Neuroscience Letters最新文献_第3页

Medial prefrontal Cortex, dopamine and glutamate modulation in regulating Reward-Seeking and frustration responses 内侧前额叶皮质，多巴胺和谷氨酸调节在调节奖励寻求和挫折反应。

IF 2 4区医学 Q3 NEUROSCIENCES

Neuroscience Letters

Pub Date : 2026-01-09 DOI: 10.1016/j.neulet.2026.138506

Crysvane Araújo de Oliveira Lima , Polliany da Silva Mendonça , Joelson Germano Crispim , Roger Luis da Silva , Ryan Cordeiro Silva , Lucas Felipe de Melo Alcantara , Filipe Silveira Duarte , Moacyr Jesus de Melo Rego , Maira Galdino da Rocha Pitta , Michelly Cristiny Pereira , Michelle Melgarejo da Rosa

Background

Behavior is often reinforced by rewarding experiences, which promote actions that yield positive outcomes contributing to adaptive decision-making. However, the absence of an anticipated reward can provoke negative emotional responses, such as frustration and anxiety, potentially leading to maladaptive behaviors. Understanding how the brain responds to reward and its omission is a growing focus in neuroscience, especially regarding how neurotransmitter systems in key circuits manage unmet expectations. The medial prefrontal cortex (mPFC), a central integrative hub, regulates downstream regions to process both rewarding and aversive outcomes. Although dopamine is known to guide reward prediction and adaptive behavior, the specific roles of dopaminergic and glutamatergic pathways in the mPFC remain unclear. Methods: In this study, we investigated the influence of mPFC and the differential roles of dopaminergic D2 and NMDA receptors within the mPFC on reward-seeking behaviors using a cued sucrose-seeking task. Results: Our results show that D2 dopamine receptor and NMDA receptor activity in the mPFC are essential for maintaining reward-seeking behaviors when expected rewards are omitted, highlighting dopamine and glutamate’s role in sustaining reward-persistent behavior. Conversely, only D2 blockade into mPFC affected cue-reward seeking behavior. Solely NMDA blockage in the mPFC and mPFC silencing reduced anxiety, suggesting a nuanced role for mPFC and glutamatergic signaling in managing the emotional response to unmet expectations. Conclusion: These findings provide new insights into how distinct neurotransmitter systems in the mPFC and mPFC itself contribute to the behavioral and emotional adjustments following reward and reward omission.

背景：行为通常通过奖励经验得到强化，这促进了产生积极结果的行为，有助于适应性决策。然而，缺乏预期的奖励会引发消极的情绪反应，如沮丧和焦虑，潜在地导致适应不良行为。了解大脑如何对奖励和它的遗漏作出反应是神经科学日益关注的焦点，特别是关于关键回路中的神经递质系统如何管理未满足的期望。内侧前额叶皮层（mPFC）是一个中央整合中枢，调节下游区域处理奖励和厌恶结果。虽然已知多巴胺指导奖励预测和适应性行为，但多巴胺能和谷氨酸能通路在mPFC中的具体作用尚不清楚。方法：在本研究中，我们研究了mPFC的影响，以及mPFC内多巴胺能D2和NMDA受体在提示蔗糖寻求任务中对奖励寻求行为的不同作用。结果：我们的研究结果表明，当预期奖励被忽略时，mPFC中D2多巴胺受体和NMDA受体的活性对于维持奖励寻求行为至关重要，突出了多巴胺和谷氨酸在维持奖励持久行为中的作用。相反，只有D2阻断进入mPFC才会影响线索奖励寻求行为。仅mPFC中的NMDA阻断和mPFC沉默减少了焦虑，这表明mPFC和谷氨酸信号在管理未满足期望的情绪反应中起着微妙的作用。结论：这些发现提供了关于mPFC和mPFC中不同的神经递质系统如何在奖励和奖励遗漏后促进行为和情绪调整的新见解。

{"title":"Medial prefrontal Cortex, dopamine and glutamate modulation in regulating Reward-Seeking and frustration responses","authors":"Crysvane Araújo de Oliveira Lima , Polliany da Silva Mendonça , Joelson Germano Crispim , Roger Luis da Silva , Ryan Cordeiro Silva , Lucas Felipe de Melo Alcantara , Filipe Silveira Duarte , Moacyr Jesus de Melo Rego , Maira Galdino da Rocha Pitta , Michelly Cristiny Pereira , Michelle Melgarejo da Rosa","doi":"10.1016/j.neulet.2026.138506","DOIUrl":"10.1016/j.neulet.2026.138506","url":null,"abstract":"<div><h3>Background</h3><div>Behavior is often reinforced by rewarding experiences, which promote actions that yield positive outcomes contributing to adaptive decision-making. However, the absence of an anticipated reward can provoke negative emotional responses, such as frustration and anxiety, potentially leading to maladaptive behaviors. Understanding how the brain responds to reward and its omission is a growing focus in neuroscience, especially regarding how neurotransmitter systems in key circuits manage unmet expectations. The medial prefrontal cortex (mPFC), a central integrative hub, regulates downstream regions to process both rewarding and aversive outcomes. Although dopamine is known to guide reward prediction and adaptive behavior, the specific roles of dopaminergic and glutamatergic pathways in the mPFC remain unclear. <strong>Methods:</strong> In this study, we investigated the influence of mPFC and the differential roles of dopaminergic D2 and NMDA receptors within the mPFC on reward-seeking behaviors using a cued sucrose-seeking task. <strong>Results:</strong> Our results show that D2 dopamine receptor and NMDA receptor activity in the mPFC are essential for maintaining reward-seeking behaviors when expected rewards are omitted, highlighting dopamine and glutamate’s role in sustaining reward-persistent behavior. Conversely, only D2 blockade into mPFC affected cue-reward seeking behavior. Solely NMDA blockage in the mPFC and mPFC silencing reduced anxiety, suggesting a nuanced role for mPFC and glutamatergic signaling in managing the emotional response to unmet expectations. <strong>Conclusion:</strong> These findings provide new insights into how distinct neurotransmitter systems in the mPFC and mPFC itself contribute to the behavioral and emotional adjustments following reward and reward omission.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"874 ","pages":"Article 138506"},"PeriodicalIF":2.0,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145952708","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}

引用次数: 0

Enhanced antidepressant effects of fluoxetine combined with quercetin: studies in vitro and in vivo 氟西汀联合槲皮素增强抗抑郁作用：体外和体内研究。

IF 2 4区医学 Q3 NEUROSCIENCES

Neuroscience Letters

Pub Date : 2026-01-08 DOI: 10.1016/j.neulet.2026.138507

Ran Yang , Yifan Mao , Jialin Yang , Hai Ma , Jianying Shen

Objectives

This study aims to explore the enhanced antidepressant effects of the commonly used depressant fluoxetine combined with a dietary supplement quercetin, using both in vitro and in vivo models.

