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}
Pub Date : 2025-11-13DOI: 10.1016/j.neulet.2025.138445
Xincan Zhao , Shuai Zhang , Shengming Jiang , Ziang Yan , Jianming Liao , Qi Tian , Chengli Liu , Wenrui Han , Guijun Wang , Lei Wang , Mingchang Li
Among subarachnoid hemorrhage (SAH) models, the endovascular perforation method is widely used but limited by complex procedures and low efficiency. In this study, we developed a modified SAH model in male C57BL/6 mice by permanently ligating the unilateral common carotid artery (CCA) while maintaining external carotid artery (ECA) patency. Using laser speckle imaging, neurological scoring, brain water content analysis, TUNEL-NeuN co-staining, and behavioral tests, we compared this modified model to the classical approach. The modified model replicated key early and long-term brain injury features—cerebral edema, neuronal apoptosis, hemodynamic changes and cognition impairment—while significantly reducing surgical time and mortality rate. Total cerebral perfusion 24 h post-SAH was higher, with no differences in edema, apoptosis, or neurological scores versus the classic ECA model. This modified SAH model offers a practical, efficient tool for translational SAH research without compromising pathophysiological accuracy.
{"title":"Reducing surgical complexity in SAH models: A modified approach for reliable early and long-term brain injury replication","authors":"Xincan Zhao , Shuai Zhang , Shengming Jiang , Ziang Yan , Jianming Liao , Qi Tian , Chengli Liu , Wenrui Han , Guijun Wang , Lei Wang , Mingchang Li","doi":"10.1016/j.neulet.2025.138445","DOIUrl":"10.1016/j.neulet.2025.138445","url":null,"abstract":"<div><div>Among subarachnoid hemorrhage (SAH) models, the endovascular perforation method is widely used but limited by complex procedures and low efficiency. In this study, we developed a modified SAH model in male C57BL/6 mice by permanently ligating the unilateral common carotid artery (CCA) while maintaining external carotid artery (ECA) patency. Using laser speckle imaging, neurological scoring, brain water content analysis, TUNEL-NeuN co-staining, and behavioral tests, we compared this modified model to the classical approach. The modified model replicated key early and long-term brain injury features—cerebral edema, neuronal apoptosis, hemodynamic changes and cognition impairment—while significantly reducing surgical time and mortality rate. Total cerebral perfusion 24 h post-SAH was higher, with no differences in edema, apoptosis, or neurological scores versus the classic ECA model. This modified SAH model offers a practical, efficient tool for translational SAH research without compromising pathophysiological accuracy.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"870 ","pages":"Article 138445"},"PeriodicalIF":2.0,"publicationDate":"2025-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145530855","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 : 2025-11-12DOI: 10.1016/j.neulet.2025.138444
Nobuhiro Watanabe, Masamichi Moriya, Harumi Hotta
Skin thermal stimulation can induce reflexive autonomic nerve responses and thereby influence endocrine functions. Melatonin, secreted from the pineal gland primarily under sympathetic control, exerts various physiological functions including sleep–wake rhythm regulation. Although photostimulation is a well-known regulator of melatonin secretion, the effect of skin thermal stimulation remains unclear. In this study, we investigated whether intermittent mild cooling stimulation of the skin alters melatonin secretion from the pineal gland in urethane-anesthetized rats. Animals were artificially ventilated, and their rectal temperatures were maintained using a heating pad and a lamp. Using in vivo microdialysis, pineal perfusate was collected every 20 min for 100 min during the animal’s light phase and the melatonin concentrations were measured via ELISA. Intermittent cooling stimulation was applied to the skin of the trunk using a Peltier-based contact thermode by alternating the temperature between 30 °C and 15 °C (15 °C/s) for 20 min. Without cooling stimulation, the melatonin concentration in the pineal perfusate remained stable for 100 min. Cooling stimulation did not affect the melatonin concentration during application but reduced it for 40 min after the stimulation was discontinued. This suppression was abolished in rats with bilateral cervical sympathetic nerve transection. Our findings suggest that intermittent mild skin cooling stimulation reflexively suppresses pineal melatonin secretion through cervical sympathetic nerves.
