Experimental Neurology最新文献

Inhibition of mitoNEET ameliorates traumatic brain injury-induced ferroptosis and cognitive dysfunction by stabilizing dihydroorotate dehydrogenase.

IF 4.6 2区医学

Experimental Neurology Pub Date : 2025-04-04 DOI: 10.1016/j.expneurol.2025.115235

Jing Li, Bowen Jia, Yejia Xu, Yang Zhao, Shangwen Wang, Rui Yang, Li Su, Xiaofeng Zeng, Qianqian Li, Chengliang Luo

{"title":"Inhibition of mitoNEET ameliorates traumatic brain injury-induced ferroptosis and cognitive dysfunction by stabilizing dihydroorotate dehydrogenase.","authors":"Jing Li, Bowen Jia, Yejia Xu, Yang Zhao, Shangwen Wang, Rui Yang, Li Su, Xiaofeng Zeng, Qianqian Li, Chengliang Luo","doi":"10.1016/j.expneurol.2025.115235","DOIUrl":"https://doi.org/10.1016/j.expneurol.2025.115235","url":null,"abstract":"Background: Due to the complexity of the causes and mechanisms of traumatic brain injury (TBI), there is still a lack of effective clinical treatments. Ferroptosis is an iron-dependent mode of cell death characterized by lipid peroxidation, which is involved in the pathophysiology of TBI. The process of ferroptosis involves mitochondria, and mitochondrial alterations are important biomarkers for the detection of ferroptosis. As an iron‑sulfur [2Fe-2S] cluster protein, mitoNEET (gene: CISD1) is located on the outer surface of mitochondria, and plays a key role in regulating cellular energy use, lipid metabolism, and mitochondrial iron content. However, whether mitoNEET is involved in regulating ferroptosis and cognitive decline caused by TBI is unclear.Results: In the present study, we observed that a mitoNEET ligand or inhibitor, NL-1 intervention significantly inhibited the occurrence of ferroptosis and alleviated neuronal injury after TBI. The gain and loss-function models of mitoNEET were then used to confirm the role of mitoNEET in ferroptosis and cognitive dysfunction after TBI. knockdown of mitoNEET alleviated cognitive dysfunction and exhibited significant anti-ferroptosis effects in a mouse model of TBI, whereas mitoNEET overexpression exerted the opposite effects. Furthermore, silencing of DHODH blocked the anti-ferroptosis and neuroprotective effects of NL-1.Conclusions: Taken together, these data demonstrated that NL-1 reversed TBI-induced ferroptosis and neurodegeneration, at least in part through the activation of mitoNEET/DHODH signaling axis. Pharmacological and gene inhibition of mitoNEET ameliorated TBI-induced ferroptosis and cognitive dysfunction. Mechanically, NL-1 may be through targeting mitoNEET to potentiate DHODH-mediated ferroptosis defense.","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":" ","pages":"115235"},"PeriodicalIF":4.6,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143795004","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}

引用次数: 0

Decreased locus coeruleus multiunit activity in a mouse model of temporal lobe seizures with impaired consciousness.

IF 4.6 2区医学

Experimental Neurology Pub Date : 2025-04-04 DOI: 10.1016/j.expneurol.2025.115233

Marcus Valcarce-Aspegren, Patrick Paszkowski, Shixin Liu, Qian Wu, Sarah McGill, Lim-Anna Sieu, Hal Blumenfeld

{"title":"Decreased locus coeruleus multiunit activity in a mouse model of temporal lobe seizures with impaired consciousness.","authors":"Marcus Valcarce-Aspegren, Patrick Paszkowski, Shixin Liu, Qian Wu, Sarah McGill, Lim-Anna Sieu, Hal Blumenfeld","doi":"10.1016/j.expneurol.2025.115233","DOIUrl":"https://doi.org/10.1016/j.expneurol.2025.115233","url":null,"abstract":"People with temporal lobe epilepsy often suffer debilitating loss of consciousness during seizures. Rodent models have previously implicated the inhibition of brainstem and basal forebrain cholinergic neurons in the cortical impairment during these periods of impaired consciousness. However, there are still other subcortical pathways that remain largely unexplored. Our goal was to record multiunit activity in the locus coeruleus (LC) in an awake mouse model to help elucidate its potential role in this pathophysiology. Recordings were performed using head-fixed mice running on a wheel with chronically implanted bipolar electrodes in the right orbitofrontal cortex and bilateral dorsal hippocampi. Focal limbic seizures were induced via the application of current pulses into the HC and multiunit recordings were simultaneously obtained from the LC. We observed a significant decrease in firing of LC neurons during ictal impairment of running wheel behavior. There was also a concurrent, significant increase in power in the 1-4 Hz band in the OFC. This provides evidence of a LC noradrenergic pathway contributing to depressed arousal in focal limbic seizures. Further elucidation of these, and other pathways, will contribute better mechanistic understanding of ictal unconsciousness and may lead to novel, improved treatments for people with epilepsy.","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":" ","pages":"115233"},"PeriodicalIF":4.6,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143795003","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}

