Neuropharmacology最新文献_第8页

Effects of predator odor stress on alcohol-induced conditioned taste aversion and lateral habenula cFos expression in rats 捕食者气味应激对大鼠酒精诱导的条件性味觉厌恶和外侧链cfo表达的影响

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2026-02-15 Epub Date: 2025-11-25 DOI: 10.1016/j.neuropharm.2025.110780

O.R. Brunke , S.M. Bonauto , E.M. Boshak , M.J. Rauch , M.M. Weera

Stress-related disorders and alcohol use disorder (AUD) frequently co-occur, yet the mechanisms linking stress coping styles to alcohol sensitivity remain unclear. Here, we tested whether acute stress exposure alters sensitivity to alcohol's aversive effects, an important factor in regulating drinking, and alcohol-induced neural activation in the lateral habenula (LHb), a brain region implicated in negative valence processing. Male and female rats were exposed to acute predator odor stress and classified as Avoiders or Non-Avoiders based on post-stress avoidance behavior. Alcohol-induced conditioned taste aversion (CTA) and alcohol challenge-evoked cFos expression in the LHb, lateral hypothalamus (LH), and central amygdala (CeA) were quantified. Female Non-Avoiders developed alcohol-induced CTA after a single conditioning session, whereas Avoiders and unstressed Controls did not, suggesting heightened sensitivity to alcohol's aversive properties in this group. No stress-related differences in CTA were observed in males. Alcohol challenge decreased LHb cFos expression in female rats across groups and selectively in male Avoiders, suggesting sex- and avoidance-dependent modulation of LHb activity. Although there were no alcohol or stress group effects on cFos in the LH or CeA, there were significant correlations in cFos expression between LH-LHb and CeA-LH. These findings suggest that stress-induced individual differences in avoidance behavior predict alcohol sensitivity and LHb responsivity in a sex-dependent manner, with implications for understanding how stress-related coping phenotypes influence vulnerability to alcohol misuse.

压力相关障碍和酒精使用障碍（AUD）经常同时发生，但将压力应对方式与酒精敏感性联系起来的机制尚不清楚。在这里，我们测试了急性应激暴露是否会改变对酒精厌恶效应的敏感性，这是调节饮酒的一个重要因素，以及酒精诱导的外侧缰核（LHb）的神经激活，这是一个与负价加工有关的大脑区域。将雄性和雌性大鼠暴露于急性捕食者气味应激下，并根据应激后回避行为将其分为回避型和非回避型。酒精诱导的条件性味觉厌恶（CTA）和酒精挑战诱发的cFos在LHb、外侧下丘脑（LH）和中央杏仁核（CeA）中的表达被量化。非回避组的女性在一次条件反射后出现了酒精诱发的CTA，而回避组和无压力对照组则没有，这表明这一组女性对酒精的厌恶特性更加敏感。在男性中没有观察到与压力相关的CTA差异。酒精刺激降低了各组雌性大鼠的LHb cFos表达，并选择性地降低了雄性回避型大鼠的LHb cFos表达，这表明LHb活性的调节依赖于性别和回避型。虽然酒精或应激组对LH或CeA中的cFos没有影响，但LH- lhb和CeA-LH之间的cFos表达有显著相关性。这些发现表明，压力诱导的回避行为的个体差异以性别依赖的方式预测酒精敏感性和LHb反应性，这对于理解压力相关的应对表型如何影响酒精滥用的易感性具有重要意义。

{"title":"Effects of predator odor stress on alcohol-induced conditioned taste aversion and lateral habenula cFos expression in rats","authors":"O.R. Brunke , S.M. Bonauto , E.M. Boshak , M.J. Rauch , M.M. Weera","doi":"10.1016/j.neuropharm.2025.110780","DOIUrl":"10.1016/j.neuropharm.2025.110780","url":null,"abstract":"<div><div>Stress-related disorders and alcohol use disorder (AUD) frequently co-occur, yet the mechanisms linking stress coping styles to alcohol sensitivity remain unclear. Here, we tested whether acute stress exposure alters sensitivity to alcohol's aversive effects, an important factor in regulating drinking, and alcohol-induced neural activation in the lateral habenula (LHb), a brain region implicated in negative valence processing. Male and female rats were exposed to acute predator odor stress and classified as Avoiders or Non-Avoiders based on post-stress avoidance behavior. Alcohol-induced conditioned taste aversion (CTA) and alcohol challenge-evoked cFos expression in the LHb, lateral hypothalamus (LH), and central amygdala (CeA) were quantified. Female Non-Avoiders developed alcohol-induced CTA after a single conditioning session, whereas Avoiders and unstressed Controls did not, suggesting heightened sensitivity to alcohol's aversive properties in this group. No stress-related differences in CTA were observed in males. Alcohol challenge decreased LHb cFos expression in female rats across groups and selectively in male Avoiders, suggesting sex- and avoidance-dependent modulation of LHb activity. Although there were no alcohol or stress group effects on cFos in the LH or CeA, there were significant correlations in cFos expression between LH-LHb and CeA-LH. These findings suggest that stress-induced individual differences in avoidance behavior predict alcohol sensitivity and LHb responsivity in a sex-dependent manner, with implications for understanding how stress-related coping phenotypes influence vulnerability to alcohol misuse.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"284 ","pages":"Article 110780"},"PeriodicalIF":4.6,"publicationDate":"2026-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145616528","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Inhibition of levodopa-induced abnormal involuntary movements (AIMs) using a selective α7 nicotinic positive allosteric modulator 选择性α7烟碱阳性变构调节剂抑制左旋多巴诱导的异常不自主运动（AIMs）

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2026-02-15 Epub Date: 2025-11-26 DOI: 10.1016/j.neuropharm.2025.110786

Yasaman Malekizadeh , Kiana Hassankhani , Alice E. Kingslake , Lucy E. Annett , Mohammed Shoaib , Mahmoud M. Iravani

Chronic administration of nicotine and nicotinic ligands have been shown to reduce levodopa-induced dyskinesia (LID) in rodents and primates. Due to its unique extra-striatal localisation and biochemical signalling properties, the α7 subtype of nicotinic acetylcholine receptors (nAChRs) may represent an important and unique target for drug development for the treatment of dyskinesia, particularly since positive allosteric modulator (PAM) at the α7 nAChRs subtype may provide an opportunity to reduce dyskinesia without side effects. In this study, we report on the anti-dyskinetic actions of a selective α7 PAM, PNU-120596 and compared its action to nicotine and other α7 nAChRs ligands. Unilaterally 6-OHDA lesioned female rats were primed with levodopa to display abnormal involuntary movements (AIMs) to model levodopa-induced dyskinesia. The effects of the α7 PAM, PNU-120596, an α7 agonist, PHA-543613 or the α7 antagonist, methyllycaconitine (MLA), as well as nicotine, a non-selective nAChR agonist were all examined on AIMs. Low doses of PNU-120596 and nicotine dose-dependently reduced AIMs, but combination of the PAM with nicotine produced only an additive effect which surprisingly, could not be demonstrated with the α7 agonist PHA-543613, while MLA dose-dependently reduced AIMS. The effects of PNU-120596 suggests that α7 PAMs may enhance the effect of basal acetylcholine on α7 receptors in the striatum and may provide a new avenue for the treatment of levodopa-induced dyskinesia. Reduction of AIMs by MLA suggests that the mechanism of AIMs reduction may involve the rapid desensitization of the α7 nAChRs subtype.