{"title":"Intermittent mild skin cooling stimulation inhibits pineal melatonin secretion in urethane-anesthetized rats","authors":"Nobuhiro Watanabe, Masamichi Moriya, Harumi Hotta","doi":"10.1016/j.neulet.2025.138444","DOIUrl":"10.1016/j.neulet.2025.138444","url":null,"abstract":"<div><div>Skin thermal stimulation can induce reflexive autonomic nerve responses and thereby influence endocrine functions. Melatonin, secreted from the pineal gland primarily under sympathetic control, exerts various physiological functions including sleep–wake rhythm regulation. Although photostimulation is a well-known regulator of melatonin secretion, the effect of skin thermal stimulation remains unclear. In this study, we investigated whether intermittent mild cooling stimulation of the skin alters melatonin secretion from the pineal gland in urethane-anesthetized rats. Animals were artificially ventilated, and their rectal temperatures were maintained using a heating pad and a lamp. Using <em>in vivo</em> microdialysis, pineal perfusate was collected every 20 min for 100 min during the animal’s light phase and the melatonin concentrations were measured via ELISA. Intermittent cooling stimulation was applied to the skin of the trunk using a Peltier-based contact thermode by alternating the temperature between 30 °C and 15 °C (15 °C/s) for 20 min. Without cooling stimulation, the melatonin concentration in the pineal perfusate remained stable for 100 min. Cooling stimulation did not affect the melatonin concentration during application but reduced it for 40 min after the stimulation was discontinued. This suppression was abolished in rats with bilateral cervical sympathetic nerve transection. Our findings suggest that intermittent mild skin cooling stimulation reflexively suppresses pineal melatonin secretion through cervical sympathetic nerves.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"870 ","pages":"Article 138444"},"PeriodicalIF":2.0,"publicationDate":"2025-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145524064","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 : 2025-11-12DOI: 10.1016/j.neulet.2025.138443
Lukasz P. Slomnicki , Emily Hodges , Christine Armstrong , Johnny Morehouse , Darlene Burke , Sujata Saraswat Ohri , Thomas P. Burris , Michal Hetman
The ligand-regulated transcription factors REV-ERBα/NR1D1 and REV-ERBβ/NR1D2 are promising neuroprotective targets. Systemic administration of the REV-ERB agonist SR9009 has been shown to reduce neuroinflammation, limit tissue loss, and enhance functional recovery in several models of acute CNS injury. To evaluate its potential in spinal cord injury (SCI), a moderate contusion was induced at the T9 level in mice. SR9009 was administered intraperitoneally at 100 mg/kg per day (two 50 mg/kg doses at ZT1 and ZT12) for the first 7 days post-injury, when tissue damage is most pronounced in this model. At 3 days post-SCI, SR9009-treated mice exhibited reduced hematoma and decreased expression of transcripts associated with blood–spinal cord barrier disruption, inflammation, and cellular stress responses. However, hindlimb functional recovery remained unchanged throughout 6 weeks of follow-up, and no significant differences in white matter sparing were observed at study completion. These findings indicate that although SR9009 reduces acute activation of some secondary injury cascades, it does not promote long-term tissue preservation or functional recovery after contusive SCI in mice.
{"title":"Limited effects of the REV-ERB agonist SR9009 after mouse spinal cord contusion: Reduced acute pathology with unaffected functional recovery and chronic white matter loss","authors":"Lukasz P. Slomnicki , Emily Hodges , Christine Armstrong , Johnny Morehouse , Darlene Burke , Sujata Saraswat Ohri , Thomas P. Burris , Michal Hetman","doi":"10.1016/j.neulet.2025.138443","DOIUrl":"10.1016/j.neulet.2025.138443","url":null,"abstract":"<div><div>The ligand-regulated transcription factors REV-ERBα/NR1D1 and REV-ERBβ/NR1D2 are promising neuroprotective targets. Systemic administration of the REV-ERB agonist SR9009 has been shown to reduce neuroinflammation, limit tissue loss, and enhance functional recovery in several models of acute CNS injury. To evaluate its potential in spinal cord injury (SCI), a moderate contusion was induced at the T9 level in mice. SR9009 was administered intraperitoneally at 100 mg/kg per day (two 50 mg/kg doses at ZT1 and ZT12) for the first 7 days post-injury, when tissue damage is most pronounced in this model. At 3 days post-SCI, SR9009-treated mice exhibited reduced hematoma and decreased expression of transcripts associated with blood–spinal cord barrier disruption, inflammation, and cellular stress responses. However, hindlimb functional recovery remained unchanged throughout 6 weeks of follow-up, and no significant differences in white matter sparing were observed at study completion. These findings indicate that although SR9009 reduces acute activation of some secondary injury cascades, it does not promote long-term tissue preservation or functional recovery after contusive SCI in mice.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"870 ","pages":"Article 138443"},"PeriodicalIF":2.0,"publicationDate":"2025-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145513441","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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