Pub Date : 2025-11-26DOI: 10.1016/j.neulet.2025.138466
Lingxia Min , Cheng Cheng , Jiafei Chen , Chao Ma , Jilan Wang , Mingliang Tan , Ran Ran , Xiaoyu Wu , Rubing Yan , Jingming Hou , Hongliang Liu , Zhou Feng
Transcutaneous auricular vagus nerve stimulation (ta-VNS) is a non-invasive neuromodulation technique with emerging therapeutic potential for various central nervous system diseases. However, its therapeutic effects and mechanisms in spinal cord injury (SCI) remain largely unexplored. In this study, we demonstrated that ta-VNS significantly improved motor function recovery in SCI patients. Diffusion tensor imaging (DTI) further indicated that ta-VNS promoted structural repair of injured axons and myelin sheaths. Using a rodent model of SCI, we found that ta-VNS facilitated remyelination, attenuated tissue damage, and enhanced motor function recovery. Mechanistically, ta-VNS upregulated the expression of the α7 nicotinic acetylcholine receptor (α7nAChR) in oligodendrocyte precursor cells (OPCs), promoting their proliferation and differentiation into mature oligodendrocytes, thereby supporting remyelination. These beneficial effects of ta-VNS were abolished by administration of a selective α7nAChR antagonist. This study identifies the α7nAChR-mediated pro-myelination axis as a novel mechanistic basis for ta-VNS therapy, thereby establishing this non-invasive neuromodulation as a compelling strategy for promoting repair and recovery after SCI.
{"title":"Transcutaneous auricular vagus nerve stimulation promotes post-spinal cord injury remyelination via α7nAChR-mediated activation of oligodendrocyte precursor cells","authors":"Lingxia Min , Cheng Cheng , Jiafei Chen , Chao Ma , Jilan Wang , Mingliang Tan , Ran Ran , Xiaoyu Wu , Rubing Yan , Jingming Hou , Hongliang Liu , Zhou Feng","doi":"10.1016/j.neulet.2025.138466","DOIUrl":"10.1016/j.neulet.2025.138466","url":null,"abstract":"<div><div>Transcutaneous auricular vagus nerve stimulation (ta-VNS) is a non-invasive neuromodulation technique with emerging therapeutic potential for various central nervous system diseases. However, its therapeutic effects and mechanisms in spinal cord injury (SCI) remain largely unexplored. In this study, we demonstrated that ta-VNS significantly improved motor function recovery in SCI patients. Diffusion tensor imaging (DTI) further indicated that ta-VNS promoted structural repair of injured axons and myelin sheaths. Using a rodent model of SCI, we found that ta-VNS facilitated remyelination, attenuated tissue damage, and enhanced motor function recovery. Mechanistically, ta-VNS upregulated the expression of the α7 nicotinic acetylcholine receptor (α7nAChR) in oligodendrocyte precursor cells (OPCs), promoting their proliferation and differentiation into mature oligodendrocytes, thereby supporting remyelination. These beneficial effects of ta-VNS were abolished by administration of a selective α7nAChR antagonist. This study identifies the α7nAChR-mediated pro-myelination axis as a novel mechanistic basis for ta-VNS therapy, thereby establishing this non-invasive neuromodulation as a compelling strategy for promoting repair and recovery after SCI.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"871 ","pages":"Article 138466"},"PeriodicalIF":2.0,"publicationDate":"2025-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145636833","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-22DOI: 10.1016/j.neulet.2025.138464
Juan Chen , Yimin Lai , Wei Li
Chronic pain has become a serious health issue, affecting more than 30% of people worldwide. One of the main mechanisms of chronic pain is central sensitization. It is well known that substance P (SP) and its receptor, Neurokinin 1 receptor (NK1R), play an important role in transmission of nociceptive signals. However, whether SP/NK1R system is involved in central sensitization in chronic pain remains controversial. In the present study, we adopted spared nerve injury (SNI) mouse model to induce neuropathic pain and assessed the role of SP/NK1R system in the development of hyperalgesia and central sensitization. We observed that hyperalgesia occurred in non-injured body part of SNI mice in tail withdrawal test. We also demonstrated hyperexcitability of S1 apical dendrites in SNI mice. Notably, the hyperalgesia behavior and hyperactivity of S1 apical dendrites were alleviated by NK1R antagonist L-703606. These results indicate that SP/NK1R system is involved in central sensitization in chronic pain.