长期服用尼古丁和尼古丁配体已被证明可以减少啮齿动物和灵长类动物左旋多巴诱导的运动障碍（LID）。由于其独特的纹状体外定位和生化信号特性，烟碱乙酰胆碱受体(nAChRs) α7亚型可能是治疗运动障碍药物开发的一个重要和独特的靶点，特别是因为α7 nAChRs亚型的正变构调节剂（PAM）可能提供了一个减少运动障碍而没有副作用的机会。在本研究中，我们报道了选择性α7 PAM PNU-120596的抗运动障碍作用，并比较了其对尼古丁和其他α7 nAChRs配体的作用。采用左旋多巴诱导单侧6-OHDA损伤雌性大鼠出现不自主运动异常（AIMs），模拟左旋多巴诱导的运动障碍。研究了α7 PAM、α7受体激动剂PNU-120596、α7受体激动剂PHA-543613、α7受体拮抗剂甲基莱卡乌碱（MLA）和非选择性nAChR受体激动剂尼古丁对AIMs的影响。低剂量PNU-120596和尼古丁剂量依赖性降低AIMs，但PAM与尼古丁联用只产生加性效应，令人惊讶的是，α7激动剂PHA-543613不能证明这一效应，而MLA剂量依赖性降低AIMs。PNU-120596的作用提示α7 PAMs可能增强基底乙酰胆碱对纹状体α7受体的作用，可能为左旋多巴诱导的运动障碍的治疗提供新的途径。MLA对AIMs的还原表明AIMs的还原机制可能与α7 nAChRs亚型的快速脱敏有关。

{"title":"Inhibition of levodopa-induced abnormal involuntary movements (AIMs) using a selective α7 nicotinic positive allosteric modulator","authors":"Yasaman Malekizadeh , Kiana Hassankhani , Alice E. Kingslake , Lucy E. Annett , Mohammed Shoaib , Mahmoud M. Iravani","doi":"10.1016/j.neuropharm.2025.110786","DOIUrl":"10.1016/j.neuropharm.2025.110786","url":null,"abstract":"<div><div>Chronic administration of nicotine and nicotinic ligands have been shown to reduce levodopa-induced dyskinesia (LID) in rodents and primates. Due to its unique extra-striatal localisation and biochemical signalling properties, the α7 subtype of nicotinic acetylcholine receptors (nAChRs) may represent an important and unique target for drug development for the treatment of dyskinesia, particularly since positive allosteric modulator (PAM) at the α7 nAChRs subtype may provide an opportunity to reduce dyskinesia without side effects. In this study, we report on the anti-dyskinetic actions of a selective α7 PAM, PNU-120596 and compared its action to nicotine and other α7 nAChRs ligands. Unilaterally 6-OHDA lesioned female rats were primed with levodopa to display abnormal involuntary movements (AIMs) to model levodopa-induced dyskinesia. The effects of the α7 PAM, PNU-120596, an α7 agonist, PHA-543613 or the α7 antagonist, methyllycaconitine (MLA), as well as nicotine, a non-selective nAChR agonist were all examined on AIMs. Low doses of PNU-120596 and nicotine dose-dependently reduced AIMs, but combination of the PAM with nicotine produced only an additive effect which surprisingly, could not be demonstrated with the α7 agonist PHA-543613, while MLA dose-dependently reduced AIMS. The effects of PNU-120596 suggests that α7 PAMs may enhance the effect of basal acetylcholine on α7 receptors in the striatum and may provide a new avenue for the treatment of levodopa-induced dyskinesia. Reduction of AIMs by MLA suggests that the mechanism of AIMs reduction may involve the rapid desensitization of the α7 nAChRs subtype.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"284 ","pages":"Article 110786"},"PeriodicalIF":4.6,"publicationDate":"2026-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145636696","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Melatonin ameliorates copper accumulation-induced cognitive impairment in Wilson disease via activation of the SIRT3/FOXO3α signaling pathway 褪黑素通过激活SIRT3/FOXO3α信号通路改善Wilson病中铜积累诱导的认知障碍

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2026-02-15 Epub Date: 2025-11-24 DOI: 10.1016/j.neuropharm.2025.110779

Luyao Wang , Limin Wu , Tingting Wang , Yike Yue , Zhenzhen Jiang , Pengyu Jiang , Huan Zhou , Lei He , Zehua Xia , Yumeng Song , Fengying Wang , Xin Xiao , Hui Han

Wilson disease (WD) was identified as a copper (Cu)-overload disorder characterized by disrupted Cu metabolism that caused multi-system damage. Accumulating clinical evidence indicated that cognitive deficits were present in patients with WD, yet the underlying mechanism remained unclear. In this work, clinical observations were first performed on 18 patients with WD associated mild cognitive impairment (WD-MCI). The pineal gland volume was found to be significantly reduced, and serum melatonin levels were markedly decreased. A correlation was observed between the abnormal melatonin secretion resulting from pineal gland atrophy and the decline in cognitive ability. This study further conducted animal experiments to explore its mechanism. Mice were allocated into a normal control group (NC group), the Wilson disease model TX mouse group (WD group), the dimercaptosuccinic acid-treated TX mouse group (DMSA group), and the melatonin-treated TX mouse group (MEL group). Cognitive function, hippocampal histomorphology, and the expression of proteins related to hippocampal oxidative stress, inflammation, autophagy, and apoptosis were assessed. Oxidative stress was evaluated by measuring the levels of malondialdehyde (MDA), glutathione (GSH), glutathione peroxidase (GSH-Px), catalase (CAT), and reactive oxygen species (ROS) in hippocampal tissues. Serum levels of melatonin, tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-18 (IL-18) were detected. Mitochondrial damage was examined via ultrastructural analysis and mitochondrial membrane potential (MMP) monitoring. The results demonstrated that the beneficial effects of melatonin were mediated through the activation of the SIRT3/FOXO3a pathway, suppression of inflammatory factors, and reduction in mitophagy, thereby inhibiting hippocampal neuronal apoptosis and improving cognitive function.