Methods

In vitro, we established both hydrogen peroxide (H₂O₂)-damaged and glutamate-damaged SH-SY5Y cells as cellular models. SH-SY5Y cells were exposed to 250 μM H₂O₂ or 16 mM glutamate and co-treated with 1 μM fluoxetine, 10 μM quercetin, or their combination for 24 h. Cell viability was detected. In vivo, we applied a chronic unpredictable mild stress (CUMS) animal model. C57BL/6 mice were treated with fluoxetine (5 or 10 mg/kg), quercetin (40 mg/kg), or their combinations. Depressive-like behaviors including Sucrose preference test (SPT), Tail suspension test (TST), and Forced swimming test (FST) were assessed. Nissl staining was carried out for observing changes in hippocampal neurons.

Results

Fluoxetine combined with quercetin protected SH-SY5Y cells from H₂O₂– or glutamate-induced damage, improved depressive-like behaviors and reduced hippocampal neuronal injury in CUMS mice, demonstrating enhanced antidepressant effects compared to monotherapy.

Conclusion

Combining fluoxetine with quercetin enhances antidepressant effects, suggesting a way to reduce the clinically required dosage of fluoxetine, thereby reducing its side effects.

目的：本研究旨在通过体外和体内模型，探讨常用抑制剂氟西汀与膳食补充剂槲皮素联合使用后的抗抑郁效果。方法：体外建立过氧化氢（H2O2）损伤和谷氨酸损伤的SH-SY5Y细胞模型。SH-SY5Y细胞暴露于250 μM H2O2或16 mM谷氨酸，并与1 μM氟西汀、10 μM槲皮素或其组合共处理24 h。检测细胞活力。在体内，我们采用慢性不可预测轻度应激（CUMS）动物模型。C57BL/6小鼠分别给予氟西汀（5或10 mg/kg）、槲皮素（40 mg/kg）或其联合治疗。抑郁样行为包括蔗糖偏好测试（SPT）、悬尾测试（TST）和强迫游泳测试（FST）。采用尼氏染色观察海马神经元的变化。结果：氟西汀联合槲皮素保护SH-SY5Y细胞免受H2O2或谷氨酸诱导的损伤，改善CUMS小鼠的抑郁样行为，减少海马神经元损伤，与单药治疗相比，显示出更强的抗抑郁作用。结论：氟西汀联合槲皮素可增强抗抑郁作用，提示减少氟西汀临床所需剂量，从而减少其副作用。

{"title":"Enhanced antidepressant effects of fluoxetine combined with quercetin: studies in vitro and in vivo","authors":"Ran Yang , Yifan Mao , Jialin Yang , Hai Ma , Jianying Shen","doi":"10.1016/j.neulet.2026.138507","DOIUrl":"10.1016/j.neulet.2026.138507","url":null,"abstract":"<div><h3>Objectives</h3><div>This study aims to explore the enhanced antidepressant effects of the commonly used depressant fluoxetine combined with a dietary supplement quercetin, using both <em>in vitro</em> and <em>in vivo</em> models.</div></div><div><h3>Methods</h3><div><em>In vitro</em>, we established both hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>)-damaged and glutamate-damaged SH-SY5Y cells as cellular models. SH-SY5Y cells were exposed to 250 μM H<sub>2</sub>O<sub>2</sub> or 16 mM glutamate and co-treated with 1 μM fluoxetine, 10 μM quercetin, or their combination for 24 h. Cell viability was detected.<!--> <em>In vivo</em>, we applied a chronic unpredictable mild stress (CUMS) animal model. C57BL/6 mice were treated with fluoxetine (5 or 10 mg/kg), quercetin (40 mg/kg), or their combinations. Depressive-like behaviors including Sucrose preference test (SPT), Tail suspension test (TST), and Forced swimming test (FST) were assessed. Nissl staining was carried out for observing changes in hippocampal neurons.</div></div><div><h3>Results</h3><div>Fluoxetine combined with quercetin protected SH-SY5Y cells from H<sub>2</sub>O<sub>2</sub>– or glutamate-induced damage, improved depressive-like behaviors and reduced hippocampal neuronal injury in CUMS mice, demonstrating enhanced antidepressant effects compared to monotherapy.</div></div><div><h3>Conclusion</h3><div>Combining fluoxetine with quercetin enhances antidepressant effects, suggesting a way to reduce the clinically required dosage of fluoxetine, thereby reducing its side effects.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"874 ","pages":"Article 138507"},"PeriodicalIF":2.0,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145949137","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}

引用次数: 0

G protein-coupled receptor 17 promotes neuropathic pain in male mice by upregulating spinal NMDAR subunit expression G蛋白偶联受体17通过上调脊髓NMDAR亚基表达促进雄性小鼠神经性疼痛。

IF 2 4区医学 Q3 NEUROSCIENCES

Neuroscience Letters

Pub Date : 2026-01-08 DOI: 10.1016/j.neulet.2026.138509

Biyun Li, Xueqin Xu, Qin Xiao, Kunyu Zhang, Xiuqin Yu, Yangqiao Xiao, Shuangshuang Lu, Wenjiao Jin, Panpan Sun, Longhui Li, Chunyu Ma, Zihao Lu, Yanqiong Wu, Changbin Ke

Neuropathic pain is a prevalent and debilitating chronic condition for which current treatments often provide inadequate relief. This constitutes a significant unmet clinical need, highlighting the importance of identifying novel molecular targets for more effective pharmacotherapy. Synaptic remodeling-mediated central sensitization is a key regulatory factor. Glutamate is a major excitatory transmitter in the central nervous system and binds to NMDA receptors in the postsynaptic membrane to promote synaptic remodeling. In C57 mice with spared nerve injury, it was noted that GPR17 and the GluN2A and GluN2B subunits of the NMDA receptor were elevated in the L4-L6 region of the spinal cord. Lentiviral knockdown of spinal GPR17 attenuated mechanical allodynia, suppressed astrocyte activation, and decreased levels of GluN2A and GluN2B subunits. GPR17 controls neuropathic pain, stimulates astrocyte activation, and NMDA receptor overexpression on neurons. Targeting GPR17 may represent a new therapeutic strategy for the management of neuropathic pain.

