Experimental Neurology最新文献

{"title":"Pharmacological PTP1B inhibition rescues motor learning, neuroinflammation, and hyperglycaemia in a mouse model of Alzheimer's disease","authors":"Zara Franklin ,&nbsp;Claire Hull ,&nbsp;Mirela Delibegovic ,&nbsp;Bettina Platt","doi":"10.1016/j.expneurol.2024.115115","DOIUrl":"10.1016/j.expneurol.2024.115115","url":null,"abstract":"<div><h3>Background</h3><div>Patients with Alzheimer's Disease (AD) frequently suffer from comorbidities such as type 2 diabetes mellitus (T2DM), accompanied by shared common pathologies such as increased inflammation and impaired glucose homeostasis. Beta-secretase 1 (BACE1), the rate limiting enzyme in AD associated beta-amyloid (Aβ) production, is also implicated in metabolic dysfunction and can increase central and peripheral protein levels of protein tyrosine phosphatase 1B (PTP1B). PTP1B is a validated target in diabetes and obesity, and is a neuroinflammatory regulator involved in degenerative processes. This study investigated the effects of the PTP1B inhibitor, trodusquemine (MSI-1436) on the cognitive and metabolic phenotypes of the neuronal human BACE1 knock-in (PLB4) mouse, a co-morbidity model of AD and T2DM, and their wild-type (PLB_WT) controls.</div></div><div><h3>Methods</h3><div>Five-month-old male PLB4 and PLB_WT mice received PTP1B inhibitor treatment (1 mg/kg intraperitoneal injection; 5 weeks). Activity and spatial habituation (Phenotyper), motor learning (RotaRod), glucose tolerance, and brain and liver molecular analyses were analysed following treatment.</div></div><div><h3>Results</h3><div>Inhibition of PTP1B improved motor learning alongside glucose tolerance in PLB4 mice, without affecting body weight/adiposity. MSI-1436 treatment led to lower protein levels of amyloid precursor protein (APP), reduced astrogliosis and restoration of the endoplasmic chaperone immunoglobulin heavy chain binding protein (BIP) in the brain, alongside decreased insulin receptor substrate-1 (IRS1) and dipeptidyl peptidase-4 (DPP4) proteins in the liver.</div></div><div><h3>Conclusion</h3><div>We provide evidence that neuronal BACE1 contributes to neuroinflammation and hyperglycaemia in PLB4 mice, and this can be partially rescued by PTP1B inhibition. Targeting PTP1B may therefore offer an attractive therapeutic approach to ameliorate co-morbidity associated pathologies in AD and T2DM.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"385 ","pages":"Article 115115"},"PeriodicalIF":4.6,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142822037","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Glial scarring limits recovery following decompressive surgery in rats with syringomyelia","authors":"Shengyu Cui ,&nbsp;Jinze Li ,&nbsp;Can Zhang ,&nbsp;Qian Li ,&nbsp;Chuan Jiang ,&nbsp;Xinyu Wang ,&nbsp;Xiaoxu Yu ,&nbsp;Kang Li ,&nbsp;Yuxin Feng ,&nbsp;Fengzeng Jian","doi":"10.1016/j.expneurol.2024.115113","DOIUrl":"10.1016/j.expneurol.2024.115113","url":null,"abstract":"<div><div>Syringomyelia is a neurological disease that is difficult to cure, and treatments often have limited effectiveness. In this study, a rat model of syringomyelia induced by epidural compression was used to investigate the factors that limit the prognosis of syringomyelia. After we treated syringomyelia rats with surgical decompression alone, MRI revealed that the syringomyelia rats did not show the expected therapeutic effect. Through cerebrospinal fluid (CSF) tracing experiments, we found that the CSF flow in the subarachnoid space (SAS) of rats was restored after decompression. This shows that the poor prognosis of syringomyelia rats in this study is not caused by CSF circulation disorders, suggesting the existence of other factors. Further, immunofluorescence revealed that there were extensive glial scars characterized by increased expression of glial fibrillary acidic protein (GFAP) and chondroitin sulfate proteoglycans (CSPGs) around the syrinx in the non-improved group compared to the improved group. To verify the limiting role of glial scarring in the prognosis of syringomyelia, we intervened with the selective astrocyte inhibitor fluorocitrate (FC). Intrathecal injection of FC significantly inhibited the formation of glial scar after decompression in syringomyelia rats and promoted the reduction of syrinx. This scar-inhibiting effect significantly improved neuronal survival, promoted axonal and myelin recovery, and showed better recovery in sensory function and fine motor control functions. These findings suggest that glial scarring around syrinx is a key factor limiting recovery of syringomyelia. By inhibiting glial scar formation, the prognosis of syringomyelia can be significantly improved, which provides a new strategy for improving clinical treatment effects.