威尔逊病（WD）被认为是一种铜（Cu）超载疾病，其特征是铜代谢紊乱，导致多系统损伤。越来越多的临床证据表明，WD患者存在认知缺陷，但其潜在机制尚不清楚。本研究首先对18例WD相关轻度认知障碍（WD- mci）患者进行临床观察。松果体体积明显减小，血清褪黑素水平明显降低。松果体萎缩引起的褪黑素分泌异常与认知能力下降有相关性。本研究进一步进行动物实验，探讨其作用机制。将小鼠分为正常对照组（NC组）、Wilson病模型TX小鼠组（WD组）、二巯基琥珀酸处理TX小鼠组（DMSA组）和褪黑素处理TX小鼠组（MEL组）。评估认知功能、海马组织形态学以及海马氧化应激、炎症、自噬和凋亡相关蛋白的表达。通过测量海马组织中丙二醛（MDA）、谷胱甘肽（GSH）、谷胱甘肽过氧化物酶（GSH- px）、过氧化氢酶（CAT）和活性氧（ROS）的水平来评估氧化应激。检测血清褪黑激素、肿瘤坏死因子-α (TNF-α)、白细胞介素-1β (IL-1β)、白细胞介素-18 （IL-18）水平。通过超微结构分析和线粒体膜电位（MMP）监测检测线粒体损伤。结果表明，褪黑激素的有益作用是通过激活SIRT3/FOXO3a通路，抑制炎症因子，减少线粒体自噬来介导的，从而抑制海马神经元凋亡，改善认知功能。

{"title":"Melatonin ameliorates copper accumulation-induced cognitive impairment in Wilson disease via activation of the SIRT3/FOXO3α signaling pathway","authors":"Luyao Wang , Limin Wu , Tingting Wang , Yike Yue , Zhenzhen Jiang , Pengyu Jiang , Huan Zhou , Lei He , Zehua Xia , Yumeng Song , Fengying Wang , Xin Xiao , Hui Han","doi":"10.1016/j.neuropharm.2025.110779","DOIUrl":"10.1016/j.neuropharm.2025.110779","url":null,"abstract":"<div><div>Wilson disease (WD) was identified as a copper (Cu)-overload disorder characterized by disrupted Cu metabolism that caused multi-system damage. Accumulating clinical evidence indicated that cognitive deficits were present in patients with WD, yet the underlying mechanism remained unclear. In this work, clinical observations were first performed on 18 patients with WD associated mild cognitive impairment (WD-MCI). The pineal gland volume was found to be significantly reduced, and serum melatonin levels were markedly decreased. A correlation was observed between the abnormal melatonin secretion resulting from pineal gland atrophy and the decline in cognitive ability. This study further conducted animal experiments to explore its mechanism. Mice were allocated into a normal control group (NC group), the Wilson disease model TX mouse group (WD group), the dimercaptosuccinic acid-treated TX mouse group (DMSA group), and the melatonin-treated TX mouse group (MEL group). Cognitive function, hippocampal histomorphology, and the expression of proteins related to hippocampal oxidative stress, inflammation, autophagy, and apoptosis were assessed. Oxidative stress was evaluated by measuring the levels of malondialdehyde (MDA), glutathione (GSH), glutathione peroxidase (GSH-Px), catalase (CAT), and reactive oxygen species (ROS) in hippocampal tissues. Serum levels of melatonin, tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-18 (IL-18) were detected. Mitochondrial damage was examined via ultrastructural analysis and mitochondrial membrane potential (MMP) monitoring. The results demonstrated that the beneficial effects of melatonin were mediated through the activation of the SIRT3/FOXO3a pathway, suppression of inflammatory factors, and reduction in mitophagy, thereby inhibiting hippocampal neuronal apoptosis and improving cognitive function.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"284 ","pages":"Article 110779"},"PeriodicalIF":4.6,"publicationDate":"2026-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145616570","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Microdosing psilocybin and its effect on creativity: Lessons learned from three double-blind placebo controlled longitudinal trials 微剂量裸盖菇素及其对创造力的影响：来自三个双盲安慰剂对照纵向试验的经验教训。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2026-02-15 Epub Date: 2025-11-02 DOI: 10.1016/j.neuropharm.2025.110732

Luisa Prochazkova , Josephine Marschall , Michiel van Elk , Ben D. Rifkin , Neil R. Schon , Donatella Fiacchino , George Fejer , Martin Kuchar , Bernhard Hommel

Background

Taking very small doses of psychedelics (LSD, truffles) over an extended period became prevalent in Western societies for its alleged cognitive benefit, including enhanced creativity. However, in the absence of robust, double-blind-controlled quantitative studies, such claims remain anecdotal.

Methods

Here we present results from 3 double-blind placebo-controlled longitudinal trials (one of which pre-registered) assessing the effects of microdosing psilocybin on convergent and divergent creativity in a well-controlled semi-naturalistic setting. To enhance statistical power and generalizability, data from all trials (N = 171) were pooled in a mega-analysis, resulting in one of the most robust laboratory-based studies on microdosing to date.

Results

We found that active microdosing increased the ratio of original responses (originality/fluency), indicating higher quality of divergent thinking in the active microdosing condition. The unadjusted originality score was significantly more pronounced in the active microdosing condition, but only when relative dosage (dose/weight of participants) was considered. Importantly, these effects survived controlling for dose guess and demographic biases. No effects of active microdosing were found for other divergent-thinking scores or convergent thinking.

Conclusion

The results suggest that the effects of truffle mirodosing are limited to the quality of divergent thinking. Moreover, our findings highlight the importance of controlling for placebo effects and prior psychedelic experience in assessing the impact of microdosing.

背景：长期服用小剂量的致幻剂（LSD，松露）在西方社会变得普遍，因为它据称对认知有好处，包括增强创造力。然而，由于缺乏强有力的双盲对照定量研究，这种说法仍然是道听途说。方法：在这里，我们展示了3个双盲安慰剂对照纵向试验的结果（其中一个是预先注册的），评估了在控制良好的半自然环境下，微剂量裸盖菇素对趋同和发散创造力的影响。为了提高统计能力和普遍性，我们将所有试验（N = 171）的数据汇总到一个大型分析中，得出了迄今为止最可靠的基于实验室的微剂量研究之一。结果：我们发现主动微剂量增加了原创反应的比率（原创性/流畅性），表明在主动微剂量条件下发散思维的质量更高。在主动微剂量条件下，未调整的原创性得分显著更明显，但仅在考虑相对剂量（参与者的剂量/体重）时才如此。重要的是，这些效应在控制剂量猜测和人口统计学偏差后仍然存在。没有发现主动微剂量对其他发散性思维得分或收敛性思维得分的影响。结论：松露剂量对发散性思维的影响是有限的。此外，我们的研究结果强调了在评估微剂量影响时控制安慰剂效应和先前迷幻经历的重要性。

