1, GRIA1 and <em>p</em>-GluN2B/GluN2B protein expression levels. In summary, we demonstrate that aerobic exercise can improve synaptic plasticity, and these effects are mediated via suppression of miR-3473e and regulation EphB2-NMDA/AMPA receptor signaling pathway, underscoring the potential of aerobic exercise to enhance cognitive function in early-stage of AD.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"189 ","pages":"Article 106023"},"PeriodicalIF":4.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144713500","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}
Pub Date : 2025-10-01Epub Date: 2025-07-31DOI: 10.1016/j.neuint.2025.106025
Cheng-Wei Lu , Tzu-Yu Lin , Wun-Jing Pan , Ya-Ying Chang , Kuan-Ming Chiu , Ming-Yi Lee , Su-Jane Wang
The effect of casticin, major polymethoxyflavone extracted from Vitex rotundifolia, on glutamate release and its underlying mechanisms was investigated in rat hippocampal synaptosomes. Casticin inhibited 4-aminopyridine (4-AP)-evoked glutamate release, with an IC50 of approximately 7.2 μM. It reduced the 4-AP-evoked increase in intrasynaptosomal Ca2+ concentration without affecting the synaptosomal membrane potential. The inhibitory effect of casticin on glutamate release was markedly prevented by ω-conotoxin GVIA, an N-type Ca2+ channel blocker, but not by ω-agatoxin VIA, a P/Q-type Ca2+ channel blocker. Further analysis of FM1-43 dye release showed that casticin suppressed glutamate release by decreasing synaptic vesicle exocytosis. Consistently, casticin also reduced 4-AP-induced phosphorylation of synapsin I, a presynaptic protein that regulates synaptic vesicle mobilization. Transmission electron microscopy (TEM) revealed that casticin decreased the proportion of release-competent synaptic vesicles in 4-AP-stimulated hippocampal synaptosomes. Taken together, these findings suggest that casticin inhibits glutamate release from rat hippocampal nerve terminals, potentially by suppression of N-type Ca2+ channel and reducing the availability of synaptic vesicles for exocytosis.
{"title":"Casticin inhibits the release of synaptic vesicular glutamate from rat hippocampal nerve terminals","authors":"Cheng-Wei Lu , Tzu-Yu Lin , Wun-Jing Pan , Ya-Ying Chang , Kuan-Ming Chiu , Ming-Yi Lee , Su-Jane Wang","doi":"10.1016/j.neuint.2025.106025","DOIUrl":"10.1016/j.neuint.2025.106025","url":null,"abstract":"<div><div>The effect of casticin, major polymethoxyflavone extracted from <em>Vitex rotundifolia</em>, on glutamate release and its underlying mechanisms was investigated in rat hippocampal synaptosomes. Casticin inhibited 4-aminopyridine (4-AP)-evoked glutamate release, with an IC<sub>50</sub> of approximately 7.2 μM. It reduced the 4-AP-evoked increase in intrasynaptosomal Ca<sup>2+</sup> concentration without affecting the synaptosomal membrane potential. The inhibitory effect of casticin on glutamate release was markedly prevented by ω-conotoxin GVIA, an N-type Ca<sup>2+</sup> channel blocker, but not by ω-agatoxin VIA, a P/Q-type Ca<sup>2+</sup> channel blocker. Further analysis of FM1-43 dye release showed that casticin suppressed glutamate release by decreasing synaptic vesicle exocytosis. Consistently, casticin also reduced 4-AP-induced phosphorylation of synapsin I, a presynaptic protein that regulates synaptic vesicle mobilization. Transmission electron microscopy (TEM) revealed that casticin decreased the proportion of release-competent synaptic vesicles in 4-AP-stimulated hippocampal synaptosomes. Taken together, these findings suggest that casticin inhibits glutamate release from rat hippocampal nerve terminals, potentially by suppression of N-type Ca<sup>2+</sup> channel and reducing the availability of synaptic vesicles for exocytosis.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"189 ","pages":"Article 106025"},"PeriodicalIF":4.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144757829","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}
Spina bifida is a complex and multifactorial congenital defect driven by both genetic and environmental factors. As such, epigenetic studies of spina bifida present an opportunity to study the joint contribution of both genes and the environment in the development of this disorder. This review focuses specifically on epigenetic research that may help us to understand the ways in which dysregulation of the epigenome and downstream cellular processes can confer increased risk of spina bifida. To do so, we discuss the epigenetic regulation of genes linked to spina bifida risk among children born with the disorder and their parents as well as evidence from experimental studies. We also discuss pathways necessary for normal neural tube development and specific documented dysregulation of these pathways in individuals with spina bifida. We conclude that the epigenome plays an important role in spina bifida etiology and should be further studied in additional populations, and tissue types, as well as cellular and animal models.