神经性疼痛是一种普遍的、使人衰弱的慢性疾病，目前的治疗方法往往不能提供足够的缓解。这构成了一个重要的未满足的临床需求，突出了识别新的分子靶点对更有效的药物治疗的重要性。突触重塑介导的中枢致敏是一个关键的调节因子。谷氨酸是中枢神经系统中一种主要的兴奋性递质，与突触后膜的NMDA受体结合，促进突触重构。在C57神经损伤小鼠中，我们发现脊髓L4-L6区GPR17和NMDA受体GluN2A和GluN2B亚基升高。慢病毒敲低脊髓GPR17可减轻机械性异常痛，抑制星形胶质细胞激活，降低GluN2A和GluN2B亚基水平。GPR17控制神经性疼痛，刺激星形胶质细胞激活和神经元上NMDA受体的过表达。靶向GPR17可能是神经性疼痛治疗的一种新的治疗策略。

{"title":"G protein-coupled receptor 17 promotes neuropathic pain in male mice by upregulating spinal NMDAR subunit expression","authors":"Biyun Li, Xueqin Xu, Qin Xiao, Kunyu Zhang, Xiuqin Yu, Yangqiao Xiao, Shuangshuang Lu, Wenjiao Jin, Panpan Sun, Longhui Li, Chunyu Ma, Zihao Lu, Yanqiong Wu, Changbin Ke","doi":"10.1016/j.neulet.2026.138509","DOIUrl":"10.1016/j.neulet.2026.138509","url":null,"abstract":"<div><div>Neuropathic pain is a prevalent and debilitating chronic condition for which current treatments often provide inadequate relief. This constitutes a significant unmet clinical need, highlighting the importance of identifying novel molecular targets for more effective pharmacotherapy. Synaptic remodeling-mediated central sensitization is a key regulatory factor. Glutamate is a major excitatory transmitter in the central nervous system and binds to NMDA receptors in the postsynaptic membrane to promote synaptic remodeling. In C57 mice with spared nerve injury, it was noted that GPR17 and the GluN2A and GluN2B subunits of the NMDA receptor were elevated in the L4-L6 region of the spinal cord. Lentiviral knockdown of spinal GPR17 attenuated mechanical allodynia, suppressed astrocyte activation, and decreased levels of GluN2A and GluN2B subunits. GPR17 controls neuropathic pain, stimulates astrocyte activation, and NMDA receptor overexpression on neurons. Targeting GPR17 may represent a new therapeutic strategy for the management of neuropathic pain.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"873 ","pages":"Article 138509"},"PeriodicalIF":2.0,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145949071","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}

引用次数: 0

Differential neuroinflammatory trajectories in the hippocampus and prefrontal cortex after acute LPS administration 急性LPS处理后海马和前额皮质的不同神经炎症轨迹。

IF 2 4区医学 Q3 NEUROSCIENCES

Neuroscience Letters

Pub Date : 2026-01-08 DOI: 10.1016/j.neulet.2026.138504

Zhouli Yue , Mengyuan Li , Jiahui Wang , Siqi Quan , Yiqi Wang , Zhanying Niu , Yucheng Li

Neuroinflammation is a key pathological feature of central nervous system disorders, yet its temporal and regional dynamics remain poorly defined. In this study, we systematically investigated neuroinflammatory responses and neuronal injury in the hippocampus and prefrontal cortex following a single intraperitoneal injection of lipopolysaccharide (LPS, 1 mg/kg) in mice. Fifty-four male C57BL/6N mice were randomly divided into six groups, and serum and brain tissues were collected at 0, 3, 6, 12, 24, and 48 h after LPS administration. Cytokine levels were detected by enzyme-linked immunosorbent assay (ELISA), neuronal injury was assessed by Nissl staining, and proteins expression was examined by Western blot. The results showed that peripheral cytokines, including interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6), exhibited a rapid and transient increase, peaking at 3 h and returning to baseline within 24 h, whereas central inflammatory responses displayed marked region- and time-dependent differences. In the hippocampus, IL-1β showed delayed but sustained elevation, peaking at 12 h and accompanied by progressive neuronal injury. In contrast, the prefrontal cortex exhibited an early cytokines surge at 3 h, with prolonged IL-1β elevation, and a biphasic pattern of neuronal damage characterized by early injury, partial recovery, and delayed exacerbation. These spatiotemporal dynamics were paralleled by differential activation of the TLR4/MyD88/NF-κB pathway. These findings reveal that LPS-induced neuroinflammation is a heterogeneous and dynamic process rather than a uniform response, providing new insight into region-specific vulnerability and the dissociation between peripheral and central inflammatory kinetics.

神经炎症是中枢神经系统疾病的一个关键病理特征，但其时间和区域动态仍不明确。在这项研究中，我们系统地研究了单次腹腔注射脂多糖（LPS, 1 mg/kg）后小鼠海马和前额皮质的神经炎症反应和神经元损伤。将54只雄性C57BL/6N小鼠随机分为6组，分别于LPS给药后0、3、6、12、24、48 h采集血清和脑组织。采用酶联免疫吸附法（ELISA）检测细胞因子水平，尼氏染色检测神经元损伤，Western blot检测蛋白表达。结果显示，包括白细胞介素-1β (IL-1β)、肿瘤坏死因子-α (TNF-α)和白细胞介素-6 （IL-6）在内的外周细胞因子表现出快速和短暂的增加，在3 h达到峰值，并在24 h内恢复到基线，而中枢炎症反应表现出明显的区域和时间依赖性差异。在海马中，IL-1β表现出延迟但持续的升高，在12 h达到峰值，并伴有进行性神经元损伤。相比之下，前额叶皮层在3 h时表现出早期细胞因子激增，IL-1β升高时间延长，神经元损伤呈双相模式，其特征是早期损伤、部分恢复和延迟恶化。这些时空动态与TLR4/MyD88/NF-κB通路的差异激活有关。这些发现表明，lps诱导的神经炎症是一个异质性和动态的过程，而不是一个统一的反应，为区域特异性易感性和外周和中枢炎症动力学之间的分离提供了新的见解。

{"title":"Differential neuroinflammatory trajectories in the hippocampus and prefrontal cortex after acute LPS administration","authors":"Zhouli Yue , Mengyuan Li , Jiahui Wang , Siqi Quan , Yiqi Wang , Zhanying Niu , Yucheng Li","doi":"10.1016/j.neulet.2026.138504","DOIUrl":"10.1016/j.neulet.2026.138504","url":null,"abstract":"<div><div>Neuroinflammation is a key pathological feature of central nervous system disorders, yet its temporal and regional dynamics remain poorly defined. In this study, we systematically investigated neuroinflammatory responses and neuronal injury in the hippocampus and prefrontal cortex following a single intraperitoneal injection of lipopolysaccharide (LPS, 1 mg/kg) in mice. Fifty-four male C57BL/6N mice were randomly divided into six groups, and serum and brain tissues were collected at 0, 3, 6, 12, 24, and 48 h after LPS administration. Cytokine levels were detected by enzyme-linked immunosorbent assay (ELISA), neuronal injury was assessed by Nissl staining, and proteins expression was examined by Western blot. The results showed that peripheral cytokines, including interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6), exhibited a rapid and transient increase, peaking at 3 h and returning to baseline within 24 h, whereas central inflammatory responses displayed marked region- and time-dependent differences. In the hippocampus, IL-1β showed delayed but sustained elevation, peaking at 12 h and accompanied by progressive neuronal injury. In contrast, the prefrontal cortex exhibited an early cytokines surge at 3 h, with prolonged IL-1β elevation, and a biphasic pattern of neuronal damage characterized by early injury, partial recovery, and delayed exacerbation. These spatiotemporal dynamics were paralleled by differential activation of the TLR4/MyD88/NF-κB pathway. These findings reveal that LPS-induced neuroinflammation is a heterogeneous and dynamic process rather than a uniform response, providing new insight into region-specific vulnerability and the dissociation between peripheral and central inflammatory kinetics.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"874 ","pages":"Article 138504"},"PeriodicalIF":2.0,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145949146","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}