{"title":"Microdosing psilocybin and its effect on creativity: Lessons learned from three double-blind placebo controlled longitudinal trials","authors":"Luisa Prochazkova , Josephine Marschall , Michiel van Elk , Ben D. Rifkin , Neil R. Schon , Donatella Fiacchino , George Fejer , Martin Kuchar , Bernhard Hommel","doi":"10.1016/j.neuropharm.2025.110732","DOIUrl":"10.1016/j.neuropharm.2025.110732","url":null,"abstract":"<div><h3>Background</h3><div>Taking very small doses of psychedelics (LSD, truffles) over an extended period became prevalent in Western societies for its alleged cognitive benefit, including enhanced creativity. However, in the absence of robust, double-blind-controlled quantitative studies, such claims remain anecdotal.</div></div><div><h3>Methods</h3><div>Here we present results from 3 double-blind placebo-controlled longitudinal trials <em>(one</em> of which pre-registered) assessing the effects of microdosing psilocybin on convergent and divergent creativity in a well-controlled semi-naturalistic setting. To enhance statistical power and generalizability, data from all trials (N = 171) were pooled in a mega-analysis, resulting in one of the most robust laboratory-based studies on microdosing to date.</div></div><div><h3>Results</h3><div>We found that active microdosing increased the ratio of original responses (originality/fluency), indicating higher quality of divergent thinking in the active microdosing condition. The unadjusted originality score was significantly more pronounced in the active microdosing condition, but only when relative dosage (dose/weight of participants) was considered. Importantly, these effects survived controlling for dose guess and demographic biases. No effects of active microdosing were found for other divergent-thinking scores or convergent thinking.</div></div><div><h3>Conclusion</h3><div>The results suggest that the effects of truffle mirodosing are limited to the quality of divergent thinking. Moreover, our findings highlight the importance of controlling for placebo effects and prior psychedelic experience in assessing the impact of microdosing.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"284 ","pages":"Article 110732"},"PeriodicalIF":4.6,"publicationDate":"2026-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145445538","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Blockage of the peri-synaptic Schwann cell nicotinic α7 receptor inhibitory drive increases the neuromuscular performance in rats with experimental autoimmune Myasthenia gravis: repurposing dipyridamole usage in myasthenics 阻断突触周围雪旺细胞烟碱α7受体抑制驱动增加实验性自身免疫性重症肌无力大鼠的神经肌肉功能：双嘧达莫在重症肌无力中的应用

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2026-02-15 Epub Date: 2025-11-19 DOI: 10.1016/j.neuropharm.2025.110775

José Bernardo Noronha-Matos , Carlos Sousa-Soares , Beatriz Alves-Oliveira , Liliana Carvalho , Magda Moutinho , Rafael Neiva , Paulo Correia-de-Sá

Acetylcholine spillover from the neuromuscular synapse triggers an inhibitory drive via the activation of nicotinic α7 receptors (α7nAChRs) on perisynaptic Schwann cells (PSCs). This mechanism involves the outflow of adenosine from PSCs via ENT1 transporters and subsequent activation of presynaptic inhibitory A₁ receptors. Reinforcement of this sensing inhibitory pathway by cholinesterase (AChE) inhibitors may partially attenuate their efficacy for Myasthenia gravis treatment. Here, we investigated whether this neuromuscular break is still operative in an experimental autoimmune Myasthenia gravis (EAMG) rat model and if it is prone to pharmacological manipulation. Phrenic nerve-hemidiaphragm preparations were isolated from control and EAMG male Wistar rats. We used fluorescence video-microscopy with FM4-64 to assess nerve-evoked (50 Hz-bursts) transmitter exocytosis. Myographic recordings were used to evaluate muscle fatigue. Transmitter exocytosis was depressed in diaphragms of EAMG rats compared to controls. Direct activation of PSCs α7nAChRs with PNU282987 or pretreatment with AChE inhibitors, like neostigmine and ambenonium, exaggerated the neuromuscular transmission deficits in EAMG animals. The α7nAChR antagonist, methyllycaconitine, reversed the neuromuscular transmission deficits caused by PNU282987, neostigmine and ambenonium. Inhibition of ENT1-mediated adenosine outflow from PSCs with dipyridamole attenuated the paradoxical inhibitory effect of neostigmine on nerve-evoked transmitter exocytosis and, thus, the neuromuscular tetanic fade in EAMG rats. In conclusion, breaking the PSC-mediated α7nAChRs inhibitory drive with methyllycaconitine and dipyridamole may synergistically improve the neuromuscular performance and prevent fatigue in EAMG rats treated with AChE inhibitors. Therefore, we suggest repurposing the old antiplatelet vasodilator, dipyridamole, as a relatively safe add-on therapy for drug-resistant Myasthenia gravis.

神经肌肉突触的乙酰胆碱溢出通过激活突触周围雪旺细胞（PSCs）上的烟碱α7受体（α7nAChRs）触发抑制驱动。该机制涉及腺苷通过ENT1转运体从psc流出，随后激活突触前抑制性A1受体。胆碱酯酶（AChE）抑制剂强化这种感知抑制途径可能部分减弱其治疗重症肌无力的疗效。在这里，我们研究了这种神经肌肉断裂在实验性自身免疫性重症肌无力（EAMG）大鼠模型中是否仍然有效，以及它是否容易受到药物操纵。从对照组和EAMG雄性Wistar大鼠中分离膈神经-膈膜制剂。我们使用FM4-64荧光视频显微镜来评估神经诱发（50赫兹爆发）递质胞外分泌。肌图记录用于评估肌肉疲劳。与对照组相比，EAMG大鼠膈肌递质胞吐减少。PNU282987直接激活PSCs α 7nachr或预处理乙酰胆碱酯酶抑制剂（如新斯的明和安苯铵）可加重EAMG动物的神经肌肉传递缺陷。α7nAChR拮抗剂甲基莱卡乌碱可逆转PNU282987、新斯的明和安苯铵所致的神经肌肉传递缺陷。双嘧达莫抑制ent1介导的PSCs腺苷流出，可减弱新斯的明对神经诱发递质胞吐的矛盾抑制作用，从而减轻EAMG大鼠的神经肌肉破伤风消退。综上所述，甲基莱卡乌碱和双嘧达莫破坏psc介导的α7nAChRs抑制驱动可协同改善乙酰胆碱抑制剂治疗的EAMG大鼠的神经肌肉性能并预防疲劳。因此，我们建议重新利用旧的抗血小板血管扩张剂，双嘧达莫，作为一种相对安全的附加治疗耐药重症肌无力。