{"title":"Involvement of substance P/NK1 receptor system in central sensitization in chronic pain","authors":"Juan Chen , Yimin Lai , Wei Li","doi":"10.1016/j.neulet.2025.138464","DOIUrl":"10.1016/j.neulet.2025.138464","url":null,"abstract":"<div><div>Chronic pain has become a serious health issue, affecting more than 30% of people worldwide. One of the main mechanisms of chronic pain is central sensitization. It is well known that substance P (SP) and its receptor, Neurokinin 1 receptor (NK1R), play an important role in transmission of nociceptive signals. However, whether SP/NK1R system is involved in central sensitization in chronic pain remains controversial. In the present study, we adopted spared nerve injury (SNI) mouse model to induce neuropathic pain and assessed the role of SP/NK1R system in the development of hyperalgesia and central sensitization. We observed that hyperalgesia occurred in non-injured body part of SNI mice in tail withdrawal test. We also demonstrated hyperexcitability of S1 apical dendrites in SNI mice. Notably, the hyperalgesia behavior and hyperactivity of S1 apical dendrites were alleviated by NK1R antagonist L-703606. These results indicate that SP/NK1R system is involved in central sensitization in chronic pain.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"871 ","pages":"Article 138464"},"PeriodicalIF":2.0,"publicationDate":"2025-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145597093","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-22DOI: 10.1016/j.neulet.2025.138465
Xiao Li , Ruijuan Liu , Ye He , Xifei Yang , Ting Li , Yan Feng
Alzheimer’s disease (AD) is the most frequent of neurodegenerative disease affecting elderly people. However, there is still no curative therapeutic strategies in clinical practice. Here, we studied whether TEMPOL as a free radical scavenger can prevent memory deficits in P301S-tau mice. We found that TEMPOL administration markedly restored learning and memory impairments inducing by P301S-tau. We showed that TEMPOL had a potent capacity of inhibiting the expression of tau protein and its phosphorylation levels. The inflammatory response and synaptic defects induced by P301S-tau was also obviously improved TEMPOL treatment. Furthermore, proteomics showed 121 reversed proteins by TEMPOL treatment were primarily involved in immune system processes, innate immune responses, inflammatory responses, autophagosome assembly, lysosome organization, and autophagy. Taken together, TEMPOL played a critical role in P301S-tau-related cognitive impairments. These findings demonstrate that TEMPOL shows promise as a multi-target therapeutic agent for AD by modulating critical pathways implicated in its pathogenesis.
{"title":"TEMPOL alleviated tau pathology and cognitive deficits induced by P301S-tau","authors":"Xiao Li , Ruijuan Liu , Ye He , Xifei Yang , Ting Li , Yan Feng","doi":"10.1016/j.neulet.2025.138465","DOIUrl":"10.1016/j.neulet.2025.138465","url":null,"abstract":"<div><div>Alzheimer’s disease (AD) is the most frequent of neurodegenerative disease affecting elderly people. However, there is still no curative therapeutic strategies in clinical practice. Here, we studied whether TEMPOL as a free radical scavenger can prevent memory deficits in P301S-tau mice. We found that TEMPOL administration markedly restored learning and memory impairments inducing by P301S-tau. We showed that TEMPOL had a potent capacity of inhibiting the expression of tau protein and its phosphorylation levels. The inflammatory response and synaptic defects induced by P301S-tau was also obviously improved TEMPOL treatment. Furthermore, proteomics showed 121 reversed proteins by TEMPOL treatment were primarily involved in immune system processes, innate immune responses, inflammatory responses, autophagosome assembly, lysosome organization, and autophagy. Taken together, TEMPOL played a critical role in P301S-tau-related cognitive impairments. These findings demonstrate that TEMPOL shows promise as a multi-target therapeutic agent for AD by modulating critical pathways implicated in its pathogenesis.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"871 ","pages":"Article 138465"},"PeriodicalIF":2.0,"publicationDate":"2025-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145597021","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Unilateral spatial neglect (USN) significantly impairs mobility in patients following a stroke. The amount and quality of evidence supporting effective treatments for USN is still limited, primarily due to the unclear nature of its underlying neural mechanisms. As lesions in USN are not localized to a specific brain region, research has underscored the importance of evaluating USN from a network-based perspective. Nevertheless, the key functional regions at the core of this network are yet to be identified. Previously, we reported that the right inferior parietal lobule (IPL) may serve as the central hub in the neural network associated with USN. Therefore, this study aimed to determine the brain network centered on the right IPL by conducting seed-based functional connectivity analysis. Our results may contribute to a better understanding of the neural mechanisms in USN.