引用次数: 0

Comparative effects of antidepressants on cocaine-induced hyperthermia in rats: a preclinical study 抗抑郁药对大鼠可卡因热疗的比较作用：一项临床前研究

IF 2 4区医学 Q3 NEUROSCIENCES

Neuroscience Letters

Pub Date : 2026-01-07 DOI: 10.1016/j.neulet.2026.138508

Tsuyoshi Okada , Seiji Obi , Manabu Takano , Katsutoshi Shioda , Shiro Suda

Purpose

Cocaine abuse is a major public health concern and is often associated with acute hyperthermia, which can be fatal and has limited pharmacological interventions for its management. Although antidepressants are frequently prescribed to cocaine users, particularly to those with comorbid depression, their safety within this context remains unclear, as some can exacerbate the toxicity of cocaine. This study aimed to evaluate the effects of various antidepressants on cocaine-induced hyperthermia in rats to identify safer treatment options.

Subjects and methods

Adult male Wistar rats received intraperitoneal injections of cocaine (30 mg/kg) following pretreatment with one of the following antidepressants: mirtazapine, fluoxetine, venlafaxine, amitriptyline, or moclobemide. To elucidate the mechanism underlying the effects of mirtazapine, the selective 5-HT2A receptor antagonists ketanserin and ritanserin were also tested. Rectal temperature was measured every 30 min for up to 240 min after cocaine administration.

Results

Cocaine administration significantly elevated body temperature in control rats. However, pretreatment with mirtazapine significantly suppressed this hyperthermic response, presumably via central 5-HT2A receptor antagonism. Ketanserin and ritanserin similarly suppressed hyperthermia, supporting this proposed mechanism. In contrast, moclobemide exacerbated the hyperthermia, venlafaxine prolonged the hyperthermic response, and fluoxetine and amitriptyline had no significant effect on the hyperthermic response.

Conclusion

Mirtazapine may be a safer antidepressant option for managing depression in cocaine users because of its capacity to suppress hyperthermia without enhancing monoamine reuptake inhibition. Notably, caution should be exercised when prescribing monoamine oxidase inhibitors and SNRIs to this population. However, further clinical studies are required to validate these findings.

目的：可卡因滥用是一个重大的公共卫生问题，通常与急性高热有关，而急性高热可能是致命的，治疗的药物干预措施有限。虽然抗抑郁药经常被开给可卡因使用者，特别是那些患有共病抑郁症的人，但在这种情况下，它们的安全性尚不清楚，因为有些药物会加剧可卡因的毒性。本研究旨在评估各种抗抑郁药对大鼠可卡因致热的影响，以确定更安全的治疗方案。研究对象和方法：成年雄性Wistar大鼠在使用米氮平、氟西汀、文拉法辛、阿米替林或莫氯贝胺等抗抑郁药物进行预处理后，腹腔注射可卡因（30 mg/kg）。为了阐明米氮平作用的机制，我们还测试了选择性5-HT2A受体拮抗剂酮色林和利坦色林。在可卡因给药后，每30分钟测量一次直肠温度，直至240分钟。结果给药后大鼠体温明显升高。然而，米氮平预处理可能通过中枢5-HT2A受体拮抗作用显著抑制了这种高热反应。克坦色林和利坦色林同样抑制高热，支持这一提出的机制。莫氯贝胺加重了热疗，文拉法辛延长了热疗反应，氟西汀和阿米替林对热疗反应无显著影响。结论米氮平具有抑制高温的作用，且不增强单胺再摄取抑制作用，可能是治疗可卡因使用者抑郁症的更安全的抗抑郁药物。值得注意的是，在给这一人群开单胺氧化酶抑制剂和SNRIs时应谨慎行事。然而，需要进一步的临床研究来验证这些发现。

{"title":"Comparative effects of antidepressants on cocaine-induced hyperthermia in rats: a preclinical study","authors":"Tsuyoshi Okada , Seiji Obi , Manabu Takano , Katsutoshi Shioda , Shiro Suda","doi":"10.1016/j.neulet.2026.138508","DOIUrl":"10.1016/j.neulet.2026.138508","url":null,"abstract":"<div><h3>Purpose</h3><div>Cocaine abuse is a major public health concern and is often associated with acute hyperthermia, which can be fatal and has limited pharmacological interventions for its management. Although antidepressants are frequently prescribed to cocaine users, particularly to those with comorbid depression, their safety within this context remains unclear, as some can exacerbate the toxicity of cocaine. This study aimed to evaluate the effects of various antidepressants on cocaine-induced hyperthermia in rats to identify safer treatment options.</div></div><div><h3>Subjects and methods</h3><div>Adult male Wistar rats received intraperitoneal injections of cocaine (30 mg/kg) following pretreatment with one of the following antidepressants: mirtazapine, fluoxetine, venlafaxine, amitriptyline, or moclobemide. To elucidate the mechanism underlying the effects of mirtazapine, the selective 5-HT2A receptor antagonists ketanserin and ritanserin were also tested. Rectal temperature was measured every 30 min for up to 240 min after cocaine administration.</div></div><div><h3>Results</h3><div>Cocaine administration significantly elevated body temperature in control rats. However, pretreatment with mirtazapine significantly suppressed this hyperthermic response, presumably via central 5-HT2A receptor antagonism. Ketanserin and ritanserin similarly suppressed hyperthermia, supporting this proposed mechanism. In contrast, moclobemide exacerbated the hyperthermia, venlafaxine prolonged the hyperthermic response, and fluoxetine and amitriptyline had no significant effect on the hyperthermic response.</div></div><div><h3>Conclusion</h3><div>Mirtazapine may be a safer antidepressant option for managing depression in cocaine users because of its capacity to suppress hyperthermia without enhancing monoamine reuptake inhibition. Notably, caution should be exercised when prescribing monoamine oxidase inhibitors and SNRIs to this population. However, further clinical studies are required to validate these findings.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"873 ","pages":"Article 138508"},"PeriodicalIF":2.0,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145939813","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}