{"title":"Blockage of the peri-synaptic Schwann cell nicotinic α7 receptor inhibitory drive increases the neuromuscular performance in rats with experimental autoimmune Myasthenia gravis: repurposing dipyridamole usage in myasthenics","authors":"José Bernardo Noronha-Matos , Carlos Sousa-Soares , Beatriz Alves-Oliveira , Liliana Carvalho , Magda Moutinho , Rafael Neiva , Paulo Correia-de-Sá","doi":"10.1016/j.neuropharm.2025.110775","DOIUrl":"10.1016/j.neuropharm.2025.110775","url":null,"abstract":"<div><div>Acetylcholine spillover from the neuromuscular synapse triggers an inhibitory drive via the activation of nicotinic α7 receptors (α7nAChRs) on perisynaptic Schwann cells (PSCs). This mechanism involves the outflow of adenosine from PSCs via ENT1 transporters and subsequent activation of presynaptic inhibitory A<sub>1</sub> receptors. Reinforcement of this sensing inhibitory pathway by cholinesterase (AChE) inhibitors may partially attenuate their efficacy for <em>Myasthenia gravis</em> treatment. Here, we investigated whether this neuromuscular break is still operative in an experimental autoimmune <em>Myasthenia gravis</em> (EAMG) rat model and if it is prone to pharmacological manipulation. Phrenic nerve-hemidiaphragm preparations were isolated from control and EAMG male Wistar rats. We used fluorescence video-microscopy with FM4-64 to assess nerve-evoked (50 Hz-bursts) transmitter exocytosis. Myographic recordings were used to evaluate muscle fatigue. Transmitter exocytosis was depressed in diaphragms of EAMG rats compared to controls. Direct activation of PSCs α7nAChRs with PNU282987 or pretreatment with AChE inhibitors, like neostigmine and ambenonium, exaggerated the neuromuscular transmission deficits in EAMG animals. The α7nAChR antagonist, methyllycaconitine, reversed the neuromuscular transmission deficits caused by PNU282987, neostigmine and ambenonium. Inhibition of ENT1-mediated adenosine outflow from PSCs with dipyridamole attenuated the paradoxical inhibitory effect of neostigmine on nerve-evoked transmitter exocytosis and, thus, the neuromuscular tetanic fade in EAMG rats. In conclusion, breaking the PSC-mediated α7nAChRs inhibitory drive with methyllycaconitine and dipyridamole may synergistically improve the neuromuscular performance and prevent fatigue in EAMG rats treated with AChE inhibitors. Therefore, we suggest repurposing the old antiplatelet vasodilator, dipyridamole, as a relatively safe add-on therapy for drug-resistant <em>Myasthenia gravis</em>.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"284 ","pages":"Article 110775"},"PeriodicalIF":4.6,"publicationDate":"2026-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145570973","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Multi-kinase-mediated alterations in Tau phosphorylation, synaptic proteins, and choline metabolism in a human neuronal in vitro model exposed to the elastin-derived hexapeptide VGVAPG 暴露于弹性蛋白衍生的六肽VGVAPG的人神经元体外模型中，多激酶介导的Tau磷酸化，突触蛋白和胆碱代谢的改变

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2026-02-15 Epub Date: 2025-11-24 DOI: 10.1016/j.neuropharm.2025.110781

Bartosz Skóra , Tomasz Piechowiak , Konrad A. Szychowski

Elastin, a key component of the extracellular matrix (ECM), undergoes degradation during aging, leading to the release of shorter bioactive fragments - among which the VGVAPG hexapeptide exhibits the highest biological activity. Although associated with aging-related neurodegeneration, the role of VGVAPG in this context has not been thoroughly investigated. Therefore, this study aimed to assess the effects of VGVAPG on Tau phosphorylation, synaptic proteins, choline metabolism, and the involvement of specific kinases in a human neuronal in vitro model, using selective inhibitors (Roscovitine, TDZD-8, SCH772984, SK1). All-trans retinoic acid (RA) and brain-derived neurotrophic factor (BDNF)-differentiated SH-SY5Y cells were employed due to their well-characterized neuronal phenotype and established utility in screening studies. Our results indicate that VGVAPG-induced signaling is mediated via SRC kinase, likely leading to activation of the RAS-RAF-ERK1/2-ELK1 pathway. This cascade results in increased CDK5 protein expression and elevated CIP2A levels, which may, in turn, inhibit PP2A function. Additionally, VGVAPG downregulated the PI3K-AKT pathway through PTEN activation, thereby relieving the inhibition of GSK3β. Consequently, we observed increased phosphorylation of Tau at S396, S404, S202/T205, and T231. Impairment of synaptic vesicle-associated proteins (SYN2, SNAP-25, SYP), along with alterations in ACh levels and AChE activity, appeared to be linked to ERK1/2 signaling, Tau accumulation, and potentially CDK5-dependent mechanisms. Overall, our findings provide novel insights into the possible contribution of the elastin-derived VGVAPG hexapeptide to the pathogenesis of aging-related neurodegeneration. While our model does not definitively confirm an AD-like phenotype, these results support the need for further investigation in more physiologically relevant systems.

弹性蛋白是细胞外基质（extracellular matrix， ECM）的关键成分，在衰老过程中会发生降解，从而释放出较短的生物活性片段，其中VGVAPG六肽具有最高的生物活性。虽然与衰老相关的神经退行性变有关，但VGVAPG在这种情况下的作用尚未得到彻底的研究。因此，本研究旨在通过选择性抑制剂（Roscovitine, TDZD-8, SCH772984, SK1），在体外人神经元模型中评估VGVAPG对Tau磷酸化、突触蛋白、胆碱代谢和特定激酶参与的影响。采用全反式维甲酸（RA）和脑源性神经营养因子（BDNF）分化的SH-SY5Y细胞，是因为它们具有良好的神经元表型特征，并且在筛选研究中具有既定的效用。我们的研究结果表明，vgvapg诱导的信号通路是通过SRC激酶介导的，可能导致RAS-RAF-ERK1/2-ELK1通路的激活。这种级联导致CDK5蛋白表达增加和CIP2A水平升高，这可能反过来抑制PP2A的功能。此外，VGVAPG通过激活PTEN下调PI3K-AKT通路，从而减轻对GSK3β的抑制。因此，我们观察到Tau蛋白在S396、S404、S202/T205和T231位点的磷酸化增加。突触囊泡相关蛋白（SYN2、SNAP-25、SYP）的损伤，以及ACh水平和AChE活性的改变，似乎与ERK1/2信号传导、Tau积累和潜在的cdk5依赖机制有关。总的来说，我们的研究结果为弹性蛋白衍生的VGVAPG六肽在衰老相关神经变性发病机制中的可能贡献提供了新的见解。虽然我们的模型并没有明确证实ad样表型，但这些结果支持了在更多生理相关系统中进一步研究的必要性。

{"title":"Multi-kinase-mediated alterations in Tau phosphorylation, synaptic proteins, and choline metabolism in a human neuronal in vitro model exposed to the elastin-derived hexapeptide VGVAPG","authors":"Bartosz Skóra , Tomasz Piechowiak , Konrad A. Szychowski","doi":"10.1016/j.neuropharm.2025.110781","DOIUrl":"10.1016/j.neuropharm.2025.110781","url":null,"abstract":"<div><div>Elastin, a key component of the extracellular matrix (ECM), undergoes degradation during aging, leading to the release of shorter bioactive fragments - among which the VGVAPG hexapeptide exhibits the highest biological activity. Although associated with aging-related neurodegeneration, the role of VGVAPG in this context has not been thoroughly investigated. Therefore, this study aimed to assess the effects of VGVAPG on Tau phosphorylation, synaptic proteins, choline metabolism, and the involvement of specific kinases in a human neuronal <em>in vitro</em> model, using selective inhibitors (Roscovitine, TDZD-8, SCH772984, SK1). All-trans retinoic acid (RA) and brain-derived neurotrophic factor (BDNF)-differentiated SH-SY5Y cells were employed due to their well-characterized neuronal phenotype and established utility in screening studies. Our results indicate that VGVAPG-induced signaling is mediated <em>via</em> SRC kinase, likely leading to activation of the RAS-RAF-ERK1/2-ELK1 pathway. This cascade results in increased CDK5 protein expression and elevated CIP2A levels, which may, in turn, inhibit PP2A function. Additionally, VGVAPG downregulated the PI3K-AKT pathway through PTEN activation, thereby relieving the inhibition of GSK3β. Consequently, we observed increased phosphorylation of Tau at S396, S404, S202/T205, and T231. Impairment of synaptic vesicle-associated proteins (SYN2, SNAP-25, SYP), along with alterations in ACh levels and AChE activity, appeared to be linked to ERK1/2 signaling, Tau accumulation, and potentially CDK5-dependent mechanisms. Overall, our findings provide novel insights into the possible contribution of the elastin-derived VGVAPG hexapeptide to the pathogenesis of aging-related neurodegeneration. While our model does not definitively confirm an AD-like phenotype, these results support the need for further investigation in more physiologically relevant systems.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"284 ","pages":"Article 110781"},"PeriodicalIF":4.6,"publicationDate":"2026-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145616572","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Purinergic signaling in Stroke and Multiple Sclerosis: Prospects for therapies 嘌呤能信号在中风和多发性硬化中的作用：治疗前景