{"title":"Involvement of the right inferior parietal lobule network in ipsilateral spatial attention","authors":"Marino Iwakiri , Yuhi Takeo , Takashi Ikeda , Masayuki Hara , Hisato Sugata","doi":"10.1016/j.neulet.2025.138463","DOIUrl":"10.1016/j.neulet.2025.138463","url":null,"abstract":"<div><div>Unilateral spatial neglect (USN) significantly impairs mobility in patients following a stroke. The amount and quality of evidence supporting effective treatments for USN is still limited, primarily due to the unclear nature of its underlying neural mechanisms. As lesions in USN are not localized to a specific brain region, research has underscored the importance of evaluating USN from a network-based perspective. Nevertheless, the key functional regions at the core of this network are yet to be identified. Previously, we reported that the right inferior parietal lobule (IPL) may serve as the central hub in the neural network associated with USN. Therefore, this study aimed to determine the brain network centered on the right IPL by conducting seed-based functional connectivity analysis. Our results may contribute to a better understanding of the neural mechanisms in USN.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"871 ","pages":"Article 138463"},"PeriodicalIF":2.0,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145582487","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-19DOI: 10.1016/j.neulet.2025.138461
Feyza Alyu Altinok , Ilhem Dallali , Ahmed Hasan , Abderaouf Boubekka , Elif Kaya Tilki , Yusuf Ozturk
Chronic alcohol consumption is a well-known risk factor for peripheral neuropathy, often presenting with thermal hyperalgesia and mechanical allodynia. While the involvement of dorsal root ganglia (DRG) neurons in alcohol-induced neuropathy (AIN) is recognized, the molecular mechanisms—particularly the role of Kv7-KCNQ potassium channel remains insufficiently understood. This research focused on evaluating the impact ofchronic alcohol exposure on Kv7 channel function and gene expression in DRG neurons, focusing on the KCNQ2 and KCNQ5 subunits.A rat model of AIN was established via oral gavage administration of 35 % ethanol (10 g/kg, twice daily) for 10 weeks. Pain hypersensitivity was evaluated using the electronic von Frey and Hargreaves tests. Quantitative real-time PCR was used to evaluate the mRNA expression of KCNQ2 and KCNQ5 channels. M−current (IM) density and neuronal excitability were assessed through whole-cell voltage-clamp and current-clamp recordings, respectively.Chronic ethanol exposure significantly reduced both mechanical and thermal thresholds, confirming the development of neuropathic pain. We observed a marked downregulation in the mRNA expression of KCNQ2 and KCNQ5 subunits, accompanied by a diminished M−current density within DRG neurons. These alterations were linked to increased neuronal excitability and heightened pain sensitivity in rats exposed to ethanol.These findings demonstrate that AIN is marked by a significant downregulation of KCNQ2 and KCNQ5 channel expression and function, contributing to elevated neuronal excitability and the onset of thermal hyperalgesia and mechanical allodynia. The suppressed activity of KCNQ/M channels within DRG neurons of AIN rats highlights Kv7 channels as promising molecular targets for AIN therapy.
