Neuropharmacology最新文献_第7页

Taltirelin treatment alleviates PTSD-like symptoms and restores neural oscillations in male mice receiving single prolonged stress 他替雷林治疗可减轻单次长时间应激的雄性小鼠ptsd样症状并恢复神经振荡。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2025-11-30 DOI: 10.1016/j.neuropharm.2025.110791

Keke Ding , Zhengrong Zhang , Jingwen Niu , Mingyue Zhu , Junjie Zhang , Lixia Chen , Shaojie Yang , Jingji Wang , Guoqi Zhu

Thyrotropin-releasing hormone (TRH) plays an important role in the regulation of emotion and cognition. However, whether TRH in the hippocampus participates in the development of post-traumatic stress disorder (PTSD)-like behaviors and the mechanisms involved remain unclear. Transcriptomic analysis was conducted to identify differentially expressed genes (DEGs) in the hippocampus of single prolonged stress (SPS), which is a well-known procedure inducing PTSD-like behaviors in rodents. The expression of pro-TRH and its receptor 1 (TRH-R1) in the hippocampus were assessed using Western blot. Taltirelin (TAL) were employed to examine their regulatory roles in PTSD-like behaviors and neural oscillations. In this study, transcriptomic analysis identified 63 DEGs in the hippocampus of SPS mice compared to controls. The DEGs were mainly involved in hormone activity, and regulated the pathways such as neuroactive ligand-receptor interaction. Western blotting showed that both pro-TRH and its receptor 1 (TRH-R1) were significantly decreased in the hippocampus of the SPS group compared to the control group. TAL treatment remedied PTSD-like behaviors and reversed abnormal hippocampal neural oscillations induced by SPS. Mechanistic investigations revealed that TAL reversed the SPS-induced dysregulation of synaptic proteins in the hippocampus. Together, administration of the TRH analog TAL ameliorates SPS-induced PTSD-like behaviors and restores neural oscillations in mice, probably through mechanisms involving modulation of neuronal synaptic transmission and plasticity.

促甲状腺素释放激素（TRH）在调节情绪和认知方面起着重要作用。然而，海马TRH是否参与创伤后应激障碍（PTSD）样行为的发展及其机制尚不清楚。通过转录组学分析，鉴定了单次延长应激（SPS）诱发鼠ptsd样行为的海马区差异表达基因（DEGs）。Western blot检测海马组织中pro-TRH及其受体1 （TRH-R1）的表达。应用他替雷林（Taltirelin， TAL）研究其对ptsd样行为和神经振荡的调节作用。在本研究中，转录组学分析发现，与对照组相比，SPS小鼠海马中存在63个DEGs。deg主要参与激素活性，并调节神经活性配体-受体相互作用等途径。Western blotting结果显示，与对照组相比，SPS组海马组织中pro-TRH及其受体1 （TRH-R1）均显著降低。TAL治疗可改善ptsd样行为，逆转SPS引起的海马神经异常振荡。机制研究显示，TAL逆转了sps诱导的海马突触蛋白失调。综上所述，TRH模拟物TAL改善了sps诱导的ptsd样行为，并恢复了小鼠的神经振荡，这可能是通过调节神经元突触传递和可塑性的机制实现的。

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引用次数: 0

P2X purinergic receptors are required for correct cortical development in human brain organoids P2X嘌呤能受体是人脑类器官皮层发育的必要条件。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2025-11-28 DOI: 10.1016/j.neuropharm.2025.110784

María Benito-León , Julia Serrano-López , Celia Llorente-Sáez , Marina Arribas-Blázquez , Luis A. Olivos-Oré , Veronica Pravata , Raquel Pérez-Sen , Esmerilda G. Delicado , Micha Drukker , Antonio R. Artalejo , Silvia Cappello , Rosa Gómez-Villafuertes , Felipe Ortega

The human neocortex represents a crucial evolutionary advance, the formation of which requires the tight and precise orchestration of both intracellular and extracellular signals. Structures grown in three-dimensional cultures, specifically human-induced pluripotent stem cells (hIPSCs)-derived cerebral organoids (COs), have been fundamental to study the signals that regulate the formation of the cortex, overcoming the limitations of 2D cultures. Amongst these, purinergic signaling driven by extracellular ATP and other nucleotides may encode crucial intercellular communications that govern central nervous system (CNS) development. The ATP that accumulates in the extracellular milieu can interact with both ionotropic P2X and metabotropic P2Y receptors on cells to exert its modulating effects. Although widely studied in different animal models, little is known about the expression and function of this signaling system in the human cortex. Thus, here we analyzed the expression of P2X receptor subunits comprehensively throughout the entire process of CO development, confirming that P2X receptors are functional in ventricular structures of the human cortex. Specifically, we detected the expression of P2X1, P2X4, and P2X6 in CO, showing distinct distributions in Nestin⁺ radial glial cells and/or DCX⁺ newborn neurons. Significantly, we also show how prolonged pharmacological inhibition of P2X activity affects CO development, resulting in smaller organoids with fewer and less well-organized cortical ventricles. Altogether, our findings point to a relevant role of purinergic signaling during the formation of the human cerebral cortex.