引用次数: 0

Electroacupuncture at GV20 and GV24 acupoints ameliorates migraine by blocking NLRP3-mediated pyroptosis via inhibiting the Piezo1 channel 电针GV20和GV24穴位通过抑制Piezo1通道阻断nlrp3介导的热凋亡来改善偏头痛。

IF 2 4区医学 Q3 NEUROSCIENCES

Neuroscience Letters

Pub Date : 2026-01-06 DOI: 10.1016/j.neulet.2026.138505

Jianchang Luo , Liyao Feng , Wenbin Xu, Jiawang Lang, Luodan Wang, Zhipeng Zhao, Boxu Lang

Migraine is a complex neuro-glio-vascular disorder, and electroacupuncture (EA) have been recommended as an alternative therapy for migraine. However, the mechanism of action of EA on GV20 (Baihui) and GV24 (Shenting) acupoints in treating migraine remains unclear. Thus, this study was performed to explore the potential mechanisms underlying the therapeutic influence of EA stimulation at GV20 and GV24 acupoints in the migraine treatment. After therapeutic effects of EA stimulation at GV20 and GV24 acupoints on migraine rat model established by dural electrical stimuli (DES) stimulation exploration, numerous approaches, such as qRT-PCR, immunofluorescence, and western blot, were applied to assess the expression of Piezo1 and pyroptosis-related proteins. Finally, Piezo1 activator (Yoda1) was used to confirm the involvement of Piezo1 channel in the treatment actions of EA stimulation at GV20 and GV24 acupoints on migraine. The results showed that EA stimulation at GV20 and GV24 acupoints forcefully alleviated the mechanical allodynia and central sensitization in rat model of migraine, also downregulated the expression of pro-inflammatory cytokines, containing TNF-α, IL-6, and IL-1β. In addition, EA stimulation at GV20 and GV24 acupoints also changed the expression of Piezo1 and pyroptosis-related proteins in rat model of migraine. Interestingly, treatment with the Yoda1 could reverse the therapeutic influences of EA stimulation at GV20 and GV24 acupoints in migraine rat model. Of note, the effect of EA stimulation at GV20 and GV24 acupoints on the expression of pyroptosis-related proteins could also be reverse by Yoda1 administration. This study emphasizes the EA efficacy at GV20 and GV24 acupoints on the migraine rat model established by DES stimulation, and proposes a mechanism involving inhibition of Piezo1 channel to block NLRP3-mediated pyroptosis in migraine.

偏头痛是一种复杂的神经-胶质-血管疾病，电针（EA）已被推荐作为偏头痛的替代疗法。然而，EA对GV20（百会）和GV24（神庭）穴治疗偏头痛的作用机制尚不清楚。因此，本研究旨在探讨EA刺激GV20和GV24穴位治疗偏头痛的潜在机制。通过硬脑膜电刺激（DES）探索建立偏头痛大鼠模型，观察EA刺激GV20和GV24穴位的治疗效果，采用qRT-PCR、免疫荧光、western blot等多种方法评估Piezo1和热休克相关蛋白的表达。最后，利用Piezo1激活剂（Yoda1）证实Piezo1通道参与EA刺激GV20和GV24穴位对偏头痛的治疗作用。结果表明，EA刺激GV20和GV24穴位可有效缓解大鼠偏头痛模型的机械异常性痛和中枢致敏，并下调促炎因子TNF-α、IL-6和IL-1β的表达。此外，EA刺激GV20和GV24穴位也改变了偏头痛大鼠模型中Piezo1和焦热相关蛋白的表达。有趣的是，Yoda1可以逆转EA刺激偏头痛大鼠GV20和GV24穴位的治疗作用。值得注意的是，EA刺激GV20和GV24穴位对焦解热相关蛋白表达的影响也可以被Yoda1逆转。本研究强调了EA作用于GV20和GV24穴位对DES刺激所致偏头痛大鼠模型的影响，并提出了通过抑制Piezo1通道阻断nlrp3介导的偏头痛热凋亡的机制。

{"title":"Electroacupuncture at GV20 and GV24 acupoints ameliorates migraine by blocking NLRP3-mediated pyroptosis via inhibiting the Piezo1 channel","authors":"Jianchang Luo , Liyao Feng , Wenbin Xu, Jiawang Lang, Luodan Wang, Zhipeng Zhao, Boxu Lang","doi":"10.1016/j.neulet.2026.138505","DOIUrl":"10.1016/j.neulet.2026.138505","url":null,"abstract":"<div><div>Migraine is a complex neuro-glio-vascular disorder, and electroacupuncture (EA) have been recommended as an alternative therapy for migraine. However, the mechanism of action of EA on GV20 (Baihui) and GV24 (Shenting) acupoints in treating migraine remains unclear. Thus, this study was performed to explore the potential mechanisms underlying the therapeutic influence of EA stimulation at GV20 and GV24 acupoints in the migraine treatment. After therapeutic effects of EA stimulation at GV20 and GV24 acupoints on migraine rat model established by dural electrical stimuli (DES) stimulation exploration, numerous approaches, such as qRT-PCR, immunofluorescence, and western blot, were applied to assess the expression of Piezo1 and pyroptosis-related proteins. Finally, Piezo1 activator (Yoda1) was used to confirm the involvement of Piezo1 channel in the treatment actions of EA stimulation at GV20 and GV24 acupoints on migraine. The results showed that EA stimulation at GV20 and GV24 acupoints forcefully alleviated the mechanical allodynia and central sensitization in rat model of migraine, also downregulated the expression of pro-inflammatory cytokines, containing TNF-α, IL-6, and IL-1β. In addition, EA stimulation at GV20 and GV24 acupoints also changed the expression of Piezo1 and pyroptosis-related proteins in rat model of migraine. Interestingly, treatment with the Yoda1 could reverse the therapeutic influences of EA stimulation at GV20 and GV24 acupoints in migraine rat model. Of note, the effect of EA stimulation at GV20 and GV24 acupoints on the expression of pyroptosis-related proteins could also be reverse by Yoda1 administration. This study emphasizes the EA efficacy at GV20 and GV24 acupoints on the migraine rat model established by DES stimulation, and proposes a mechanism involving inhibition of Piezo1 channel to block NLRP3-mediated pyroptosis in migraine.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"874 ","pages":"Article 138505"},"PeriodicalIF":2.0,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145934358","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}

引用次数: 0

The role of childhood trauma in hippocampal subfield alterations in lithium-treated type I bipolar disorder and healthy controls: A subfield volumetry MRI study 儿童创伤在锂治疗的I型双相情感障碍和健康对照者海马亚区改变中的作用：一项亚区容量MRI研究

IF 2 4区医学 Q3 NEUROSCIENCES

Neuroscience Letters

Pub Date : 2026-01-04 DOI: 10.1016/j.neulet.2026.138503

Júnior Aparecido-de-Almeida , Marcio Gerhardt Soeiro-de-Souza

Background

Type I bipolar disorder (BD-I) affects approximately 1% of the global population, and alterations in the morphology of the hippocampus, a cerebral region critical for memory and emotional regulation, may play an important role in its pathophysiology. Childhood Adversity (CA), including abuse and neglect, has been linked to structural hippocampal changes and elevated psychiatric risk, yet the impact of CA on hippocampal subfields in BD remains poorly understood.