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"385 ","pages":"Article 115113"},"PeriodicalIF":4.6,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142817720","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":"The role of the CCL5-CCR5 axis in microglial activation leading to postoperative cognitive dysfunction","authors":"Yuanyuan An ,&nbsp;Yu Yao ,&nbsp;Huan Liu ,&nbsp;Yuqing Xi ,&nbsp;Mengying Pi ,&nbsp;Rui Xu ,&nbsp;Yulin Huang ,&nbsp;Shuming Li ,&nbsp;Xiaoping Gu","doi":"10.1016/j.expneurol.2024.115114","DOIUrl":"10.1016/j.expneurol.2024.115114","url":null,"abstract":"<div><div>Postoperative cognitive dysfunction (POCD) is a common complication following surgeries involving general anesthesia. Although the CCL5-CCR5 axis is implicated in various neurological conditions, its role in POCD remains unclear. In our POCD model, we observed an increase in CCL5 and CCR5 levels concurrent with microglial activation and significant upregulation of inflammatory cytokines IL-6 and IL-1β. Administration of MVC, a CCR5 antagonist, alleviated neuroinflammation, prevented dendritic spine loss, and improved cognitive deficits by inhibiting the CCR5/CREB/NLRP1 pathway. However, the cognitive benefits of MVC were reversed by the CREB inhibitor 666–15. Our findings highlight the potential of targeting the CCL5-CCR5 axis as a therapeutic strategy for preventing and treating POCD.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"385 ","pages":"Article 115114"},"PeriodicalIF":4.6,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142817722","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epidural electrical stimulation combined with photobiomodulation restores hindlimb motor function in rats with thoracic spinal cord injury","authors":"Xiao-Jun Guo ,&nbsp;Le-Wei He ,&nbsp;Jia-Qi Chang ,&nbsp;Wen-Nan Su ,&nbsp;Ting Feng ,&nbsp;Yi-Meng Gao ,&nbsp;Yuan-Yuan Wu ,&nbsp;Can Zhao ,&nbsp;Jia-Sheng Rao","doi":"10.1016/j.expneurol.2024.115112","DOIUrl":"10.1016/j.expneurol.2024.115112","url":null,"abstract":"<div><div>Epidural electrical stimulation (EES) could restore motor function of paralyzed limbs of patients with spinal cord injury (SCI). However, its invasiveness limits its application in early stage of injury. Photobiomodulation (PBM) utilizes infrared light for percutaneous irradiation of the spinal cord to protect nerve tissue, delay muscle atrophy, and can be applied in early stage of SCI due to its non-invasiveness. This study tested the effect of the combination of EES and PBM on promoting motor function recovery in SCI rats. Severe contusion was induced at the T9 spinal segment in female rats, EES (applied to the L2 and S1 spinal cord segments) with treadmill training was conducted one week after the injury, and PBM percutaneous irradiation started at the injured segment on the day of surgery. In the third week post-injury, electromyographic and gait performance during training were recorded. Besides, the muscles of the hind limbs and the spinal cord on the caudal side of the injured segment were extracted. The results demonstrate that compared to the EES- or PBM-only group, this combined therapy led to several indicators returning to intact levels, including behavioral and electrophysiological, the gait patterns was also closer to intact rats. Additionally, the combined treatment group showed minimal muscle atrophy and maximal preservation of the injured spinal cord on the caudal side, with this histological improvement correlated with motor function recovery. Taken together, our results showed that this combined therapy was a more effective treatment for improving motor dysfunction after SCI which could protect the damaged spinal cord and promote the recovery of motor function in rats with SCI.