人类新皮层是一个重要的进化过程，它的形成需要细胞内和细胞外信号紧密而精确的协调。在三维培养物中生长的结构，特别是人类诱导的多能干细胞（hIPSCs）衍生的脑类器官（COs），已经成为研究调节皮层形成的信号的基础，克服了二维培养物的局限性。其中，由细胞外ATP和其他核苷酸驱动的嘌呤能信号可能编码控制中枢神经系统（CNS）发育的关键细胞间通讯。在细胞外环境中积累的ATP可以与细胞上的嗜离子性P2X和代谢性P2Y受体相互作用，发挥其调节作用。尽管在不同的动物模型中进行了广泛的研究，但对该信号系统在人类皮层中的表达和功能知之甚少。因此，我们全面分析了CO发育全过程中P2X受体亚基的表达，证实了P2X受体在人皮层脑室结构中的功能。具体来说，我们检测到P2X1、P2X4和P2X6在CO中的表达，在Nestin+放射状胶质细胞和/或DCX+新生神经元中有明显的分布。值得注意的是，我们还展示了P2X活性的长期药理抑制如何影响CO的发育，导致类器官更小，皮质脑室更少，组织更不完善。总之，我们的发现指出了嘌呤能信号在人类大脑皮层形成过程中的相关作用。

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引用次数: 0

Oxytocin may promote hippocampal neurogenesis in ischemic stroke rats via a pathway related to DNMT1-mediated Wnt3a/β-catenin 催产素可能通过dnmt1介导的Wnt3a/β-catenin通路促进缺血性脑卒中大鼠海马神经发生

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2025-11-26 DOI: 10.1016/j.neuropharm.2025.110785

Xiaofan Li , Guang Shi , Wanshu Guo , Kaishu Wen , Yifei Liu , Jiayue Cheng , Meichi Liu , Yuehui Yang , Xinyu Fan

DNA methylation plays a pivotal role in neuroprotection after ischemic stroke. Oxytocin, a neuropeptide renowned for its involvement anti-inflammatory and antioxidant activities, emerges as a promising candidate for the treatment of stroke. Here, we employed a transient middle cerebral artery occlusion (tMCAO) rat model to explore the underlying mechanisms of oxytocin's therapeutic potential. We utilized the Morris Water Maze, novel object recognition, and intruder tests to assess spatial memory, cognitive memory, and social memory abilities in rats, respectively. RNA sequencing and Western blotting were employed to detect alterations in mRNA expression and protein expression levels in the hippocampus. Daily oxytocin administration (0.1 and 1.0 mg/kg, subcutaneous) for seven days significantly reduced infarct volume, restored the expression of 1100 genes, including NQO1 and HO1, and robustly promoted hippocampal neurogenesis in tMCAO rats. These effects translated into enhanced neurological function and improved learning and memory abilities. Remarkably, our findings reveal that oxytocin-induced neurogenesis is intimately linked to the activation of the Wnt3a/β-catenin signaling pathway with Nrf2 as a key downstream target. Furthermore, it is possible that oxytocin, acting through its receptors, inhibited the tMCAO-induced binding of DNMT1 to MeCP2, thereby preventing the increase in DNA methylation at the Wnt3a gene. In summary, our study implies a possible involvement of oxytocin in the activation of the DNMT1-mediated Wnt3a/β-catenin signaling pathway. It may contribute to enhancing hippocampal neurogenesis and ameliorating memory impairments in rats with ischemic stroke. This hints that oxytocin holds great promise as a potential therapeutic agent for promoting post-stroke neurogenesis.

DNA甲基化在缺血性脑卒中后的神经保护中起关键作用。催产素是一种神经肽，因其抗炎和抗氧化活性而闻名，是治疗中风的有希望的候选者。本研究采用短暂性大脑中动脉闭塞（tMCAO）大鼠模型来探讨催产素治疗潜力的潜在机制。利用Morris水迷宫、新物体识别和入侵者测试分别评估大鼠的空间记忆、认知记忆和社会记忆能力。采用RNA测序和Western blotting检测海马组织mRNA和蛋白表达水平的变化。每天给予催产素（0.1和1.0 mg/kg，皮下注射）7天后，可显著减少脑梗死体积，恢复NQO1和HO1等1100个基因的表达，并显著促进tMCAO大鼠海马神经发生。这些效果转化为增强的神经功能和改善的学习和记忆能力。值得注意的是，我们的研究结果表明，催产素诱导的神经发生与Wnt3a/β-catenin信号通路的激活密切相关，Nrf2是一个关键的下游靶点。此外，催产素可能通过其受体作用，抑制了tmcao诱导的DNMT1与MeCP2的结合，从而阻止了Wnt3a基因DNA甲基化的增加。总之，我们的研究提示催产素可能参与dnmt1介导的Wnt3a/β-catenin信号通路的激活。它可能有助于促进缺血性脑卒中大鼠海马神经发生和改善记忆障碍。这暗示催产素作为促进中风后神经发生的潜在治疗剂具有很大的前景。