引用次数: 0

Comparative analysis of functional network dynamics in high and low alcohol preference mice.

IF 4.6 2区医学

Experimental Neurology Pub Date : 2025-04-04 DOI: 10.1016/j.expneurol.2025.115238

Zilin Wang, Yingying Zhao, Ze Wang, Nongyuan Sun, Wen Yu, Quying Feng, Hee Young Kim, Feifei Ge, Xin Yang, Xiaowei Guan

{"title":"Comparative analysis of functional network dynamics in high and low alcohol preference mice.","authors":"Zilin Wang, Yingying Zhao, Ze Wang, Nongyuan Sun, Wen Yu, Quying Feng, Hee Young Kim, Feifei Ge, Xin Yang, Xiaowei Guan","doi":"10.1016/j.expneurol.2025.115238","DOIUrl":"https://doi.org/10.1016/j.expneurol.2025.115238","url":null,"abstract":"Individual variability preference is a typical characteristic of alcohol drinking behaviors, with a higher risk for the development of alcohol use disorders (AUDs) in high alcohol preference (HP) populations. Here, we created a map of alcohol-related brain regions through c-Fos profiling, and comparatively investigated the differences of functional neural networks between the HP mice and low alcohol preference (LP) mice. We found that neuronal activity in some brain regions, such as ventral tegmental area (VTA), was altered in both HP and LP mice, indicating that these neurons were universally sensitive to alcohol. Most importantly, several brain regions, such as the prefrontal cortex and insular cortex, exhibited significantly higher c-Fos expression in HP mice than that in LP mice and displayed broader and stronger neural connections across brain networks, suggesting that these brain regions are the potential targets for individual alcohol preference. Graph theory-based analysis unraveled a decrease in brain modularity in HP networks, yet with more centralized connection patterns, and maintained higher communication efficiency and redundancy. Furthermore, LP mice switched the central network hubs, with the key differential network centered on nucleus accumbens shell (NAc Sh), nucleus accumbens core (NAc C), VTA, and anterior insular cortex (AIC), indicating that these brain regions and related neural circuits, such as NAc Sh-AIC may be involved in regulating individual alcohol preference. These results provide novel insights into the neural connections governing individual preferences to alcohol consumption, which may contribute to AUDs prediction and pharmacotherapy.","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":" ","pages":"115238"},"PeriodicalIF":4.6,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143795002","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}

引用次数: 0

Theta-gamma phase-amplitude coupling as a promising neurophysiological biomarker for evaluating the efficacy of low-intensity focused ultrasound stimulation on vascular dementia treatment.

IF 4.6 2区医学

Experimental Neurology Pub Date : 2025-04-04 DOI: 10.1016/j.expneurol.2025.115237

Faqi Wang, Jing Ren, Qiuquan Cai, Rong Liang, Ling Wang, Qing Yang, Yutao Tian, Chenguang Zheng, Jiajia Yang, Dong Ming