{"title":"Epigenetic dysregulation and the etiology of spina bifida","authors":"Tabitha Lumour-Mensah , Susan Korrick , Bernardo Lemos , Maitreyi Mazumdar","doi":"10.1016/j.neuint.2025.106033","DOIUrl":"10.1016/j.neuint.2025.106033","url":null,"abstract":"<div><div>Spina bifida is a complex and multifactorial congenital defect driven by both genetic and environmental factors. As such, epigenetic studies of spina bifida present an opportunity to study the joint contribution of both genes and the environment in the development of this disorder. This review focuses specifically on epigenetic research that may help us to understand the ways in which dysregulation of the epigenome and downstream cellular processes can confer increased risk of spina bifida. To do so, we discuss the epigenetic regulation of genes linked to spina bifida risk among children born with the disorder and their parents as well as evidence from experimental studies. We also discuss pathways necessary for normal neural tube development and specific documented dysregulation of these pathways in individuals with spina bifida. We conclude that the epigenome plays an important role in spina bifida etiology and should be further studied in additional populations, and tissue types, as well as cellular and animal models.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"189 ","pages":"Article 106033"},"PeriodicalIF":4.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144843983","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}
Pub Date : 2025-10-01Epub Date: 2025-08-12DOI: 10.1016/j.neuint.2025.106032
Jayantee Kalita , Aditi Pandey , Firoz M. Nizami , Ashish K. Dubey , Bikash Baishya
Lennox-Gastaut syndrome (LGS) is an epileptic encephalopathy characterized by multiple types of seizures typically occurring between 1 and 7 years of age, cognitive impairment and characteristic electroencephalographic abnormalities. Circulating metabolomic profile may give insight into the ongoing metabolic pathway abnormalities in these patients, but there is no such study. We report NMR based metabolomic profile in LGS and its association with clinical severity, MRI changes and EEG findings. LGS children between 2 and 18 years were included based on clinical and EEG diagnostic criteria. Detailed neurological examinations, frequency and type of seizures, EEG changes, cranial MRI and NMR based serum metabolomic profile were measured. The Clinical Global Impairment Severity Scale (CGI-S) was used to rate severity of LGS. Twenty-six LGS patients and 11 healthy matched controls were included. The median age of the patients was 6 (range 2–17) years, and 19 were males. Their median CGI-S score was 6, and all had more than one type of seizures. Seven metabolites namely lactate, glucose, glutamate, pyruvate, glutamine, glycine, citrate and creatinine were crucial for discrimination of LGS from the controls, among which glutamate was upregulated and citrate, pyruvate, and glutamine were down regulated in LGS. Glutamate associated with developmental quotient (r = −0.48) and pyruvate with focal seizures (r = 0.47) and cystic encephalomalacia on cranial MRI (p = 0.02). NMR metabolomic profile including glutamate, glutamine, glycine, glucose, pyruvate, lactate, citrate and creatinine can discriminate LGS from the controls. Role of antiglutamatergic drugs may be beneficial in controlling seizures, and needs future study.