{"title":"Alcohol-induced neuropathy associated downregulation of Kv7 channels in primary nociceptors","authors":"Feyza Alyu Altinok , Ilhem Dallali , Ahmed Hasan , Abderaouf Boubekka , Elif Kaya Tilki , Yusuf Ozturk","doi":"10.1016/j.neulet.2025.138461","DOIUrl":"10.1016/j.neulet.2025.138461","url":null,"abstract":"<div><div>Chronic alcohol consumption is a well-known risk factor for peripheral neuropathy, often presenting with thermal hyperalgesia and mechanical allodynia. While the involvement of dorsal root ganglia (DRG) neurons in alcohol-induced neuropathy (AIN) is recognized, the molecular mechanisms—particularly the role of Kv7-KCNQ potassium channel remains insufficiently understood. This research focused on evaluating the impact ofchronic alcohol exposure on Kv7 channel function and gene expression in DRG neurons, focusing on the KCNQ2 and KCNQ5 subunits.A rat model of AIN was established via oral gavage administration of 35 % ethanol (10 g/kg, twice daily) for 10 weeks. Pain hypersensitivity was evaluated using the electronic von Frey and Hargreaves tests. Quantitative real-time PCR was used to evaluate the mRNA expression of KCNQ2 and KCNQ5 channels. M−current (IM) density and neuronal excitability were assessed through whole-cell voltage-clamp and current-clamp recordings, respectively.Chronic ethanol exposure significantly reduced both mechanical and thermal thresholds, confirming the development of neuropathic pain. We observed a marked downregulation in the mRNA expression of KCNQ2 and KCNQ5 subunits, accompanied by a diminished M−current density within DRG neurons. These alterations were linked to increased neuronal excitability and heightened pain sensitivity in rats exposed to ethanol.These findings demonstrate that AIN is marked by a significant downregulation of KCNQ2 and KCNQ5 channel expression and function, contributing to elevated neuronal excitability and the onset of thermal hyperalgesia and mechanical allodynia. The suppressed activity of KCNQ/M channels within DRG neurons of AIN rats highlights Kv7 channels as promising molecular targets for AIN therapy.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"871 ","pages":"Article 138461"},"PeriodicalIF":2.0,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145564566","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-19DOI: 10.1016/j.neulet.2025.138460
Yu Xiang , Zeyu Zhang , Yunrui Jiang , Hongen Wei
Activity-dependent neuroprotective protein (ADNP), a major risk gene for autism spectrum disorder (ASD) and intellectual disability (ID), is critical for brain development and cognition. Among its regulated processes, autophagy is notably affected, with mTORC1 overactivation acting as a negative regulator and frequently reported in ASD. Rapamycin can rescue ASD-related behaviors, and everolimus (EVR), an optimized derivative, is widely applied in clinical practice. However, its role in ADNP-related pathology remains unknown. Here, we established a prefrontal cortex (PFC) ADNP knockdown (KD) mouse model to examine behavioral and molecular consequences, and whether EVR provides benefit. We found that ADNP KD resulted in mTORC1 pathway activation, autophagy impairment, learning and memory deficits, and anxiety-like behaviors, concurrent with dysregulation of microtubule and synaptic proteins. Daily intraperitoneal EVR (5 mg/kg) can effectively alleviate the behavioral and molecular phenotypes caused by ADNP deficiency in the PFC, thereby establishing a strong rationale for targeting the mTOR pathway in treating ADNP-related cognitive impairments.