Methods

Eighty‑five euthymic patients with BD-I on stable lithium therapy (age 18–40), and 59 healthy controls were assessed (both groups trauma-exposed with score of Childhood Trauma Questionnaire (CTQ) > 25). Volumes of 12 hippocampal subfields were measured using FreeSurfer v6.0.0 and ENIGMA protocols. Partial correlations between CTQ subscale scores and subfield volumes were identified, controlling for age, sex, lithium use, and intracranial volume.

Results

In the BD-I group, higher physical neglect scores correlated with larger right hippocampal volumes: total hippocampus, CA1, hippocampal fissure, and presubiculum, whereas high emotional abuse scores were associated with increased left hippocampal fissure and subiculum volume. No significant associations were observed in controls, indicating specificity of trauma‑related alterations in BD-I.

Conclusion

Different CA subtypes yield distinct volumetric signatures in BD-I: physical neglect seems to drive expansion especially in right‑hemisphere subfields, while emotional abuse appears to enlarge the left subiculum. These findings highlight potential neuroplasticity biomarkers and may help inform early and targeted interventions.

背景： I型双相情感障碍（BD）影响全球约1%的人口，海马（记忆和情绪调节的关键大脑区域）形态的改变可能在其病理生理中发挥重要作用。童年逆境（CA），包括虐待和忽视，与海马结构变化和精神风险升高有关，但CA对双相障碍海马亚区的影响尚不清楚。方法：对85例接受稳定锂治疗的 I型BD患者（年龄 18-40岁）和59名健康对照者（两组均有创伤暴露，儿童创伤问卷（CTQ）得分 > 25）进行评估。使用FreeSurfer v6.0.0和ENIGMA协议测量12个海马子区体积。在控制了年龄、性别、锂离子使用和颅内容积的情况下，CTQ子量表得分与子场容积之间存在部分相关性。结果：在BD组中，较高的身体忽视得分与较大的右侧海马体积相关：海马总体积、CA1、海马裂和耻骨下体积，而较高的情绪虐待得分与较大的左侧海马裂和耻骨下体积相关。在对照组中未观察到显著相关性，表明BD-I中创伤相关改变的特异性。结论：不同的CA亚型在BD-I中产生不同的体积特征：身体忽视似乎驱动扩张，尤其是在右半球亚区，而情绪虐待似乎扩大了左肩带下。这些发现突出了潜在的神经可塑性生物标志物，可能有助于告知早期和有针对性的干预措施。

{"title":"The role of childhood trauma in hippocampal subfield alterations in lithium-treated type I bipolar disorder and healthy controls: A subfield volumetry MRI study","authors":"Júnior Aparecido-de-Almeida , Marcio Gerhardt Soeiro-de-Souza","doi":"10.1016/j.neulet.2026.138503","DOIUrl":"10.1016/j.neulet.2026.138503","url":null,"abstract":"<div><h3>Background</h3><div>Type I bipolar disorder (BD-I) affects approximately 1% of the global population, and alterations in the morphology of the hippocampus, a cerebral region critical for memory and emotional regulation, may play an important role in its pathophysiology. Childhood Adversity (CA), including abuse and neglect, has been linked to structural hippocampal changes and elevated psychiatric risk, yet the impact of CA on hippocampal subfields in BD remains poorly understood.</div></div><div><h3>Methods</h3><div>Eighty‑five euthymic patients with BD-I on stable lithium therapy (age 18–40), and 59 healthy controls were assessed (both groups trauma-exposed with score of Childhood Trauma Questionnaire (CTQ) > 25). Volumes of 12 hippocampal subfields were measured using FreeSurfer v6.0.0 and ENIGMA protocols. Partial correlations between CTQ subscale scores and subfield volumes were identified, controlling for age, sex, lithium use, and intracranial volume.</div></div><div><h3>Results</h3><div>In the BD-I group, higher physical neglect scores correlated with larger right hippocampal volumes: total hippocampus, CA1, hippocampal fissure, and presubiculum, whereas high emotional abuse scores were associated with increased left hippocampal fissure and subiculum volume. No significant associations were observed in controls, indicating specificity of trauma‑related alterations in BD-I.</div></div><div><h3>Conclusion</h3><div>Different CA subtypes yield distinct volumetric signatures in BD-I: physical neglect seems to drive expansion especially in right‑hemisphere subfields, while emotional abuse appears to enlarge the left subiculum. These findings highlight potential neuroplasticity biomarkers and may help inform early and targeted interventions.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"874 ","pages":"Article 138503"},"PeriodicalIF":2.0,"publicationDate":"2026-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145912385","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}

引用次数: 0

Prolonged exposure of cerebrocortical neurons to diazepam induces downregulation of surface α1-containing GABAA receptors and uncoupling of GABA/benzodiazepine site interactions through different mechanisms 脑皮质神经元长时间暴露于地西泮可通过不同机制下调表面含α1的GABAA受体，并使GABA/苯二氮卓位点相互作用解偶联。

IF 2 4区医学 Q3 NEUROSCIENCES

Neuroscience Letters

Pub Date : 2025-12-23 DOI: 10.1016/j.neulet.2025.138495

Leydi Carolina González Gómez, María Clara Gravielle

GABA_A receptors play a crucial role in mediating fast inhibitory neurotransmission in the central nervous system. These receptors are targets of numerous pharmacological agents used clinically to control neuronal excitability in different neurological disorders. Sustained stimulation of GABA_A receptors by endogenous or exogenous modulators leads to adaptive homeostatic alterations in the receptor function. In particular, chronic benzodiazepine administration results in tolerance to most of the behavioral effects, limiting the clinical use of these drugs for long-term treatments. In previous studies, we found that prolonged exposure of rat cerebrocortical neurons to diazepam produces uncoupling of GABA/benzodiazepine site interactions and decreased expression of the GABA_A receptor α1 subunit gene, mediated by a mechanism involving the activation of L-type voltage-gated calcium channels (L-VGCCs). This work aimed to further explore the molecular basis of GABA_A receptor regulation induced by prolonged benzodiazepine stimulation. Our findings indicate that diazepam increases intracellular calcium levels, confirming the dependence of benzodiazepine-induced GABA_A receptor regulation on calcium entry through L-VGCCs. Immunocytochemical analyses revealed that sustained diazepam treatment reduces the expression of α1-containing GABA_A receptors on the cell surface, which likely impacts functional receptors. By knocking-down α1 subunit expression, we demonstrated that α1 downregulation alone results in minor, non-significant uncoupling, suggesting that additional GABA_A receptor modifications contribute to the observed uncoupling. Altogether, our results suggest that persistent exposure of GABA_A receptors to benzodiazepines produces uncoupling and downregulation of functional α1-containing GABA_A receptors through two distinct mechanisms, both initiated by calcium influx through L-VGCCs.