{"title":"Circulating metabolomic changes in Lennox-Gastaut syndrome: correlation with clinico-radiological severity","authors":"Jayantee Kalita , Aditi Pandey , Firoz M. Nizami , Ashish K. Dubey , Bikash Baishya","doi":"10.1016/j.neuint.2025.106032","DOIUrl":"10.1016/j.neuint.2025.106032","url":null,"abstract":"<div><div>Lennox-Gastaut syndrome (LGS) is an epileptic encephalopathy characterized by multiple types of seizures typically occurring between 1 and 7 years of age, cognitive impairment and characteristic electroencephalographic abnormalities. Circulating metabolomic profile may give insight into the ongoing metabolic pathway abnormalities in these patients, but there is no such study. We report NMR based metabolomic profile in LGS and its association with clinical severity, MRI changes and EEG findings. LGS children between 2 and 18 years were included based on clinical and EEG diagnostic criteria. Detailed neurological examinations, frequency and type of seizures, EEG changes, cranial MRI and NMR based serum metabolomic profile were measured. The Clinical Global Impairment Severity Scale (CGI-S) was used to rate severity of LGS. Twenty-six LGS patients and 11 healthy matched controls were included. The median age of the patients was 6 (range 2–17) years, and 19 were males. Their median CGI-S score was 6, and all had more than one type of seizures. Seven metabolites namely lactate, glucose, glutamate, pyruvate, glutamine, glycine, citrate and creatinine were crucial for discrimination of LGS from the controls, among which glutamate was upregulated and citrate, pyruvate, and glutamine were down regulated in LGS. Glutamate associated with developmental quotient (r = −0.48) and pyruvate with focal seizures (r = 0.47) and cystic encephalomalacia on cranial MRI (p = 0.02). NMR metabolomic profile including glutamate, glutamine, glycine, glucose, pyruvate, lactate, citrate and creatinine can discriminate LGS from the controls. Role of antiglutamatergic drugs may be beneficial in controlling seizures, and needs future study.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"189 ","pages":"Article 106032"},"PeriodicalIF":4.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144854188","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}
Pub Date : 2025-10-01Epub Date: 2025-08-05DOI: 10.1016/j.neuint.2025.106030
Mackenzie R. Berschel , Maria Nikodemova , Jose R. Oberto, Alexandria B. Marciante, Alysha Michaelson, Gordon S. Mitchell
Cervical spinal cord injuries (cSCI) are associated with decreased breathing ability. Although no treatment options are currently available, moderate acute intermittent hypoxia (mAIH) is a promising therapeutic modality to improve breathing function after cSCI. Moderate AIH elicits phrenic motor plasticity via distinct, competing serotonin- or adenosine-driven mechanisms that interact via powerful crosstalk inhibition that constrains or even abolishes plasticity. The dominant mechanism driving plasticity depends on the spinal serotonin/adenosine balance. Shortly after cSCI, repeated AIH exposure elicits plasticity via an adenosine-dependent mechanism but reverts to serotonin-dominance with chronic cSCI. In healthy CNS, microglia regulate AIH-induced phrenic motor plasticity via enzymatic activities of ectonucleotidases (CD39, CD73) by converting extracellular ATP to adenosine. We hypothesized that cSCI increases microglial ectonucleotidase expression, elevating adenosine levels that may alter therapeutic responses to mAIH post-cSCI. We assessed microglial CD39 and CD73 expression at the subacute (1 & 2 weeks) and chronic (8 weeks) stages post C2-hemisection, both at the injury site (C1–C3) and in spinal segments containing phrenic motor neurons below the injury (C3–C6). Both enzymes were upregulated (mRNA & protein) 1- and 2-weeks post injury but returned to baseline by 8 weeks. In association, spinal adenosine increased significantly at 2, but not 8 weeks post-injury. Further, microglial CD39 and CD73 expression strongly correlate with P2Y12 receptor expression. Thus, shifting adenosine levels between subacute and early chronic cSCI may impact mechanism regulating mAIH-induced respiratory motor plasticity and breathing recovery at different times post-cSCI.