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2026-02-15 Epub Date: 2025-11-24 DOI: 10.1016/j.neuropharm.2025.110783

Abraham Cisneros-Mejorado , Antònia Colom-Casasnovas , Alberto Pérez-Samartín , Carlos Matute

Stroke and multiple sclerosis involve oxygen and nutrient deprivation in the brain as well as inflammation, all of which lead to the release of glutamate and ATP. These compounds can cause excitotoxicity, contributing to neuronal and glial damage. Purinergic signaling, mediated by ATP and adenosine, regulates neuroinflammatory and neuroprotective mechanisms, playing a pivotal role in CNS injury. Key elements such as pannexin-1 hemichannels, calcium homeostasis modulator-1 (CalHM1), purinergic P2X7 receptors, and downstream intermediaries of ATP release contribute to neurotoxicity and inflammatory processes. Notably, P2X7 and P2X4 receptors are critical targets for reducing neuronal damage caused by microglia-mediated inflammation and repair, respectively. Additionally, the interaction between purinergic signaling and GABA type A (GABA_A) receptors opens new therapeutic possibilities by potentially promoting a balance in neurotransmission modulation and mitigating excitotoxicity. Experimental evidence and recent pharmacological developments, including P2X7 antagonists, P2X4 positive allosteric modulators, P1 agonists, and modulators of GABA_A receptors, offer promising avenues for translating preclinical findings into effective therapies for cerebrovascular diseases. Further clinical investigations are necessary to validate these interventions to attenuate tissue damage and foster repair in multiple sclerosis lesions and post-ischemic penumbra.

中风和多发性硬化症涉及大脑中的氧气和营养剥夺以及炎症，所有这些都会导致谷氨酸和ATP的释放。这些化合物可引起兴奋性毒性，导致神经元和神经胶质损伤。嘌呤能信号通过ATP和腺苷介导，调节神经炎症和神经保护机制，在中枢神经系统损伤中起关键作用。关键元件如pannexin-1半通道、钙稳态调节剂-1 （CalHM1）、嘌呤能P2X7受体和ATP释放的下游介质有助于神经毒性和炎症过程。值得注意的是，P2X7和P2X4受体分别是减少小胶质细胞介导的炎症和修复引起的神经元损伤的关键靶点。此外，嘌呤能信号和GABAA型（GABAA）受体之间的相互作用通过潜在地促进神经传递调节的平衡和减轻兴奋性毒性开辟了新的治疗可能性。实验证据和最近的药理学进展，包括P2X7拮抗剂、P2X4阳性变张力调节剂、P1激动剂和GABAA受体调节剂，为将临床前研究结果转化为有效的脑血管疾病治疗提供了有希望的途径。进一步的临床研究需要验证这些干预措施，以减轻组织损伤，促进修复多发性硬化症病变和缺血后半暗区。

{"title":"Purinergic signaling in Stroke and Multiple Sclerosis: Prospects for therapies","authors":"Abraham Cisneros-Mejorado , Antònia Colom-Casasnovas , Alberto Pérez-Samartín , Carlos Matute","doi":"10.1016/j.neuropharm.2025.110783","DOIUrl":"10.1016/j.neuropharm.2025.110783","url":null,"abstract":"<div><div>Stroke and multiple sclerosis involve oxygen and nutrient deprivation in the brain as well as inflammation, all of which lead to the release of glutamate and ATP. These compounds can cause excitotoxicity, contributing to neuronal and glial damage. Purinergic signaling, mediated by ATP and adenosine, regulates neuroinflammatory and neuroprotective mechanisms, playing a pivotal role in CNS injury. Key elements such as pannexin-1 hemichannels, calcium homeostasis modulator-1 (CalHM1), purinergic P2X7 receptors, and downstream intermediaries of ATP release contribute to neurotoxicity and inflammatory processes. Notably, P2X7 and P2X4 receptors are critical targets for reducing neuronal damage caused by microglia-mediated inflammation and repair, respectively. Additionally, the interaction between purinergic signaling and GABA type A (GABA<sub>A</sub>) receptors opens new therapeutic possibilities by potentially promoting a balance in neurotransmission modulation and mitigating excitotoxicity. Experimental evidence and recent pharmacological developments, including P2X7 antagonists, P2X4 positive allosteric modulators, P1 agonists, and modulators of GABA<sub>A</sub> receptors, offer promising avenues for translating preclinical findings into effective therapies for cerebrovascular diseases. Further clinical investigations are necessary to validate these interventions to attenuate tissue damage and foster repair in multiple sclerosis lesions and post-ischemic penumbra.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"284 ","pages":"Article 110783"},"PeriodicalIF":4.6,"publicationDate":"2026-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145616571","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Glutamatergic neurons in the ventral hippocampal CA1 participate in the regulation of comorbidity of chronic pain and depression 海马腹侧CA1区谷氨酸能神经元参与慢性疼痛和抑郁共病的调节

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2026-02-01 Epub Date: 2025-10-31 DOI: 10.1016/j.neuropharm.2025.110755

Wei Meng , Yihang Lv , Zihan Ren , Weidong Zang , Songxue Su , Jing Cao , Cui Li

Background

Chronic pain and depression are highly comorbid conditions that pose a significant clinical challenge, yet the underlying neural circuitry mechanisms are poorly understood. The ventral hippocampal CA1 (vCA1) has been implicated in both pain and affective processing, but its specific role in this comorbidity remains unclear.

Methods

We combined immunofluorescence, whole-cell patch-clamp recordings, and pathway-specific chemogenetic and optogenetic manipulations to investigate the role of vCA1 glutamatergic neurons and their downstream targets in a chronic constriction injury (CCI) mouse model. Behavioral assays were used to assess nociceptive, depressive, and anxiety-related phenotypes.