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"385 ","pages":"Article 115112"},"PeriodicalIF":4.6,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142817642","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":"Electrical impedance myography detects progressive pathological alterations in the hindlimb muscle of the PMP22-C3 mice, an animal model of CMT1A","authors":"Atsuki Taruta ,&nbsp;Tetsuaki Hiyoshi ,&nbsp;Akina Harada ,&nbsp;Masato Nakashima","doi":"10.1016/j.expneurol.2024.115111","DOIUrl":"10.1016/j.expneurol.2024.115111","url":null,"abstract":"<div><div>Charcot-Marie-Tooth type 1A (CMT1A) is the most common inherited peripheral dysmyelinating neuropathy. Although lower limb muscle weakness is the most important factor affecting the quality of life of patients with CMT1A, existing clinical measures for its evaluation have limitations, including low sensitivity in detecting disease progression. Electrical impedance myography (EIM) is a newer tool that enables noninvasive evaluation of muscle state by measuring muscle composition, and potentially supports the evaluation of neuromuscular disease progression and treatment effects. To determine the potential of EIM as a CMT1A biomarker, we obtained natural history data for EIM from the gastrocnemius muscle of the PMP22-C3 mice, an animal model of CMT1A. Alterations in the EIM parameters, weak hindlimb grip strength, decreased muscle fiber size, and changes in the mRNA expression of genes related to neuromuscular junction dysfunction were found. These changes were more pronounced at later stages (12 and 18 weeks of age) than at earlier stage (6 weeks of age), indicating that EIM can detect disease progression in PMP22-C3 mice. Our preclinical findings support the use of EIM as a potential translational biomarker for assessing progressive changes in the pathological muscle state in CMT1A.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"385 ","pages":"Article 115111"},"PeriodicalIF":4.6,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142817706","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"hPSCs-derived brain organoids for disease modeling, toxicity testing and drug evaluation","authors":"Na Xie ,&nbsp;Jinrong Bai ,&nbsp;Ya Hou ,&nbsp;Jia Liu ,&nbsp;Yi Zhang ,&nbsp;Xianli Meng ,&nbsp;Xiaobo Wang","doi":"10.1016/j.expneurol.2024.115110","DOIUrl":"10.1016/j.expneurol.2024.115110","url":null,"abstract":"<div><div>Due to the differences and variances in genetic background, <em>in vitro</em> and animal models cannot meet the modern medical exploration of real human brain structure and function. Recently, brain organoids generated by human pluripotent stem cells (hPSCs) can mimic the structure and physiological function of human brain, being widely used in medical research. Brain organoids generated from normal hPSCs or patient-derived induced pluripotent stem cells offer a more promising approach for the study of diverse human brain diseases. More importantly, the use of the established brain organoid model for drug evaluation is conducive to shorten the clinical transformation period. Herein, we summarize methods for the identification of brain organoids from cellular diversity, morphology and neuronal activity, brain disease modeling, toxicity testing, and drug evaluation. Based on this, it is hoped that this review will provide new insights into the pathogenesis of brain diseases and drug research and development, promoting the rapid development of brain science.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"385 ","pages":"Article 115110"},"PeriodicalIF":4.6,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142817721","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":"Time restricted feeding alters the behavioural and physiological outcomes to repeated mild traumatic brain injury in male and female rats","authors":"A. Zaini ,&nbsp;P.K. Morgan ,&nbsp;B. Cardwell ,&nbsp;E. Vlassopoulos ,&nbsp;M. Sgro ,&nbsp;C.N. Li ,&nbsp;S. Salberg ,&nbsp;N.A. Mellett ,&nbsp;J. Christensen ,&nbsp;P.J. Meikle ,&nbsp;A.J. Murphy ,&nbsp;B.J. Marsland ,&nbsp;R. Mychasiuk ,&nbsp;G.R. Yamakawa","doi":"10.1016/j.expneurol.2024.115108","DOIUrl":"10.1016/j.expneurol.2024.115108","url":null,"abstract":"<div><div>Mild traumatic brain injury (mTBI) research has had limited success translating treatments from preclinical models to clinical application for concussion. One major factor that has been overlooked is the near 24-hour availability of food, both for experimental nocturnal rodents and patients suffering from mTBI. Here, we characterised the impact of food restriction limited to either the inactive (day) or the active phase (night), on repetitive mTBI (RmTBI) - induced outcomes in male and female rats. We found that active phase fed rats consumed more food, had increased body weight, and reduced brain weights. Behaviourally, active phase feeding increased motor coordination