{"title":"Everolimus ameliorates cognitive deficits and synaptic dysfunction in mice with prefrontal cortical ADNP knockdown","authors":"Yu Xiang , Zeyu Zhang , Yunrui Jiang , Hongen Wei","doi":"10.1016/j.neulet.2025.138460","DOIUrl":"10.1016/j.neulet.2025.138460","url":null,"abstract":"<div><div>Activity-dependent neuroprotective protein (ADNP), a major risk gene for autism spectrum disorder (ASD) and intellectual disability (ID), is critical for brain development and cognition. Among its regulated processes, autophagy is notably affected, with mTORC1 overactivation acting as a negative regulator and frequently reported in ASD. Rapamycin can rescue ASD-related behaviors, and everolimus (EVR), an optimized derivative, is widely applied in clinical practice. However, its role in ADNP-related pathology remains unknown. Here, we established a prefrontal cortex (PFC) ADNP knockdown (KD) mouse model to examine behavioral and molecular consequences, and whether EVR provides benefit. We found that ADNP KD resulted in mTORC1 pathway activation, autophagy impairment, learning and memory deficits, and anxiety-like behaviors, concurrent with dysregulation of microtubule and synaptic proteins. Daily intraperitoneal EVR (5 mg/kg) can effectively alleviate the behavioral and molecular phenotypes caused by ADNP deficiency in the PFC, thereby establishing a strong rationale for targeting the mTOR pathway in treating ADNP-related cognitive impairments.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"871 ","pages":"Article 138460"},"PeriodicalIF":2.0,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145564585","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-19DOI: 10.1016/j.neulet.2025.138462
Valfran da Silva Lima , Guilherme Luz Emerick , Valéria Dornelles Gindri Sinhorin , Ritane Rose da Silva Lima , Helidi Schaiane da Silva , Kaiany Fernanda da Silva , Antônio Carlos Alves de Sousa , Francielly Rieger Silveira , Amanda Lika Mizuno Saito , Evelyn Lezzo Estevam , Márcia Queiroz Latorraca
Memory impairment diseases have become a serious health problem worldwide. In this context, an animal model capable of recognizing substances with the ability to recover memory disorders would be welcome. Thus, the present work aims to evaluate the effect of piracetam on reversal of scopolamine-induced memory deficit in male Swiss mice (n = 6) after fifteen days of treatment. To achieve this objective, behavioral, oxidative and cholinesterase inhibition markers were used. Memory impairment was evaluated by object and social recognition and step-down inhibitory avoidance tests. The evaluation of the redox state included superoxide dismutase, catalase, glutathione-s-transferase, glutathione peroxidase, thiobarbituric acid reactive substances, carbonyl proteins, ascorbic acid, and reduced glutathione. Scopolamine caused cognitive deficit, evidenced by the reduction in latency period and in the discrimination index (DI) of aversive, social, and declarative memories. However, piracetam significantly reversed those deficits. Scopolamine has increased the levels of thiobarbituric acid reactive substances. Scopolamine inhibited significantly brain and plasma cholinesterase activity. In conclusion, scopolamine at a dose of 0.8 mg/kg for 15 days induced memory deficit, oxidative damage and cholinesterase inhibition in brain of mice. Furthermore, piracetam at a dose of 200 mg/kg could reverse the memory impairment induced by scopolamine by mechanisms that are independent of the antioxidant action and cholinesterase inhibition. The present model has showed great sensibility and could be used to evaluate other drugs with the potential for the treatment of diseases related to memory damage.