{"title":"Theta-gamma phase-amplitude coupling as a promising neurophysiological biomarker for evaluating the efficacy of low-intensity focused ultrasound stimulation on vascular dementia treatment.","authors":"Faqi Wang, Jing Ren, Qiuquan Cai, Rong Liang, Ling Wang, Qing Yang, Yutao Tian, Chenguang Zheng, Jiajia Yang, Dong Ming","doi":"10.1016/j.expneurol.2025.115237","DOIUrl":"https://doi.org/10.1016/j.expneurol.2025.115237","url":null,"abstract":"Low-intensity focused ultrasound stimulation (LIFUS) has garnered attention for its potential in vascular dementia (VD) treatment. However, the lack of sufficient data supporting its efficacy and elucidating its mechanisms of action limits its further clinical translation and application. Considerable researches support the idea that LIFUS can improve the disturbance of neural oscillation modes caused by a variety of neurological diseases. However, the effect of LIFUS on neural oscillation modes in VD remains unclear. Therefore, this study aims to investigate the therapeutic effects of LIFUS on neural oscillation modes in VD. To achieve this purpose, the VD model was established via the bilateral common carotid artery occlusion, followed by two weeks of LIFUS treatment targeting the bilateral hippocampus. The therapeutic effects of LIFUS were evaluated by behavioral tests and cerebral blood flow measurement. Electrophysiological signals were recorded from the hippocampal CA1 and CA3 and medial prefrontal cortex (mPFC). The results indicated LIFUS could effectively improve cognitive dysfunction in VD rats. The underlying electrophysiological mechanisms involved the restoration of phase-amplitude coupling (PAC) of theta-gamma oscillations within both the CA3-CA1 local circuit and the hippocampus-mPFC cross-brain circuit. Classification results based on PAC characteristics suggested that PAC metrics are effective for evaluating the efficacy of LIFUS in treating VD, with optimal recognition performance observed in the hippocampus-mPFC cross-brain circuit. Our findings provide neuroelectrophysiological insights into the mechanisms of LIFUS in VD treatment and propose a promising diagnostic biomarker for evaluating LIFUS efficacy in future applications.","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":" ","pages":"115237"},"PeriodicalIF":4.6,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143795006","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}

引用次数: 0

Impaired synaptic plasticity in behaving mice by inactivation of presenilin and accumulation of the neurexin gamma-secretase proteolytic substrate.

IF 4.6 2区医学

Experimental Neurology Pub Date : 2025-04-03 DOI: 10.1016/j.expneurol.2025.115241

Francisco Arias-Aragón, Ana C Sánchez-Hidalgo, Agnès Gruart, Amalia Martinez-Mir, José M Delgado-García, Francisco G Scholl

{"title":"Impaired synaptic plasticity in behaving mice by inactivation of presenilin and accumulation of the neurexin gamma-secretase proteolytic substrate.","authors":"Francisco Arias-Aragón, Ana C Sánchez-Hidalgo, Agnès Gruart, Amalia Martinez-Mir, José M Delgado-García, Francisco G Scholl","doi":"10.1016/j.expneurol.2025.115241","DOIUrl":"https://doi.org/10.1016/j.expneurol.2025.115241","url":null,"abstract":"Mutations in presenilin (PSEN1/2) genes are the main cause of familial Alzheimer's disease (fAD). Presenilin (PS) form the active component of the gamma-secretase complex, a protease that cleaves the C-terminal fragment (CTF) of multiple membrane proteins. The generation of mice lacking Psen1/2 genes in adult forebrain and of knockin mice expressing fAD-linked PSEN1 mutations favored a loss of function mechanism for PS/gamma-secretase in AD. In vitro, inactivation of PS impairs short- and long-term plasticity, but if PS regulates synaptic plasticity in vivo is not known, nor is it known the contribution of specific gamma-secretase substrates. In this study, we performed electrophysiological recordings at medial prefrontal cortex-basolateral (mPFC-BLA) synapse of behaving mice during fear conditioning, a type of associative memory. In controls, fear-conditioning decreases paired-pulse facilitation of the mPFC-BLA synapse, likely reflecting a memory-dependent increase in release probability. In contrast, PScKOtam mice lacking Psen1/2 genes in forebrain neurons in a tamoxifen-regulated manner show decreased paired-pulse facilitation at mPFC-BLA synapse along with impaired memory. Neurexins (Nrxns) are presynaptic membrane proteins processed by PS/gamma-secretase. Importantly, paired-pulse facilitation is further decreased in PScKOtam;NrxnCTF mice expressing increased NrxnCTF levels in PS-deficient neurons. Moreover, high-frequency stimulation induces long-term potentiation (LTP) at mPFC-BLA synapse of control mice, but LTP is impaired in PScKOtam mice and fully inhibited in PScKOtam;NrxnCTF mice. These findings suggest that PS enables learning-dependent adaptations in short and long-term synaptic plasticity by, at least in part, preventing the accumulation of NrxnCTF, pointing at NrxnCTF as a relevant factor downstream of PS dysfunction in AD.","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":" ","pages":"115241"},"PeriodicalIF":4.6,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143788245","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}

引用次数: 0

DCI improves diabetic encephalopathy by modulating the BDNF/NF-κB/GSK-3β pathway.