Results

We observed reduced excitability of vCA1 and ventral dentate gyrus (vDG) neurons in the comorbidity model. Inhibition or ablation of vCA1 glutamatergic neurons in naïve mice induced both nociceptive hypersensitivity and depression-like behaviors, whereas suppression of vDG neurons elicited depression-like behaviors without altering nociceptive sensitivity. Conversely, optogenetic and chemogenetic activation of vCA1 glutamatergic neurons alleviated CCI-induced nociceptive hypersensitivity and depression behaviors. A functional divergence was identified in the downstream pathways of vCA1: projections to the nucleus accumbens (NAc) and thalamic reticular nucleus (TRN) selectively modulated nociceptive hypersensitivity, whereas projections to the lateral septum (LS) specifically regulated depression-like behaviors.

Conclusion

These findings establish vCA1 glutamatergic neurons as a critical hub in pain-depression comorbidity, and delineate distinct pathways that differentially govern nociceptive and depressive behaviors.

背景：慢性疼痛和抑郁是高度合并症，对临床构成重大挑战，但其潜在的神经回路机制尚不清楚。腹侧海马CA1 （vCA1）与疼痛和情感处理有关，但其在这种共病中的具体作用尚不清楚。方法：结合免疫荧光、全细胞膜片钳记录、途径特异性化学发生和光遗传学操作，研究vCA1谷氨酸能神经元及其下游靶点在慢性收缩性损伤（CCI）小鼠模型中的作用。行为分析用于评估伤害性、抑郁和焦虑相关表型。结果：在共病模型中，我们观察到vCA1和腹状齿状回（vDG）神经元的兴奋性降低。抑制或消蚀naïve小鼠的vCA1谷氨酸能神经元可诱导伤害性超敏反应和抑郁样行为，而抑制vDG神经元可诱导抑郁样行为，但不改变伤害性敏感性。相反，vCA1谷氨酸能神经元的光遗传学和化学遗传学激活可减轻cci诱导的伤害性超敏反应和抑郁行为。在vCA1的下游通路中发现了功能差异：对伏隔核（NAc）和丘脑网状核（TRN）的投射选择性地调节伤害性超敏反应，而对外侧隔（LS）的投射特异性地调节抑郁样行为。结论：这些发现证实了vCA1谷氨酸能神经元是疼痛-抑郁共病的关键中枢，并描绘了不同的通路，不同地控制伤害性和抑郁行为。

{"title":"Glutamatergic neurons in the ventral hippocampal CA1 participate in the regulation of comorbidity of chronic pain and depression","authors":"Wei Meng , Yihang Lv , Zihan Ren , Weidong Zang , Songxue Su , Jing Cao , Cui Li","doi":"10.1016/j.neuropharm.2025.110755","DOIUrl":"10.1016/j.neuropharm.2025.110755","url":null,"abstract":"<div><h3>Background</h3><div>Chronic pain and depression are highly comorbid conditions that pose a significant clinical challenge, yet the underlying neural circuitry mechanisms are poorly understood. The ventral hippocampal CA1 (vCA1) has been implicated in both pain and affective processing, but its specific role in this comorbidity remains unclear.</div></div><div><h3>Methods</h3><div>We combined immunofluorescence, whole-cell patch-clamp recordings, and pathway-specific chemogenetic and optogenetic manipulations to investigate the role of vCA1 glutamatergic neurons and their downstream targets in a chronic constriction injury (CCI) mouse model. Behavioral assays were used to assess nociceptive, depressive, and anxiety-related phenotypes.</div></div><div><h3>Results</h3><div>We observed reduced excitability of vCA1 and ventral dentate gyrus (vDG) neurons in the comorbidity model. Inhibition or ablation of vCA1 glutamatergic neurons in naïve mice induced both nociceptive hypersensitivity and depression-like behaviors, whereas suppression of vDG neurons elicited depression-like behaviors without altering nociceptive sensitivity. Conversely, optogenetic and chemogenetic activation of vCA1 glutamatergic neurons alleviated CCI-induced nociceptive hypersensitivity and depression behaviors. A functional divergence was identified in the downstream pathways of vCA1: projections to the nucleus accumbens (NAc) and thalamic reticular nucleus (TRN) selectively modulated nociceptive hypersensitivity, whereas projections to the lateral septum (LS) specifically regulated depression-like behaviors.</div></div><div><h3>Conclusion</h3><div>These findings establish vCA1 glutamatergic neurons as a critical hub in pain-depression comorbidity, and delineate distinct pathways that differentially govern nociceptive and depressive behaviors.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"283 ","pages":"Article 110755"},"PeriodicalIF":4.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145431879","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Iguratimod attenuates diabetic cognitive impairment via suppressing B cell activation and CD8+ T cell cytotoxicity Iguratimod通过抑制B细胞活化和CD8+ T细胞毒性减轻糖尿病认知障碍。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2026-02-01 Epub Date: 2025-11-05 DOI: 10.1016/j.neuropharm.2025.110761

Qingsheng Yin , Runtao Su , Xuan Nie , Ping Liu , Jie Bu , Haiting Luo , Ruiting Liu , Hong Guo , Li Liu , Bin Wang , Jianchun Yu , Pengwei Zhuang , Yanjun Zhang

Diabetes-induced cognitive impairment (DCI) is a common complication in diabetic patients with an unclear pathogenesis, and there are currently no approved therapeutic drugs available. Iguratimod (IGU) is a novel small molecule immunosuppressant used to treat rheumatoid arthritis. Given the emerging evidence that immune responses mediate cognitive impairment, our study is the first to explore the effects of IGU on cognitive function in DCI mice and the underlying mechanisms. After the establishment of the DCI mouse model, IGU was given by gavage once a day for 8 weeks. Our results show that IGU significantly improves cognitive function in DCI mice and has neuroprotective effects. Further analysis showed that IGU maintained cellular homeostasis in the brain of DCI mice, in particular, it reduced the proportion of B and CD8 T lymphocytes, and significantly inhibited the activation of infiltrating B cells and the expression of cytotoxic factors in CD8 T cells in the brain of DCI mice. In addition, IGU also significantly inhibited B cell activation and CD8 T cell cytotoxicity in the peripheral blood of mice. In our clinical cohort, peripheral Siglec-G⁺ B cells were increased in DCI and showed a non-significant but negative association with cognitive function, in line with the concept that immune activation underlies cognitive deficits. Overall, IGU effectively ameliorates the cognitive function of DCI mice by inhibiting B cell activation and CD8 T cell cytotoxicity, which may be a potential alternative drug for the treatment of DCI.