{"title":"Piracetam reverses scopolamine-induced memory disorder in mice: an animal model using behavioral, oxidative, and cholinesterase biomarkers","authors":"Valfran da Silva Lima , Guilherme Luz Emerick , Valéria Dornelles Gindri Sinhorin , Ritane Rose da Silva Lima , Helidi Schaiane da Silva , Kaiany Fernanda da Silva , Antônio Carlos Alves de Sousa , Francielly Rieger Silveira , Amanda Lika Mizuno Saito , Evelyn Lezzo Estevam , Márcia Queiroz Latorraca","doi":"10.1016/j.neulet.2025.138462","DOIUrl":"10.1016/j.neulet.2025.138462","url":null,"abstract":"<div><div>Memory impairment diseases have become a serious health problem worldwide. In this context, an animal model capable of recognizing substances with the ability to recover memory disorders would be welcome. Thus, the present work aims to evaluate the effect of piracetam on reversal of scopolamine-induced memory deficit in male Swiss mice (n = 6) after fifteen days of treatment. To achieve this objective, behavioral, oxidative and cholinesterase inhibition markers were used. Memory impairment was evaluated by object and social recognition and step-down inhibitory avoidance tests. The evaluation of the redox state included superoxide dismutase, catalase, glutathione-s-transferase, glutathione peroxidase, thiobarbituric acid reactive substances, carbonyl proteins, ascorbic acid, and reduced glutathione. Scopolamine caused cognitive deficit, evidenced by the reduction in latency period and in the discrimination index (DI) of aversive, social, and declarative memories. However, piracetam significantly reversed those deficits. Scopolamine has increased the levels of thiobarbituric acid reactive substances. Scopolamine inhibited significantly brain and plasma cholinesterase activity. In conclusion, scopolamine at a dose of 0.8 mg/kg for 15 days induced memory deficit, oxidative damage and cholinesterase inhibition in brain of mice. Furthermore, piracetam at a dose of 200 mg/kg could reverse the memory impairment induced by scopolamine by mechanisms that are independent of the antioxidant action and cholinesterase inhibition. The present model has showed great sensibility and could be used to evaluate other drugs with the potential for the treatment of diseases related to memory damage.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"871 ","pages":"Article 138462"},"PeriodicalIF":2.0,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145573866","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-15DOI: 10.1016/j.neulet.2025.138447
Yuan Huang , Yunlan Xie , Liru Liu , Danxia Fan , Wen Le , Xiaoying Zhang , Tingting Peng , Wenhui Li , Huijuan Lin , Lu He , Hongmei Tang , Kaishou Xu
Constraint-induced movement therapy (CIMT) enhances hand function in hemiplegic cerebral palsy (HCP) and stroke, partly by strengthening corticospinal tract (CST) projections, while down-regulated Nogo-A has been shown to facilitate neural regeneration in stroke and multiple sclerosis. However, their combined therapeutic effect remains unclear. Therefore, this study explored the impact of CIMT combined with Nogo-A downregulation on CST remodeling and motor function in HCP mice. Mice were randomly assigned to five groups: control, HCP, HCP + CIMT, HCP + SN (siRNA-Nogo-A treatment) and HCP + SN + CIMT. Rotarod and grip test were performed to assess the motor function. Western blot and immunofluorescence staining were performed to quantify Nogo-A and PKCγ expression in the M1 region. Diffusion tensor imaging and transmission electron microscopy were applied to assess fractional anisotropy (FA) of CST and myelin remodeling. Compared with controls, the HCP group exhibited significant motor dysfunction and myelin impairment, characterized by increased Nogo-A expression, decreased PKCγ expression, and reduced FA value of CST (p < 0.05). In contrast, mice treated with CIMT or SN exhibited improved motor function, reduced Nogo-A expression, elevated PKCγ expression, increased FA value of CST, and enhanced myelin remodeling compared with the HCP group (p < 0.05). Notably, CIMT and SN exerted synergistic effects, as the HCP + SN + CIMT group outperformed either single-treatment group (p < 0.05). These findings suggest CIMT combined with Nogo-A downregulation synergistically enhances motor function in HCP mice by reducing Nogo-A expression in M1 region and promoting CST remodeling.
约束诱导运动疗法（CIMT）增强偏瘫脑瘫（HCP）和中风患者的手部功能，部分是通过增强皮质脊髓束（CST）投射，而下调Nogo-A已被证明可促进中风和多发性硬化症患者的神经再生。然而，它们的联合治疗效果尚不清楚。因此，本研究探讨了CIMT联合Nogo-A下调对HCP小鼠CST重塑和运动功能的影响。小鼠随机分为5组：对照组、HCP、HCP + CIMT、HCP + SN （siRNA-Nogo-A治疗）和HCP + SN + CIMT。采用旋转杆和握力试验评估运动功能。Western blot和免疫荧光染色定量检测M1区Nogo-A和PKCγ的表达。应用扩散张量成像和透射电镜观察CST各向异性分数（FA）和髓鞘重塑。与对照组相比，HCP组表现出明显的运动功能障碍和髓磷脂损伤，其特征是Nogo-A表达增加，pkc - γ表达降低，CST FA值降低(p