IF 4.6 2区医学

Experimental Neurology Pub Date : 2025-04-03 DOI: 10.1016/j.expneurol.2025.115236

Haizhu Zhang, Xiao Han, Zhuoting Zhu, Gengyin Wang, Xinyu Sun, Shuang Li, Yirong Liu, Yuxin Zhang, Linghuan Gao

{"title":"DCI improves diabetic encephalopathy by modulating the BDNF/NF-κB/GSK-3β pathway.","authors":"Haizhu Zhang, Xiao Han, Zhuoting Zhu, Gengyin Wang, Xinyu Sun, Shuang Li, Yirong Liu, Yuxin Zhang, Linghuan Gao","doi":"10.1016/j.expneurol.2025.115236","DOIUrl":"https://doi.org/10.1016/j.expneurol.2025.115236","url":null,"abstract":"Diabetic encephalopathy (DE) involves cognitive dysfunction and structural brain changes due to diabetes, with a complex pathogenesis and no specific treatments available. D-chiral inositol (DCI), a bioactive molecule from dietary sources, has hypoglycemic and anti-inflammatory effects, but its role in DE and the mechanisms involved are still unclear. This study focused on male db/db mice, treated continuously with D-chiral inositol (DCI) at doses of 35 and 70 mg/kg/day for 8 weeks. Cognitive function was evaluated using the Morris water maze test, while pathological changes in the hippocampus and cortex were assessed through hematoxylin-eosin (HE) staining and Nissl staining. Protein expression related to synapses, inflammation, apoptosis, and neurofibrillary tangles, as well as mRNA levels, were analyzed using qRT-PCR, immunohistochemistry, and Western blotting to evaluate DCI's effects on DE. The results showed that DCI improved learning and memory in db/db mice, reduced nuclear pyknosis and neuronal loss, normalized PSD95 and SYN protein levels, and modulated inflammatory and apoptosis-related factors in the hippocampus and cortex. Additionally, DCI increased the expression of BDNF, IκB-α, and p-GSK-3β (Ser9), while decreasing levels of NF-κB p65, p-GSK3 (α + β) (Y216 + Y279), P-Tau (Thr231), and P-Tau (Ser396). These findings suggest that DCI may alleviate DE by modulating the BDNF/NF-κB/GSK-3β signaling pathway.","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":" ","pages":"115236"},"PeriodicalIF":4.6,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143788244","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}

引用次数: 0

iPLA2β/p38 MAPK alleviates the blood brain barrier disruption and brain injury in rats after TBI by inhibiting autophagy and tight junction damage: In vitro and in vivo studies

IF 4.6 2区医学

Experimental Neurology Pub Date : 2025-04-02 DOI: 10.1016/j.expneurol.2025.115228

Yonghong Bi , Pengyu Duan , Lan Luo , Xiaoyan Li , Xiangcheng Zhao , Longfei Li , Jiali Chen , Bing Zhang