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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 : 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。

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引用次数: 0

An industrial perspective on ligand bias in GPCR drug discovery GPCR药物发现中配体偏置的工业前景

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2025-11-25 DOI: 10.1016/j.neuropharm.2025.110782

James P. Farmer , James E. Mason , Nicholas D. Holliday , Stephen J. Briddon , Leigh A. Stoddart

Since the initial identification of ligand bias in the late 1990s, the possibility of designing new clinical compounds that preferentially target select signalling pathways has been attractive to drug developers. The potential for maximising efficacy and minimising on-target side-effects at early lead optimisation stages could significantly improve the success rate of discovery programmes. However, the search for truly biased ligands poses additional challenges to the considerable existing difficulties facing any lead compound on its route to clinical licensing. As such, despite their potential advantages, the development of biased ligands has been limited within the wider pharmaceutical industry so far. Here, we give our current perspective on the landscape of biased ligand development and an overview of the wider implications that must be considered when entering a biased ligand discovery programme.

自20世纪90年代末首次发现配体偏性以来，设计优先靶向选定信号通路的新型临床化合物的可能性一直吸引着药物开发人员。在早期先导优化阶段最大化疗效和最小化靶侧副作用的潜力可以显著提高发现方案的成功率。然而，寻找真正偏颇的配体对任何先导化合物在其获得临床许可的道路上面临的相当大的困难提出了额外的挑战。因此，尽管有潜在的优势，偏置配体的发展到目前为止在更广泛的制药工业中受到限制。在这里，我们给出了我们目前对偏配体发展前景的看法，并概述了在进入偏配体发现计划时必须考虑的更广泛的影响。

引用次数: 0

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 : 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。

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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 : 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。

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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 : 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。

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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 : 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。

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引用次数: 0

Increased activity of GSK3β in NAc D2-MSNs contributes to methamphetamine-induced conditioned place prefernence NAc D2-MSNs中GSK3β活性的增加有助于甲基苯丙胺诱导的条件位置偏好。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2025-11-22 DOI: 10.1016/j.neuropharm.2025.110774

Jincen Liu , Yue Feng , Yudian Ye , Haotian Ma , Xilin Shao , Xinyue Yan , Shuguang Wei , Peng Yan , Jianghua Lai

Glycogen synthase kinase 3β (GSK3β) in the nucleus accumbens (NAc) is implicated in drug addiction, but its specific role in methamphetamine (METH)-induced conditioned place preference (CPP), including the critical phase and the involved medium spiny neuron (MSN) subtype, remains unclear. Here, we targeted three critical phases of the CPP paradigm (acquisition, consolidation, expression) by either systemic delivering or localized intra-NAc microinjecting inhibitor of GSK3β to investigate the phase-specific roles of GSK3β in METH-induced CPP. And the effects of GSK3β on D1-/D2-type MSN activity dynamics were delineated through in vivo fiber photometry calcium imaging. Our study found that METH-paired context enhanced GSK3β activity in NAc. Systemic GSK3β suppression with lithium chloride (LiCl) attenuated METH-induced CPP across all phases, whereas intra-NAc suppression with 0.1 ng SB216763 was effective only when administered during acquisition phase. Furthermore, we identified that the METH-paired context-associated elevation in GSK3β activity predominantly localized to NAc D2-MSNs but not NAc D1-MSNs. Selective knockdown of GSK3β expression in NAc D2-MSNs attenuated METH-induced CPP by reactivating D2-MSNs coupled with concurrent suppression of D1-MSN activity. This study reveals a cell-type-specific dysregulation of GSK3β signaling in the context of METH reward processing, highlighting the contrasting roles of D1-and D2-MSNs in addiction-related plasticity.

伏隔核（NAc）中的糖原合成酶激酶3β (GSK3β)与药物成瘾有关，但其在甲基苯丙胺（METH）诱导的条件位置偏好（CPP）中的具体作用，包括关键期和所涉及的中棘神经元（MSN）亚型，目前尚不清楚。在这里，我们通过系统递送或局部nac内微注射GSK3β抑制剂，针对CPP范式的三个关键阶段（获得、巩固和表达）来研究GSK3β在甲基甲醚诱导的CPP中的阶段性作用。通过体内纤维光度法钙显像研究了GSK3β对D1-/ d2型MSN活性动力学的影响。我们的研究发现，meth配对的上下文增强了NAc中GSK3β的活性。用氯化锂（LiCl）系统性抑制GSK3β可在所有阶段减弱甲基醚诱导的CPP，而用0.1 ng SB216763抑制nac仅在获取阶段有效。此外，我们发现甲基配对上下文相关的GSK3β活性升高主要定位于NAc D2-MSNs，而不是NAc D1-MSNs。选择性敲低NAc D2-MSNs中GSK3β的表达，通过重新激活D2-MSNs并同时抑制D1-MSN活性来减弱meth诱导的CPP。本研究揭示了甲基安非他明奖励加工中GSK3β信号的细胞类型特异性失调，突出了D1-和d2 - msn在成瘾相关可塑性中的不同作用。

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