deficits and caused changes to thermal nociceptive processing following RmTBI. Hypothalamic transcriptomic analysis revealed minor changes in response to RmTBI, and genes associated with oxytocin-vasopressin regulation in response to inactive phase, but not active phase feeding. These transcript changes were absent in females, where the overall effect of RmTBI was minor. Prefrontal cortex lipidomics revealed an increase in sphingomyelin synthesis following injury and marked sex differences in response to feeding. Of the lipids that changed and overlapped between the prefrontal cortex and serum, dihydroceramides, sphingomyelins, and hexosylceramides, were higher in the serum but lower in the prefrontal cortex. Together, these results demonstrate that feeding time alters outcomes to RmTBI, independent of the hypothalamic transcriptome, and injury-specific lipids may serve as useful biomarkers in RmTBI diagnosis.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"385 ","pages":"Article 115108"},"PeriodicalIF":4.6,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142812478","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Early trigeminal and sensory impairment and lysosomal dysfunction in accurate models of Wolfram syndrome","authors":"Kerli Tulva ,&nbsp;Aleksander Pirajev ,&nbsp;Akbar Zeb ,&nbsp;Asya E. Aksoy ,&nbsp;Azizah Bello ,&nbsp;Benjamin Lee ,&nbsp;Baldvin F. Guðjónsson ,&nbsp;Sigridur B. Helgadottir ,&nbsp;Toomas Jagomäe ,&nbsp;Andrea García-Llorca ,&nbsp;Thor Eysteinsson ,&nbsp;Monika Jürgenson ,&nbsp;Mario Plaas ,&nbsp;Eero Vasar ,&nbsp;Allen Kaasik ,&nbsp;Miriam A. Hickey","doi":"10.1016/j.expneurol.2024.115099","DOIUrl":"10.1016/j.expneurol.2024.115099","url":null,"abstract":"<div><div>Wolfram syndrome (WS) is a rare condition caused by homozygous or compound heterozygous mutations in the WFS1 gene primarily. It is diagnosed on the basis of early-onset diabetes mellitus and optic nerve atrophy. Patients complain of trigeminal-like migraines and show deficits in vibration sensation, but the underlying cause is unknown. Using accurate cell models and two separate, accurate rodent models of WS that show excellent face and construct validity, here we have examined trigeminus, sensation and sensory neuronal function in WS. Analysis of ex vivo and in vivo MRI sequences revealed profound trigeminal atrophy in each rodent model, a novel finding in WS. Optic nerve atrophy is a diagnostic sign in WS, and trigeminal atrophy occurred at the time of earliest loss of optic nerve volume. We also observed deficits in mechanical sensation in our mouse WS model, and pathological analysis revealed extensive inflammation in trigeminal sensory nucleus, both of which are novel findings in WS. Sensory neurons (dorsal root ganglia) showed impaired calcium handling upon depolarisation and reduced mitochondrial membrane potential. Finally, lysosomes were smaller, soma lysosome content was decreased and importantly, lysosome acidity was impaired in sensory neurons, all of which are novel findings in WS. We validated these findings using two separate publicly available datasets, both from WS patient fibroblast-derived neural stem cells. We observed a highly significant functional enrichment of GO cellular component lysosome-related terms among the differentially expressed proteins and genes, with the majority of lysosome-related proteins being downregulated. These data reveal extensive impairments in the trigeminal pathway and nociceptive neurons in WS that may contribute to trigeminal and sensory symptoms observed in patients. Moreover, we note that mutations in WFS1 are relatively common and, given the importance of WFS1 for sensory function, our data may also shed light on sensory impairments in general.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"385 ","pages":"Article 115099"},"PeriodicalIF":4.6,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142812460","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Environmental enrichment-induced cognitive recovery after a moderate pediatric traumatic brain injury is associated with the gut microbiota and neuroinflammation","authors":"Jonathan Zamudio-Flores ,&nbsp;Daniel Cerqueda ,&nbsp;Bryan Phillips-Farfán ,&nbsp;Shaday Guerrero-Flores ,&nbsp;Ana Fernanda Salinas-García ,&nbsp;Esperanza Meléndez-Herrera ,&nbsp;Nelly Sélem-Mojica ,&nbsp;Anthony E. Kline ,&nbsp;Naima Lajud","doi":"10.1016/j.expneurol.2024.115109","DOIUrl":"10.1016/j.expneurol.2024.115109","url":null,"abstract":"<div><div>Pediatric