{"title":"iPLA2β/p38 MAPK alleviates the blood brain barrier disruption and brain injury in rats after TBI by inhibiting autophagy and tight junction damage: In vitro and in vivo studies","authors":"Yonghong Bi , Pengyu Duan , Lan Luo , Xiaoyan Li , Xiangcheng Zhao , Longfei Li , Jiali Chen , Bing Zhang","doi":"10.1016/j.expneurol.2025.115228","DOIUrl":"10.1016/j.expneurol.2025.115228","url":null,"abstract":"<div><div>Traumatic brain injury (TBI) is one of the major causes of morbidity and mortality among adults. Blood brain barrier (BBB) damage is one of the main factors of secondary injury following TBI. However, whether iPLA2β activity affected vascular endothelial cells after TBI and its mechanism remains unclear. To investigate this, Feeney's weight-drop model in rats and H2O2 induced oxidative stress model in bEnd.3 cells were established, s-BEL (an inhibitor of iPLA2β) and ATP (an agonist of iPLA2β) were used for treatment. Behavioral assessments, BBB permeability, Immunofluorescence, Transmission Electron Microscopy, ROS, etc. are applied in the research. We found that TBI lead to autophagy in cerebral vascular endothelial cells of rats. s-BEL exacerbated ZO1 and Occludin damage, as well as BBB disruption through autophagy, whereas ATP protected the BBB from damage. Inhibiting autophagy reduced ZO1 and Occludin damage caused by decreased iPLA2β activity in bEnd.3. Inhibiting p38 MAPK could alleviate excessive autophagy and the damage to ZO1 and Occludin. In conclusion, the decreased iPLA2β activity following TBI in rats leads to increased autophagy in vascular endothelial cells and BBB disruption. The iPLA2β/p38 MAPK pathway could inhibit endothelial cells autophagy, alleviate tight junction damage and BBB disruption, thereby improving brain injury.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"389 ","pages":"Article 115228"},"PeriodicalIF":4.6,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143776982","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}

引用次数: 0

Behaviour profile characterization of PS19 and rTg4510 tauopathy mouse models: A systematic review and a meta-analysis.

IF 4.6 2区医学

Experimental Neurology Pub Date : 2025-04-02 DOI: 10.1016/j.expneurol.2025.115234

Renata L Alves, Ana Gonçalves, Iryna Voytyuk, David Harrison

{"title":"Behaviour profile characterization of PS19 and rTg4510 tauopathy mouse models: A systematic review and a meta-analysis.","authors":"Renata L Alves, Ana Gonçalves, Iryna Voytyuk, David Harrison","doi":"10.1016/j.expneurol.2025.115234","DOIUrl":"https://doi.org/10.1016/j.expneurol.2025.115234","url":null,"abstract":"The rTg4510 and PS19 mouse models are widely used in tauopathy research. Alzheimer's disease (AD) is the most prevalent among tauopathies. Behavioural tests are frequently used to assess emotional, cognitive, and motor behaviours in mouse models of AD. Cognitive deficits begin to manifest in rTg4510 mice around 3 months of age and in PS19 mice around 6 months. However, it's widely recognized that behavioural outcomes can vary due to environmental factors, health status, and husbandry practices, causing phenotypic differences between facilities. This study aims to consolidate current knowledge of the behavioural phenotypes of these two mouse models. We conducted a comprehensive literature review using keyword searches with Boolean operators across databases up to January 2024. Additional studies were included from manual searches. A total of 23 articles were reviewed for rTg4510 mice and 52 for PS19 mice. We extracted methodological details and key findings from each study. Results for rTg4510 mice show consistent findings regarding locomotion, memory and learning, and neurological dysfunction. However, the limited studies on motor and balance behaviour revealed no significant differences, while anxiety-like behaviour showed some inconsistencies. PS19 mice demonstrate more robust results for anxiety-like behaviour, memory and learning, and locomotion, while findings for balance and coordination are more inconsistent. Although there is overall coherence in certain aspects of the behavioural profiles of these tauopathy mouse models, it is crucial to recognize experimental heterogeneity and profile behavioural baselines to optimize the testing of both genetic and pharmacological interventions.","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":" ","pages":"115234"},"PeriodicalIF":4.6,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143788242","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}

引用次数: 0

Mechanisms of functional improvement behind nusinersen treatment in adult spinal muscular atrophy. 努西那生治疗成人脊髓性肌萎缩症的功能改善机制。

IF 4.6 2区医学

Experimental Neurology Pub Date : 2025-04-01 DOI: 10.1016/j.expneurol.2025.115230

Pei-Feng Hsieh, Hsing-Jung Lai, Yih-Chih Kuo, Chih-Chao Yang, Po-Ya Huang, Chen-Hung Ting, Shao-Ting Tai, Chia-Hsin Kao, Yi-Chieh Tsai, Hsi-Wen Huang, Jeng-Yi Shieh, Han Chiou, Lo-Fan Jeng, Wen-Chin Weng, Li-Kai Tsai