GABAA受体在中枢神经系统的快速抑制性神经传递中起着至关重要的作用。这些受体是临床上用于控制不同神经系统疾病中神经元兴奋性的许多药理学药物的靶点。内源性或外源性调节剂对GABAA受体的持续刺激可导致受体功能的适应性稳态改变。特别是，长期服用苯二氮卓类药物导致对大多数行为影响的耐受性，限制了这些药物用于长期治疗的临床使用。在之前的研究中，我们发现长时间暴露于地西平的大鼠大脑皮质神经元会导致GABA/苯二氮卓位点相互作用的解耦，GABAA受体α1亚基基因的表达降低，其机制涉及l型电压门控钙通道（L-VGCCs）的激活。本工作旨在进一步探讨长时间苯二氮卓类药物刺激诱导GABAA受体调控的分子基础。我们的研究结果表明，地西泮增加细胞内钙水平，证实了苯二氮卓诱导的GABAA受体对钙通过l - vgc进入的依赖性。免疫细胞化学分析显示，持续地西泮治疗降低了细胞表面含α1的GABAA受体的表达，这可能影响了功能受体。通过下调α1亚基的表达，我们发现α1的下调只会导致轻微的、不显著的解偶联，这表明额外的GABAA受体修饰有助于观察到的解偶联。总之，我们的研究结果表明，GABAA受体持续暴露于苯二氮卓类药物会通过两种不同的机制产生含有α1的功能性GABAA受体的解偶联和下调，这两种机制都是由钙通过l - vgc内流引发的。

{"title":"Prolonged exposure of cerebrocortical neurons to diazepam induces downregulation of surface α1-containing GABAA receptors and uncoupling of GABA/benzodiazepine site interactions through different mechanisms","authors":"Leydi Carolina González Gómez, María Clara Gravielle","doi":"10.1016/j.neulet.2025.138495","DOIUrl":"10.1016/j.neulet.2025.138495","url":null,"abstract":"<div><div>GABA<sub>A</sub> receptors play a crucial role in mediating fast inhibitory neurotransmission in the central nervous system. These receptors are targets of numerous pharmacological agents used clinically to control neuronal excitability in different neurological disorders. Sustained stimulation of GABA<sub>A</sub> receptors by endogenous or exogenous modulators leads to adaptive homeostatic alterations in the receptor function. In particular, chronic benzodiazepine administration results in tolerance to most of the behavioral effects, limiting the clinical use of these drugs for long-term treatments. In previous studies, we found that prolonged exposure of rat cerebrocortical neurons to diazepam produces uncoupling of GABA/benzodiazepine site interactions and decreased expression of the GABA<sub>A</sub> receptor α1 subunit gene, mediated by a mechanism involving the activation of L-type voltage-gated calcium channels (L-VGCCs). This work aimed to further explore the molecular basis of GABA<sub>A</sub> receptor regulation induced by prolonged benzodiazepine stimulation. Our findings indicate that diazepam increases intracellular calcium levels, confirming the dependence of benzodiazepine-induced GABA<sub>A</sub> receptor regulation on calcium entry through L-VGCCs. Immunocytochemical analyses revealed that sustained diazepam treatment reduces the expression of α1-containing GABA<sub>A</sub> receptors on the cell surface, which likely impacts functional receptors. By knocking-down α1 subunit expression, we demonstrated that α1 downregulation alone results in minor, non-significant uncoupling, suggesting that additional GABA<sub>A</sub> receptor modifications contribute to the observed uncoupling. Altogether, our results suggest that persistent exposure of GABA<sub>A</sub> receptors to benzodiazepines produces uncoupling and downregulation of functional α1-containing GABA<sub>A</sub> receptors through two distinct mechanisms, both initiated by calcium influx through L-VGCCs.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"873 ","pages":"Article 138495"},"PeriodicalIF":2.0,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145834447","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}

引用次数: 0

Recovery from cuprizone induced incontinence is not dependent upon remyelination 铜酮引起的尿失禁的恢复不依赖于髓鞘再生。

IF 2 4区医学 Q3 NEUROSCIENCES

Neuroscience Letters

Pub Date : 2025-12-21 DOI: 10.1016/j.neulet.2025.138494

Anirudhya Lahiri, Lucille E Papile, Zaenab Dhari, Jake T Lustig, Evan T Lombardo, Erica R Lavoie, Pearl A Sutter, Stephen J Crocker

Dysfunction in bladder control (incontinence) is a significant comorbidity in multiple sclerosis that diminishes patients’ quality of life and is a leading cause of hospitalization. Recent evidence indicates that CNS demyelination is sufficient to induce incontinence, while bladder control is also restored following remyelination. Based on this strong association, we hypothesized that remyelination is necessary for the restoration of bladder function control after acute demyelination. To test this, we evaluated changes in bladder function in mice in which Myelin regulatory factor (Myrf) was conditionally knocked out in oligodendrocyte precursor cells (OPC)(PDGFR⍺- CreER^TM, Myrf^fl/fl (Myrf-cKO)) and compared these with control groups during and after being subjected to cuprizone treatment. Here, we report that acute demyelination leads to bladder control dysfunction which was evidenced by significantly increased voiding behavior irrespective of genotype. However, during the remyelination phase, we observed an amelioration of incontinence in all groups, including mice in which remyelination fails (e.g. Myrf-cKO mice). These data suggest that while active demyelination can initiate loss of bladder function control, failed remyelination is not an impediment to potential adaptive changes which may facilitate restoration of proper bladder function.

膀胱控制功能障碍（尿失禁）是多发性硬化症的重要合并症，它降低了患者的生活质量，是住院治疗的主要原因。最近的证据表明，中枢神经系统脱髓鞘足以引起尿失禁，而膀胱控制也恢复后，髓鞘再生。基于这种强烈的关联，我们假设在急性脱髓鞘后，再脱髓鞘对于膀胱功能控制的恢复是必要的。为了验证这一点，我们评估了髓磷脂调节因子（Myrf）在少突胶质前细胞（OPC）（PDGFR - CreERTM, Myrffl/fl (Myrf- cko)）中被有条件敲除的小鼠膀胱功能的变化，并将其与对照组进行比较。在这里，我们报道急性脱髓鞘导致膀胱控制功能障碍，这可以通过显着增加的排尿行为来证明，而与基因型无关。然而，在髓鞘再生阶段，我们观察到所有组尿失禁的改善，包括髓鞘再生失败的小鼠（如Myrf-cKO小鼠）。这些数据表明，虽然活动性脱髓鞘会导致膀胱功能失控，但脱髓鞘失败并不妨碍潜在的适应性改变，这可能有助于膀胱功能的正常恢复。