{"title":"Increased spinal adenosine after subacute cervical injury correlates with sustained upregulation of CD39 and CD73 in microglia","authors":"Mackenzie R. Berschel , Maria Nikodemova , Jose R. Oberto, Alexandria B. Marciante, Alysha Michaelson, Gordon S. Mitchell","doi":"10.1016/j.neuint.2025.106030","DOIUrl":"10.1016/j.neuint.2025.106030","url":null,"abstract":"<div><div>Cervical spinal cord injuries (cSCI) are associated with decreased breathing ability. Although no treatment options are currently available, moderate acute intermittent hypoxia (mAIH) is a promising therapeutic modality to improve breathing function after cSCI. Moderate AIH elicits phrenic motor plasticity <em>via</em> distinct, competing serotonin- or adenosine-driven mechanisms that interact <em>via</em> powerful crosstalk inhibition that constrains or even abolishes plasticity. The dominant mechanism driving plasticity depends on the spinal serotonin/adenosine balance. Shortly after cSCI, repeated AIH exposure elicits plasticity <em>via</em> an adenosine-dependent mechanism but reverts to serotonin-dominance with chronic cSCI. In healthy CNS, microglia regulate AIH-induced phrenic motor plasticity <em>via</em> enzymatic activities of ectonucleotidases (CD39, CD73) by converting extracellular ATP to adenosine. We hypothesized that cSCI increases microglial ectonucleotidase expression, elevating adenosine levels that may alter therapeutic responses to mAIH post-cSCI. We assessed microglial CD39 and CD73 expression at the subacute (1 & 2 weeks) and chronic (8 weeks) stages post C2-hemisection, both at the injury site (C1–C3) and in spinal segments containing phrenic motor neurons below the injury (C3–C6). Both enzymes were upregulated (mRNA & protein) 1- and 2-weeks post injury but returned to baseline by 8 weeks. In association, spinal adenosine increased significantly at 2, but not 8 weeks post-injury. Further, microglial CD39 and CD73 expression strongly correlate with P2Y12 receptor expression. Thus, shifting adenosine levels between subacute and early chronic cSCI may impact mechanism regulating mAIH-induced respiratory motor plasticity and breathing recovery at different times post-cSCI.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"189 ","pages":"Article 106030"},"PeriodicalIF":4.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144779560","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}
Pub Date : 2025-10-01Epub Date: 2025-08-12DOI: 10.1016/j.neuint.2025.106034
Dan Pu , Ye Jin , Longxing Wang , Renjun Wang , Lingyu Li , Yang Song , Xiaofei Han
Alzheimer's disease (AD) is characterized by the pathological hallmarks of β-amyloid deposition and Tau protein hyperphosphorylation, with memory loss and cognitive dysfunction as its primary clinical manifestations. The incidence of AD has been progressively increasing in recent years. Short-chain fatty acids (SCFAs), key effector molecules in host-gut microbial interactions, play a crucial role in maintaining central nervous system homeostasis. In this study, AD mouse model was established via AlCl3/D-gal induction. The effects of mixed SCFA intervention on spatial learning and memory in AD model mice were assessed using behavioral tests, including the Morris Water Maze. Levels of pro-inflammatory cytokines and activities of oxidative stress-related enzymes in brain and colon tissues were quantified using ELISA and commercial kits. Key protein expression levels were analyzed by Western blot, immunohistochemistry, and immunofluorescence. Results demonstrated that SCFAs significantly alleviated cognitive dysfunction in AD model, reduced Tau hyperphosphorylation at T181, T231 and S396 sites, suppressed pro-inflammatory cytokine release, and enhanced antioxidant capacity, but with no reversal in elevated Aβ levels in AD model. Mechanistically, SCFAs inhibited glial cell activation, upregulated MCT-1 and tight junction proteins in the blood-brain barrier and strengthened gut-brain barrier integrity, potentially regulating small molecule trans-barrier transport. Furthermore, examination of relevant protein expressions revealed that SCFAs activated HDAC1 and inhibited overexpressed HDAC3 and Keap-1 in AD mice model. These findings suggest that SCFAs may regulate epigenetic modifications in the brain of AD to exert neuroprotective effects. This study provides novel evidence supporting the potential of symbiotic microbe-derived SCFAs in alleviating AD.