{"title":"Mechanisms of functional improvement behind nusinersen treatment in adult spinal muscular atrophy.","authors":"Pei-Feng Hsieh, Hsing-Jung Lai, Yih-Chih Kuo, Chih-Chao Yang, Po-Ya Huang, Chen-Hung Ting, Shao-Ting Tai, Chia-Hsin Kao, Yi-Chieh Tsai, Hsi-Wen Huang, Jeng-Yi Shieh, Han Chiou, Lo-Fan Jeng, Wen-Chin Weng, Li-Kai Tsai","doi":"10.1016/j.expneurol.2025.115230","DOIUrl":"https://doi.org/10.1016/j.expneurol.2025.115230","url":null,"abstract":"Nusinersen treatment not only prevents neurological deterioration in presymptomatic or early symptomatic children with spinal muscular atrophy (SMA) but promotes functional improvement in the later plateau phase in adults with SMA, though the mechanisms for such functional improvement are not fully understood. We evaluated the motor behaviors and electrophysiological performance of 10 consecutive adult patients with SMA before and 2, 6, 10 months after nusinersen treatment. Adult SMA mice (Smn-/-SMN2+/+) were treated with nusinersen intracerebroventricularly for 2 months with analysis of the SMN transcripts and proteins expression, motor function, electrophysiology, and pathology of spinal cord and muscles. SMA patients showed motor function improvement in 10 months after nusinersen treatment with an increase in compound muscle action potential (CMAP) amplitude and motor unit number estimation (MUNE). Nusinersen augmented the expression of full-length SMN transcripts and proteins in SMA mice. SMA mice receiving nusinersen treatment showed a motor behavioral improvement with an increase in MUNE. Although nusinersen treatment partially prevented spinal motor neuron death, there was no obvious elevation in motor neuron density despite an increase in MUNE, indicating the reactivation of quiescent motor neurons. Nusinersen treatment not only eliminated progressive denervation at the neuromuscular junction (NMJ), but also promoted NMJ innervation, implying the existence of reinnervation. The functional improvements observed with nusinersen treatment in adults with SMA during the later plateau phase primarily result from two mechanisms: the revival of live but functionless motor neurons and the reinnervation of NMJs through axonal sprouting and the formation of new motor units.","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":" ","pages":"115230"},"PeriodicalIF":4.6,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143779545","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}

引用次数: 0

Astrocytic N-myc downstream-regulated gene 2 is involved in neural injury induced by sepsis-associated encephalopathy

IF 4.6 2区医学

Experimental Neurology Pub Date : 2025-03-30 DOI: 10.1016/j.expneurol.2025.115229

Chang Xu, Tingting Gu, Bingjie Liu, Haoran Qu, Qingzhen Liu, Lidong Zhang, Anqi Yin

{"title":"Astrocytic N-myc downstream-regulated gene 2 is involved in neural injury induced by sepsis-associated encephalopathy","authors":"Chang Xu, Tingting Gu, Bingjie Liu, Haoran Qu, Qingzhen Liu, Lidong Zhang, Anqi Yin","doi":"10.1016/j.expneurol.2025.115229","DOIUrl":"10.1016/j.expneurol.2025.115229","url":null,"abstract":"<div><div>SAE is a systemic inflammatory response syndrome resulting from severe infection, which can progress to multiorgan dysfunction and mortality. Astrocytic-specific NDRG2, a stress response gene, has been implicated in regulating astrocyte reactivity and glutamate homeostasis in various neurological disorders. In this study, we initially investigated the expression and functional role of NDRG2 in SAE. Our results demonstrated that the upregulation of NDRG2 primarily inhibited Na+/K+-ATPase β1 and EAAT2, subsequently leading to glutamate toxicity and then induced astrocyte activation, neuronal dysfunction, and cellular apoptosis, ultimately leading to cognitive impairment. The deficiency of NDRG2 significantly mitigated these detrimental changes, including astrocytic activation, impaired glutamate clearance, and cognitive deficits in SAE, partly through the modulation of Na+/K+-ATPase β1. Our findings may provide new strategies for the intervention and treatment of patients with SAE in the future.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"389 ","pages":"Article 115229"},"PeriodicalIF":4.6,"publicationDate":"2025-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143763315","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}

引用次数: 0