{"title":"Recovery from cuprizone induced incontinence is not dependent upon remyelination","authors":"Anirudhya Lahiri, Lucille E Papile, Zaenab Dhari, Jake T Lustig, Evan T Lombardo, Erica R Lavoie, Pearl A Sutter, Stephen J Crocker","doi":"10.1016/j.neulet.2025.138494","DOIUrl":"10.1016/j.neulet.2025.138494","url":null,"abstract":"<div><div>Dysfunction in bladder control (incontinence) is a significant comorbidity in multiple sclerosis that diminishes patients’ quality of life and is a leading cause of hospitalization. Recent evidence indicates that CNS demyelination is sufficient to induce incontinence, while bladder control is also restored following remyelination. Based on this strong association, we hypothesized that remyelination is necessary for the restoration of bladder function control after acute demyelination. To test this, we evaluated changes in bladder function in mice in which Myelin regulatory factor (<em>Myrf</em>) was conditionally knocked out in oligodendrocyte precursor cells (OPC)(PDGFR⍺- CreER<sup>TM</sup>, <em>Myrf</em><sup>fl/fl</sup> (<em>Myrf</em>-cKO)) and compared these with control groups during and after being subjected to cuprizone treatment. Here, we report that acute demyelination leads to bladder control dysfunction which was evidenced by significantly increased voiding behavior irrespective of genotype. However, during the remyelination phase, we observed an amelioration of incontinence in all groups, including mice in which remyelination fails (e.g. <em>Myrf</em>-cKO mice). These data suggest that while active demyelination can initiate loss of bladder function control, failed remyelination is not an impediment to potential adaptive changes which may facilitate restoration of proper bladder function.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"873 ","pages":"Article 138494"},"PeriodicalIF":2.0,"publicationDate":"2025-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145820217","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}

引用次数: 0

Chlorogenic acid exerts anti-inflammation and neuroprotective effect in pentylenetetrazole-induced epilepsy mouse model by regulating microglia polarization via Nrf2/HO-1 pathway 绿原酸通过Nrf2/HO-1通路调节小胶质细胞极化，在戊四唑致癫痫小鼠模型中发挥抗炎和神经保护作用

IF 2 4区医学 Q3 NEUROSCIENCES

Neuroscience Letters

Pub Date : 2025-12-19 DOI: 10.1016/j.neulet.2025.138493

Yi Sun , Jiayu Wang , Aoyuan Zhang , Ankang Hu , Lianlian Wu

Chlorogenic acid (CGA) possesses diverse biological functions, including antioxidant, anti-inflammatory, and anti-apoptotic, both in vitro and in vivo. Recent studies have suggested that CGA also has neuroprotective effects. However, its potential to alleviate seizures and attenuate epilepsy-related neuropathology remains unclear. This study investigated the effects and underlying mechanisms of CGA in a pentylenetetrazole (PTZ)-induced epilepsy mouse model. CGA treatment significantly reduced epileptic seizures. Nissl and NeuN immunofluorescence staining revealed that CGA also significantly reduced neuronal damage. Furthermore, CGA promoted microglial polarization from the pro-inflammatory M1 to the anti-inflammatory M2 phenotype and suppressed neuroinflammation, evidenced by iNOS/IBA-1 and Arg-1/IBA-1 immunofluorescence and RT-PCR. BrdU staining revealed that CGA inhibited epilepsy-induced aberrant neurogenesis. In addition, behavioral tests showed improved cognitive performance following CGA treatment. Finally, western blot analysis indicated the activation of the Nrf2/HO-1 pathway, and Nrf2 knockdown reversed CGA’s effects. These findings suggest that CGA exerts anti-seizure and neuroprotective effects via microglial modulation through the Nrf2/HO-1 pathway.

绿原酸（Chlorogenic acid， CGA）在体内体外均具有抗氧化、抗炎、抗细胞凋亡等多种生物学功能。最近的研究表明，CGA也有神经保护作用。然而，其减轻癫痫发作和减轻癫痫相关神经病理的潜力仍不清楚。本研究探讨了CGA在戊四唑（PTZ）诱导癫痫小鼠模型中的作用及其机制。CGA治疗显著减少癫痫发作。Nissl和NeuN免疫荧光染色显示，CGA还能显著减轻神经元损伤。此外，通过iNOS/IBA-1和Arg-1/IBA-1免疫荧光和RT-PCR， CGA促进小胶质细胞从促炎M1表型向抗炎M2表型极化，抑制神经炎症。BrdU染色显示CGA抑制癫痫诱导的异常神经发生。此外，行为测试显示CGA治疗后认知能力有所改善。最后，western blot分析表明Nrf2/HO-1通路激活，Nrf2敲低逆转了CGA的作用。这些发现表明，CGA通过Nrf2/HO-1途径调节小胶质细胞发挥抗癫痫和神经保护作用。

{"title":"Chlorogenic acid exerts anti-inflammation and neuroprotective effect in pentylenetetrazole-induced epilepsy mouse model by regulating microglia polarization via Nrf2/HO-1 pathway","authors":"Yi Sun , Jiayu Wang , Aoyuan Zhang , Ankang Hu , Lianlian Wu","doi":"10.1016/j.neulet.2025.138493","DOIUrl":"10.1016/j.neulet.2025.138493","url":null,"abstract":"<div><div>Chlorogenic acid (CGA) possesses diverse biological functions, including antioxidant, anti-inflammatory, and anti-apoptotic, both <em>in vitro and in vivo</em>. Recent studies have suggested that CGA also has neuroprotective effects. However, its potential to alleviate seizures and attenuate epilepsy-related neuropathology remains unclear. This study investigated the effects and underlying mechanisms of CGA in a pentylenetetrazole (PTZ)-induced epilepsy mouse model. CGA treatment significantly reduced epileptic seizures. Nissl and NeuN immunofluorescence staining revealed that CGA also significantly reduced neuronal damage. Furthermore, CGA promoted microglial polarization from the pro-inflammatory M1 to the anti-inflammatory M2 phenotype and suppressed neuroinflammation, evidenced by iNOS/IBA-1 and Arg-1/IBA-1 immunofluorescence and RT-PCR. BrdU staining revealed that CGA inhibited epilepsy-induced aberrant neurogenesis. In addition, behavioral tests showed improved cognitive performance following CGA treatment. Finally, western blot analysis indicated the activation of the Nrf2/HO-1 pathway, and Nrf2 knockdown reversed CGA’s effects. These findings suggest that CGA exerts anti-seizure and neuroprotective effects via microglial modulation through the Nrf2/HO-1 pathway.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"873 ","pages":"Article 138493"},"PeriodicalIF":2.0,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145799681","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}

引用次数: 0