{"title":"Constraint-induced movement therapy combined with Nogo-A downregulation enhances corticospinal tract remodeling and motor function in hemiplegic cerebral palsy mice","authors":"Yuan Huang , Yunlan Xie , Liru Liu , Danxia Fan , Wen Le , Xiaoying Zhang , Tingting Peng , Wenhui Li , Huijuan Lin , Lu He , Hongmei Tang , Kaishou Xu","doi":"10.1016/j.neulet.2025.138447","DOIUrl":"10.1016/j.neulet.2025.138447","url":null,"abstract":"<div><div>Constraint-induced movement therapy (CIMT) enhances hand function in hemiplegic cerebral palsy (HCP) and stroke, partly by strengthening corticospinal tract (CST) projections, while down-regulated Nogo-A has been shown to facilitate neural regeneration in stroke and multiple sclerosis. However, their combined therapeutic effect remains unclear. Therefore, this study explored the impact of CIMT combined with Nogo-A downregulation on CST remodeling and motor function in HCP mice. Mice were randomly assigned to five groups: control, HCP, HCP + CIMT, HCP + SN (siRNA-Nogo-A treatment) and HCP + SN + CIMT. Rotarod and grip test were performed to assess the motor function. Western blot and immunofluorescence staining were performed to quantify Nogo-A and PKCγ expression in the M1 region. Diffusion tensor imaging and transmission electron microscopy were applied to assess fractional anisotropy (FA) of CST and myelin remodeling. Compared with controls, the HCP group exhibited significant motor dysfunction and myelin impairment, characterized by increased Nogo-A expression, decreased PKCγ expression, and reduced FA value of CST (<em>p</em> < 0.05). In contrast, mice treated with CIMT or SN exhibited improved motor function, reduced Nogo-A expression, elevated PKCγ expression, increased FA value of CST, and enhanced myelin remodeling compared with the HCP group (<em>p</em> < 0.05). Notably, CIMT and SN exerted synergistic effects, as the HCP + SN + CIMT group outperformed either single-treatment group (<em>p</em> < 0.05). These findings suggest CIMT combined with Nogo-A downregulation synergistically enhances motor function in HCP mice by reducing Nogo-A expression in M1 region and promoting CST remodeling.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"870 ","pages":"Article 138447"},"PeriodicalIF":2.0,"publicationDate":"2025-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145541633","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Depression is a debilitating psychiatric illness, and its etiology as well as resistance to current pharmacological treatments are increasingly associated with low-grade inflammation. Environmental enrichment (EE), a paradigm that combines sensory and cognitive stimulation, social interaction, and voluntary physical activity, has been widely used to alleviate depression-like behaviours in rodent models, focusing on exposure to psychosocial stressors. However, the potential benefits of EE against depression-like behaviours triggered by immune activation remain unexplored. In this study, male C57BL/6 mice were housed under standard conditions or in EE. After six weeks, mice received an intraperitoneal injection of either physiological saline (vehicle) or lipopolysaccharide (LPS), a potent immunologic stimulus. Twenty-four hours later, anhedonia and behavioural despair were evaluated using the tail suspension test (i.e., frequency, latency, and time of immobility) and the splash test (i.e., latency, frequency, and time of grooming), respectively. LPS administration induced behavioural alterations consistent with depression-like behaviours characterised by increased immobility and decreased grooming. Remarkably, EE exposure prevented the development of LPS-induced depression-like behaviours in the tail suspension test and improved specific parameters in the splash test. Taken together, these findings highlight the therapeutic potential of EE as a non-pharmacological strategy for preventing or alleviating immune system activation-associated depression.