{"title":"Combined supplementation of short-chain fatty acids reduces hyperphosphorylation of Tau at T181,T231 and S396 sites and improves cognitive impairment in a chemically induced AD mouse model via regulation of HDAC and Keap1","authors":"Dan Pu , Ye Jin , Longxing Wang , Renjun Wang , Lingyu Li , Yang Song , Xiaofei Han","doi":"10.1016/j.neuint.2025.106034","DOIUrl":"10.1016/j.neuint.2025.106034","url":null,"abstract":"<div><div>Alzheimer's disease (AD) is characterized by the pathological hallmarks of β-amyloid deposition and Tau protein hyperphosphorylation, with memory loss and cognitive dysfunction as its primary clinical manifestations. The incidence of AD has been progressively increasing in recent years. Short-chain fatty acids (SCFAs), key effector molecules in host-gut microbial interactions, play a crucial role in maintaining central nervous system homeostasis. In this study, AD mouse model was established via AlCl<sub>3</sub>/D-gal induction. The effects of mixed SCFA intervention on spatial learning and memory in AD model mice were assessed using behavioral tests, including the Morris Water Maze. Levels of pro-inflammatory cytokines and activities of oxidative stress-related enzymes in brain and colon tissues were quantified using ELISA and commercial kits. Key protein expression levels were analyzed by Western blot, immunohistochemistry, and immunofluorescence. Results demonstrated that SCFAs significantly alleviated cognitive dysfunction in AD model, reduced Tau hyperphosphorylation at T181, T231 and S396 sites, suppressed pro-inflammatory cytokine release, and enhanced antioxidant capacity, but with no reversal in elevated Aβ levels in AD model. Mechanistically, SCFAs inhibited glial cell activation, upregulated MCT-1 and tight junction proteins in the blood-brain barrier and strengthened gut-brain barrier integrity, potentially regulating small molecule <em>trans</em>-barrier transport. Furthermore, examination of relevant protein expressions revealed that SCFAs activated HDAC1 and inhibited overexpressed HDAC3 and Keap-1 in AD mice model. These findings suggest that SCFAs may regulate epigenetic modifications in the brain of AD to exert neuroprotective effects. This study provides novel evidence supporting the potential of symbiotic microbe-derived SCFAs in alleviating AD.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"189 ","pages":"Article 106034"},"PeriodicalIF":4.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144852112","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}
Pub Date : 2025-10-01Epub Date: 2025-07-07DOI: 10.1016/j.neuint.2025.106019
Naghme Bagheri , Giorgi Margvelani , Tai-Wei Chiang , Peter T. Nelson , Trees-Juen Chuang , Stefan Stamm
The microtubule associated protein tau (MAPT) and TAR DNA binding protein (TARDBP) genes play crucial roles in neurodegeneration. The tau protein encoded by MAPT is the main component of tau tangles, a pathologic hallmark of “tauopathies” such as Alzheimer's disease (AD). Cytosolic accumulations of TDP-43, encoded by TARDBP are characteristic for LATE (Limbic-predominant age-related TDP-43 encephalopathy) and other TDPopathies. In addition to the well-characterized mRNA splicing isoforms, both genes generate a multitude of circular RNAs (circRNAs). Both MAPT and TARDBP express circular RNA-specific exons characterized by suboptimal splice sites and lengths and are frequently derived from Alu-elements. Most circTau and to date all circTARDBP RNAs expressed in brain are human-specific, suggesting a possible unique contribution to human brain disease. TARDBP and MAPT circRNAs harbor open reading frames and circTau RNAs were shown to be translated into polypeptides in cells. Thus, circRNAs from the MAPT and TARDBP genes should be considered in molecular analysis of AD, LATE and other neurological diseases.
{"title":"Circular RNAs from the MAPT and TARDBP genes: Novel players in neurodegeneration?","authors":"Naghme Bagheri , Giorgi Margvelani , Tai-Wei Chiang , Peter T. Nelson , Trees-Juen Chuang , Stefan Stamm","doi":"10.1016/j.neuint.2025.106019","DOIUrl":"10.1016/j.neuint.2025.106019","url":null,"abstract":"<div><div>The microtubule associated protein tau (<em>MAPT</em>) and TAR DNA binding protein (<em>TARDBP</em>) genes play crucial roles in neurodegeneration. The tau protein encoded by <em>MAPT</em> is the main component of tau tangles, a pathologic hallmark of “tauopathies” such as Alzheimer's disease (AD). Cytosolic accumulations of TDP-43, encoded by <em>TARDBP</em> are characteristic for LATE (Limbic-predominant age-related TDP-43 encephalopathy) and other TDPopathies. In addition to the well-characterized mRNA splicing isoforms, both genes generate a multitude of circular RNAs (circRNAs). Both <em>MAPT</em> and <em>TARDBP</em> express circular RNA-specific exons characterized by suboptimal splice sites and lengths and are frequently derived from Alu-elements. Most circTau and to date all circTARDBP RNAs expressed in brain are human-specific, suggesting a possible unique contribution to human brain disease. TARDBP and MAPT circRNAs harbor open reading frames and circTau RNAs were shown to be translated into polypeptides in cells. Thus, circRNAs from the <em>MAPT</em> and <em>TARDBP</em> genes should be considered in molecular analysis of AD, LATE and other neurological diseases.