traumatic brain injury (TBI) is a significant health concern, yet access to rehabilitation therapies for children remains limited. Environmental enrichment (EE) is a preclinical model of neurorehabilitation that promotes behavioral recovery and reduces neuroinflammation after TBI. While the gut microbiota has recently emerged as a potential therapeutic target for treating TBI sequelae in adults, its role in recovery after pediatric TBI remains unclear. Therefore, our aim was to assess the effect of EE on gut microbiota and its correlation with cognition as well as microglial morphology in a preclinical model of pediatric TBI. Male rats underwent a controlled cortical impact of moderate severity or sham injury at postnatal day 21 and were then randomly assigned to either EE or standard (STD) housing. Cognition was evaluated using the Morris water maze (MWM) on post-injury days 14–19. Microglial morphology and caecum microbiota was characterized on post-injury day 21. Cognitive deficits and increased microglial activation in the ipsilateral cortex were observed in the STD-housed TBI rats but not those in EE. TBI decreased microbiota α-diversity, while PERMANOVA analysis showed that both TBI and EE modified microbiota β-diversity. Furthermore, regression models indicated that microglial morphology in the ipsilateral cortex and <em>Lactobacillus reuteri</em> predicted behavioral outcomes, while <em>Prevotellaceae NK3B31</em> was associated with microglial morphology. The data suggest that EE mitigates TBI-induced alterations in gut microbiota and that there is a complex interplay between EE, microbiota and microglial morphology that predicts behavioral recovery in pediatric rats.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"385 ","pages":"Article 115109"},"PeriodicalIF":4.6,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142812464","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":"Treadmill exercise supplemented by OPN promote axon regeneration through the IGF-1R/Akt/mTOR signaling pathway","authors":"Qin Zhao ,&nbsp;Ci Li ,&nbsp;Yangjie Xu ,&nbsp;Juan Zhong ,&nbsp;Hongzhen Liu ,&nbsp;Ying Yin ,&nbsp;Yuan Liu ,&nbsp;Ce Yang Prof ,&nbsp;Lehua Yu ,&nbsp;Li Liu ,&nbsp;Lu Pan ,&nbsp;Botao Tan","doi":"10.1016/j.expneurol.2024.115096","DOIUrl":"10.1016/j.expneurol.2024.115096","url":null,"abstract":"<div><div>Regeneration of the corticospinal tract (CST) is considered a therapeutic target to achieve improved recovery of motor function after spinal cord injury (SCI), which is an incurable CNS damage that affects millions of people. Exercise training is effective in improving multiple functions in spinal cord-injured patients. However, the effects of exercise training on axon regeneration have not been sufficiently reported. Osteopontin (OPN) has great potential application as a neuroprotective agent for the repair of the nervous system. Studies have shown that the extent of axon regeneration strongly correlates with the expression of OPN. Our previous studies demonstrated that treadmill exercise supplemented by OPN enhances motor function recovery, but axon regeneration is still limited. Extending the treadmill exercise for 12 weeks, we observed promoted axon regeneration, motor function improvement, and signaling pathway activation in mice with SCI after supplementing OPN. Axon regeneration was observed with an anterograde tracer, motor function recovery was evaluated by animal ethology and electrophysiology, and the levels of IGF-1R/Akt/mTOR signaling pathway were evaluated. The results showed that the CST of C5 crushed mice regenerated and formed synaptic connections with neurons after treadmill exercise supplemented by OPN, the horizontal ladder and cylinder rearing test of injured limbs were improved, motor evoked potential also suggested enhanced nerve conduction, and the expression of p-IR, p-Akt, and p-S6 were increased. And the improvements were more obvious than that of the exercise group. Collectively, our study found that treadmill exercise supplemented by OPN promote axon regeneration and motor function through the IGF-1R/Akt/mTOR signaling pathways, and these improvements can be inhibited by rapamycin and Methyl-β-CD(M-B-CD).</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"385 ","pages":"Article 115096"},"PeriodicalIF":4.6,"publicationDate":"2024-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142806594","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}