{"title":"Environmental enrichment prevents depression-like behaviours induced by immune system activation in male mice","authors":"Alexandre Kanashiro , Priscila Medeiros , Ana Carolina Medeiros , Frederico Rogério Ferreira , Alline Cristina de Campos , Tatiana Barichello , Norberto Cysne Coimbra","doi":"10.1016/j.neulet.2025.138450","DOIUrl":"10.1016/j.neulet.2025.138450","url":null,"abstract":"<div><div>Depression is a debilitating psychiatric illness, and its etiology as well as resistance to current pharmacological treatments are increasingly associated with low-grade inflammation. Environmental enrichment (EE), a paradigm that combines sensory and cognitive stimulation, social interaction, and voluntary physical activity, has been widely used to alleviate depression-like behaviours in rodent models, focusing on exposure to psychosocial stressors. However, the potential benefits of EE against depression-like behaviours triggered by immune activation remain unexplored. In this study, male C57BL/6 mice were housed under standard conditions or in EE. After six weeks, mice received an intraperitoneal injection of either physiological saline (vehicle) or lipopolysaccharide (LPS), a potent immunologic stimulus. Twenty-four hours later, anhedonia and behavioural despair were evaluated using the tail suspension test (i.e., frequency, latency, and time of immobility) and the splash test (i.e., latency, frequency, and time of grooming), respectively. LPS administration induced behavioural alterations consistent with depression-like behaviours characterised by increased immobility and decreased grooming. Remarkably, EE exposure prevented the development of LPS-induced depression-like behaviours in the tail suspension test and improved specific parameters in the splash test. Taken together, these findings highlight the therapeutic potential of EE as a non-pharmacological strategy for preventing or alleviating immune system activation-associated depression.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"870 ","pages":"Article 138450"},"PeriodicalIF":2.0,"publicationDate":"2025-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145530865","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-13DOI: 10.1016/j.neulet.2025.138449
Richmond Arthur , Uma Shanker , Manjinder Singh , Thakur Gurjeet Singh , Puneet Kumar
Neurotoxicity, characterised by the structural and functional disruption of the nervous system, remains a major contributor to the pathophysiology of neurodegenerative disorders. It is mostly caused by oxidative stress, excitotoxicity, mitochondrial dysfunction, and neuroinflammation, which results in gradual neuronal damage and death. Despite breakthroughs in understanding its underlying principles, effective therapeutic strategies to alleviate neurotoxic harm are still limited. Beyond its antimalarial action, artemisinin, a sesquiterpene lactone obtained from Artemisia annua, has recently attracted attention for its strong anti-inflammatory, antioxidant, and neuroprotective qualities. QA was bilaterally injected directly into the rat striatum to simulate neurotoxic conditions, followed by a 21-day artemisinin treatment. On days 0, 14, and 21, motor coordination was evaluated through behavioural assessments, including narrow beam walking, the open field test, and rotarod performance. Striatal homogenates were tested for oxidative stress parameters. qRT-PCR was used for molecular investigations. Hematoxylin and eosin staining was used to investigate histopathological changes in the striatum. Results indicated that artemisinin mitigated neurotoxicity in the experimental rats. It reduced oxidative stress and inflammatory and apoptotic markers in striatal homogenates. In conclusion, artemisinin efficiently reduced neurotoxic damage, indicating its promise as a potential neuroprotective alternative for neurodegenerative diseases.
{"title":"Artemisinin attenuates quinolinic acid-induced neurotoxicity by suppressing neuroinflammatory and apoptotic gene expression in rats","authors":"Richmond Arthur , Uma Shanker , Manjinder Singh , Thakur Gurjeet Singh , Puneet Kumar","doi":"10.1016/j.neulet.2025.138449","DOIUrl":"10.1016/j.neulet.2025.138449","url":null,"abstract":"<div><div>Neurotoxicity, characterised by the structural and functional disruption of the nervous system, remains a major contributor to the pathophysiology of neurodegenerative disorders. It is mostly caused by oxidative stress, excitotoxicity, mitochondrial dysfunction, and neuroinflammation, which results in gradual neuronal damage and death. Despite breakthroughs in understanding its underlying principles, effective therapeutic strategies to alleviate neurotoxic harm are still limited. Beyond its antimalarial action, artemisinin, a sesquiterpene lactone obtained from <em>Artemisia annua</em>, has recently attracted attention for its strong anti-inflammatory, antioxidant, and neuroprotective qualities. QA was bilaterally injected directly into the rat striatum to simulate neurotoxic conditions, followed by a 21-day artemisinin treatment. On days 0, 14, and 21, motor coordination was evaluated through behavioural assessments, including narrow beam walking, the open field test, and rotarod performance. Striatal homogenates were tested for oxidative stress parameters. qRT-PCR was used for molecular investigations. Hematoxylin and eosin staining was used to investigate histopathological changes in the striatum. Results indicated that artemisinin mitigated neurotoxicity in the experimental rats. It reduced oxidative stress and inflammatory and apoptotic markers in striatal homogenates. In conclusion, artemisinin efficiently reduced neurotoxic damage, indicating its promise as a potential neuroprotective alternative for neurodegenerative diseases.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"870 ","pages":"Article 138449"},"PeriodicalIF":2.0,"publicationDate":"2025-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145530794","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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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