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"189 ","pages":"Article 106019"},"PeriodicalIF":4.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144599022","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}
Pub Date : 2025-10-01Epub Date: 2025-08-08DOI: 10.1016/j.neuint.2025.106031
Raima Sing , Deep Shikha , Chandan Goswami
Microglia play an important role in the immunity of the central nervous system, crucial in maintaining homeostasis. However, under diseased conditions, this cell accumulates Fe2+/3+, triggering inflammatory and neurotoxic effects that contribute to neurodegenerative disorders such as Alzheimer's and Parkinson's. Hence, the study of dysregulated microglial activation and overload of Fe2+/3+ is crucial in the context of neurodegenerative conditions. Emerging research has identified cold-sensitive ion channels, i.e., TRPM8 in microglia, which can regulate key subcellular functions. This study explores the regulatory function of the TRPM8 in Fe2+/3+ metabolism and its implications for potential ferroptosis in BV2 microglial cells. We used highly specific fluorescence probes, pharmacological modulators of TRPM8 and performed life cell imaging to understand the uptake of Transferrin-488, mitochondrial Fe2+-level, cellular Ca2+-levels in live BV2 cells under different experimental conditions. Our findings reveal that TRPM8 activation leads to enhanced Transferrin-488-mediated cytosolic Fe3+-uptake, disrupts mitochondrial superoxide levels, and promotes cell death. Interestingly, under inflammatory conditions induced by LPS treatment, TRPM8 exhibits a distinct functional role. These results position TRPM8 as an important regulator of microglial Fe2+/3+ metabolism. This study indicates the involvement of TRPM8 in overload of Fe2+/3+ leading to ferroptosis and potential for M1-M2 polarization in microglia. These findings impose TRPM8 as a potential therapeutic target for neurodegenerative diseases, and aging.
{"title":"TRPM8 modulation alters uptake of Transferrin-mediated Fe3+, mitochondrial Fe2+ and intracellular Ca2+-levels in microglia","authors":"Raima Sing , Deep Shikha , Chandan Goswami","doi":"10.1016/j.neuint.2025.106031","DOIUrl":"10.1016/j.neuint.2025.106031","url":null,"abstract":"<div><div>Microglia play an important role in the immunity of the central nervous system, crucial in maintaining homeostasis. However, under diseased conditions, this cell accumulates Fe<sup>2+/3+</sup>, triggering inflammatory and neurotoxic effects that contribute to neurodegenerative disorders such as Alzheimer's and Parkinson's. Hence, the study of dysregulated microglial activation and overload of Fe<sup>2+/3+</sup> is crucial in the context of neurodegenerative conditions. Emerging research has identified cold-sensitive ion channels, i.e., TRPM8 in microglia, which can regulate key subcellular functions. This study explores the regulatory function of the TRPM8 in Fe<sup>2+/3+</sup> metabolism and its implications for potential ferroptosis in BV2 microglial cells. We used highly specific fluorescence probes, pharmacological modulators of TRPM8 and performed life cell imaging to understand the uptake of Transferrin-488, mitochondrial Fe<sup>2+</sup>-level, cellular Ca<sup>2+</sup>-levels in live BV2 cells under different experimental conditions. Our findings reveal that TRPM8 activation leads to enhanced Transferrin-488-mediated cytosolic Fe<sup>3+</sup>-uptake, disrupts mitochondrial superoxide levels, and promotes cell death. Interestingly, under inflammatory conditions induced by LPS treatment, TRPM8 exhibits a distinct functional role. These results position TRPM8 as an important regulator of microglial Fe<sup>2+/3+</sup> metabolism. This study indicates the involvement of TRPM8 in overload of Fe<sup>2+/3+</sup> leading to ferroptosis and potential for M1-M2 polarization in microglia. These findings impose TRPM8 as a potential therapeutic target for neurodegenerative diseases, and aging.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"189 ","pages":"Article 106031"},"PeriodicalIF":4.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144815473","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}
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