糖尿病性认知障碍（DCI）是糖尿病患者常见的并发症，发病机制尚不清楚，目前尚无批准的治疗药物。Iguratimod （IGU）是一种用于治疗类风湿性关节炎的新型小分子免疫抑制剂。鉴于免疫反应介导认知障碍的新证据，我们的研究首次探讨了IGU对DCI小鼠认知功能的影响及其潜在机制。DCI小鼠模型建立后，IGU以灌胃方式给予，每天1次，连续8周。我们的研究结果表明，IGU显著改善DCI小鼠的认知功能，并具有神经保护作用。进一步分析表明，IGU维持了DCI小鼠脑内细胞稳态，特别是降低了B淋巴细胞和CD8 T淋巴细胞的比例，显著抑制了DCI小鼠脑内浸润性B细胞的活化和CD8 T细胞中细胞毒因子的表达。此外，IGU还能显著抑制小鼠外周血B细胞活化和CD8 T细胞毒性。在我们的临床队列中，外周Siglec-G+ B细胞在DCI中增加，并与认知功能表现出不显著的负相关，这与免疫激活是认知缺陷的基础这一概念一致。综上所述，IGU通过抑制B细胞活化和CD8 T细胞毒性，有效改善DCI小鼠的认知功能，可能是治疗DCI的潜在替代药物。

{"title":"Iguratimod attenuates diabetic cognitive impairment via suppressing B cell activation and CD8+ T cell cytotoxicity","authors":"Qingsheng Yin , Runtao Su , Xuan Nie , Ping Liu , Jie Bu , Haiting Luo , Ruiting Liu , Hong Guo , Li Liu , Bin Wang , Jianchun Yu , Pengwei Zhuang , Yanjun Zhang","doi":"10.1016/j.neuropharm.2025.110761","DOIUrl":"10.1016/j.neuropharm.2025.110761","url":null,"abstract":"<div><div>Diabetes-induced cognitive impairment (DCI) is a common complication in diabetic patients with an unclear pathogenesis, and there are currently no approved therapeutic drugs available. Iguratimod (IGU) is a novel small molecule immunosuppressant used to treat rheumatoid arthritis. Given the emerging evidence that immune responses mediate cognitive impairment, our study is the first to explore the effects of IGU on cognitive function in DCI mice and the underlying mechanisms. After the establishment of the DCI mouse model, IGU was given by gavage once a day for 8 weeks. Our results show that IGU significantly improves cognitive function in DCI mice and has neuroprotective effects. Further analysis showed that IGU maintained cellular homeostasis in the brain of DCI mice, in particular, it reduced the proportion of B and CD8 T lymphocytes, and significantly inhibited the activation of infiltrating B cells and the expression of cytotoxic factors in CD8 T cells in the brain of DCI mice. In addition, IGU also significantly inhibited B cell activation and CD8 T cell cytotoxicity in the peripheral blood of mice. In our clinical cohort, peripheral Siglec-G<sup>+</sup> B cells were increased in DCI and showed a non-significant but negative association with cognitive function, in line with the concept that immune activation underlies cognitive deficits. Overall, IGU effectively ameliorates the cognitive function of DCI mice by inhibiting B cell activation and CD8 T cell cytotoxicity, which may be a potential alternative drug for the treatment of DCI.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"283 ","pages":"Article 110761"},"PeriodicalIF":4.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145471369","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The association of the Wnt/β-catenin signaling pathway with Alzheimer's disease Wnt/β-catenin信号通路与阿尔茨海默病的关系

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2026-02-01 Epub Date: 2025-11-06 DOI: 10.1016/j.neuropharm.2025.110754

JiaYing Ma, Yi Liu, Desheng Lu, Qi Sun

With the global rise in population aging, the incidence of Alzheimer's disease (AD) continues to increase, posing a substantial burden on individuals, families, and healthcare systems. However, at present, the drugs approved by FDA for treating AD can only relieve symptoms, but cannot cure or reverse the disease. Therefore, it is urgent to study the signal pathways related to AD and the drugs to improve the pathological changes of AD.The Wnt/β-catenin signaling pathway, known for its functional diversity, evolutionary conservation, and relevance to multiple diseases, holds a pivotal role in both basic research and therapeutic development. This pathway is essential for regulating critical biological processes, including embryonic development, tissue homeostasis, cell proliferation, differentiation, and apoptosis.In AD, downregulation of the Wnt/β-catenin signaling pathway has been implicated in key pathological features, such as tau hyperphosphorylation, amyloid-β (Aβ) accumulation, neuronal degeneration, synaptic loss, cognitive impairment, oxidative stress, mitochondrial dysfunction, blood-brain barrier disruption, and neuroinflammation. This review comprehensively discusses the deregulation of the Wnt/β-catenin pathway in AD and how it contributes to disease progression. Furthermore, we highlighted emerging pharmacological activators of this pathway exhibiting potential as therapeutic agents for AD.

随着全球人口老龄化的加剧，阿尔茨海默病（AD）的发病率持续增加，给个人、家庭和医疗保健系统带来了沉重的负担。然而，目前FDA批准的治疗AD的药物只能缓解症状，不能治愈或逆转疾病。因此，迫切需要研究与AD相关的信号通路以及改善AD病理改变的药物。Wnt/β-catenin信号通路以其功能多样性、进化保守性和与多种疾病的相关性而闻名，在基础研究和治疗开发中都发挥着关键作用。这一途径对于调节关键的生物过程至关重要，包括胚胎发育、组织稳态、细胞增殖、分化和凋亡。在AD中，Wnt/β-catenin信号通路的下调与关键病理特征有关，如tau过度磷酸化、淀粉样蛋白-β (Aβ)积累、神经元变性、突触丧失、认知障碍、氧化应激、线粒体功能障碍、血脑屏障破坏和神经炎症。这篇综述全面讨论了Wnt/β-catenin通路在AD中的失调及其如何促进疾病进展。此外，我们强调了这一途径的新兴药理激活剂，显示出作为阿尔茨海默病治疗剂的潜力。

{"title":"The association of the Wnt/β-catenin signaling pathway with Alzheimer's disease","authors":"JiaYing Ma, Yi Liu, Desheng Lu, Qi Sun","doi":"10.1016/j.neuropharm.2025.110754","DOIUrl":"10.1016/j.neuropharm.2025.110754","url":null,"abstract":"<div><div>With the global rise in population aging, the incidence of Alzheimer's disease (AD) continues to increase, posing a substantial burden on individuals, families, and healthcare systems. However, at present, the drugs approved by FDA for treating AD can only relieve symptoms, but cannot cure or reverse the disease. Therefore, it is urgent to study the signal pathways related to AD and the drugs to improve the pathological changes of AD.The Wnt/β-catenin signaling pathway, known for its functional diversity, evolutionary conservation, and relevance to multiple diseases, holds a pivotal role in both basic research and therapeutic development. This pathway is essential for regulating critical biological processes, including embryonic development, tissue homeostasis, cell proliferation, differentiation, and apoptosis.In AD, downregulation of the Wnt/β-catenin signaling pathway has been implicated in key pathological features, such as tau hyperphosphorylation, amyloid-β (Aβ) accumulation, neuronal degeneration, synaptic loss, cognitive impairment, oxidative stress, mitochondrial dysfunction, blood-brain barrier disruption, and neuroinflammation. This review comprehensively discusses the deregulation of the Wnt/β-catenin pathway in AD and how it contributes to disease progression. Furthermore, we highlighted emerging pharmacological activators of this pathway exhibiting potential as therapeutic agents for AD.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"283 ","pages":"Article 110754"},"PeriodicalIF":4.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145477076","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0