Neuropharmacology最新文献_第10页

Gut microbiota-mediated amino acid reprogramming in ketamine-induced neurotoxicity: A novel microbiota-amino acid-mitochondrial axis associated with cognitive deficits 氯胺酮诱导的神经毒性中肠道菌群介导的氨基酸重编程：一种与认知缺陷相关的新型菌群-氨基酸-线粒体轴。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2026-02-01 Epub Date: 2025-10-27 DOI: 10.1016/j.neuropharm.2025.110748

Ying Wei , Xiaojing Song , Zhiwei Jia , Xiang Liu , Xiaoqin Chen , Xinyi Zhan , Xue Mei , Linchuan Liao

Ketamine, a noncompetitive N-methyl-D-aspartate receptor antagonist, is associated with chronic abuse leading to schizophrenia-like cognitive deficits. The gut-brain axis may play a role in mediating substance-induced neurotoxicity; however, its involvement in ketamine-induced cognitive impairment remains poorly understood. Here, chronic ketamine exposure was administered intraperitoneally to C57BL/6N mice to examine its effects on gut microbiota homeostasis and associated amino acid metabolism. Cognitive deficits were evaluated using the Y-maze and novel object recognition (NOR) tests. Hippocampal ultrastructure was assessed by transmission electron microscopy (TEM). Multi-omics integration included 16S rRNA sequencing, untargeted and targeted plasma metabolomics, and Spearman correlation analysis. The results showed that ketamine-exposed mice exhibited significant cognitive impairments, including impaired spontaneous alternation in the Y-maze (P < 0.05) and a reduced discrimination index in the NOR test (P < 0.01). TEM analysis revealed hippocampal mitochondrial damage, accompanied by chromatin condensation. Gut microbiota analysis indicated dysbiosis, with a notable increase in Lachnospiraceae, Bacteroidaceae, Helicobacteraceae, and Rikenellaceae and a decrease in Verrucomicrobiaceae and Prevotellaceae at the family level. Plasma amino acid levels were also disrupted, with a significant decrease in L-glutamine, L-lysine, L-threonine and an increase in L-cysteic acid. Furthermore, strong correlations were observed between the abundance of Bacteroides, branched-chain amino acids (BCAAs), and cognitive scores (|ρ| > 0.6, P < 0.05). This study identifies the microbiota-amino acid-mitochondrial axis as the underlying mechanism driving ketamine-induced neurotoxicity. It highlights the correlation between gut microbiota-associated amino acid reprogramming and this process, offering potential targets for microbiome-based interventions to combat substance-related cognitive impairments.

氯胺酮是一种非竞争性n -甲基- d -天冬氨酸受体拮抗剂，与长期滥用导致精神分裂症样认知缺陷有关。肠脑轴可能在介导物质诱导的神经毒性中起作用；然而，它在氯胺酮引起的认知障碍中的作用仍然知之甚少。本研究对C57BL/6N小鼠进行慢性氯胺酮腹腔注射，以研究其对肠道微生物群稳态和相关氨基酸代谢的影响。使用y形迷宫和新物体识别（NOR）测试评估认知缺陷。透射电镜观察海马超微结构。多组学整合包括16S rRNA测序、非靶向和靶向血浆代谢组学以及Spearman相关分析。结果表明，氯胺酮暴露小鼠表现出明显的认知障碍，包括y形迷宫自发交替功能受损（P< 0.05）和NOR测试中辨别指数降低（P< 0.01）。透射电镜分析显示海马线粒体损伤，并伴有染色质凝聚。肠道菌群分析显示菌群失调，在科水平上，毛螺科、拟杆菌科、幽门杆菌科和里氏杆菌科显著增加，Verrucomicrobiaceae和Prevotellaceae显著减少。血浆氨基酸水平也被打乱，l -谷氨酰胺、l -赖氨酸、l -苏氨酸显著降低，l -半胱氨酸升高。此外，拟杆菌、支链氨基酸（BCAAs）丰度与认知评分之间存在强相关性（|ρ| > 0.6， P< 0.05）。本研究确定了微生物-氨基酸-线粒体轴作为驱动氯胺酮诱导的神经毒性的潜在机制。它强调了肠道微生物群相关氨基酸重编程与这一过程之间的相关性，为基于微生物群的干预措施提供了潜在的目标，以对抗物质相关的认知障碍。

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引用次数: 0

TREK-1 channel blockade mediates the antidepressant-like effects of hydroxynorketamine TREK-1通道阻断介导羟诺氯胺酮抗抑郁样作用。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2026-02-01 Epub Date: 2025-10-28 DOI: 10.1016/j.neuropharm.2025.110751

Yingcai Song , Yujie Song , Weijia Du , Xinyan Yu , Yujie Li , Liuliu Chang , Xueying Huang , Binglu Ye , Tianyu Li , Yang Li , Bing Zhang , Zhendong Xu , Zhiqiang Liu

The ketamine metabolite (2R,6R)-hydroxynorketamine [(2R,6R)-HNK] exhibits rapid antidepressant effects without the psychotomimetic or addictive side effects associated with ketamine, making it a promising therapeutic candidate. However, the precise molecular targets and mechanisms underlying its antidepressant actions remain controversial. In this study, we identified TREK-1, a two-pore domain potassium channel, as a key target of (2R,6R)-HNK. Electrophysiological experiments revealed that (2R,6R)-HNK selectively inhibits TREK-1 currents, with an IC₅₀ close to its effective antidepressant concentration. TREK-1 is widely expressed in the brain, and its activity in the mPFC has been implicated in regulating depressive-like behaviors. Early-life stress increases TREK-1 expression in the mPFC, impairing synaptic plasticity and neural circuit formation, which contributes to emotional disorders. Further investigations demonstrated that (2R,6R)-HNK enhances the firing frequency of mPFC pyramidal neurons and upregulates synaptic plasticity-related proteins, including CREB and PSD95. Crucially, the antidepressant effects of (2R,6R)-HNK were abolished in mice with pyramidal neuron-specific knockdown of TREK-1 in the mPFC, confirming the essential role of TREK-1 inhibition in mediating (2R,6R)-HNK's actions. Our findings establish TREK-1 as a critical target for (2R,6R)-HNK's rapid antidepressant effects, providing new insights into the mechanisms of depression treatment and the development of novel therapeutics.

氯胺酮代谢物(2R,6R)-羟诺氯胺酮[(2R,6R)-HNK]表现出快速的抗抑郁作用，而没有氯胺酮相关的拟精神或成瘾性副作用，使其成为一种有前景的治疗候选药物。然而，其抗抑郁作用的精确分子靶点和机制仍然存在争议。在本研究中，我们发现TREK-1是一个双孔结构域钾通道，是(2R,6R)-HNK的关键靶点。电生理实验显示(2R,6R)-HNK选择性抑制TREK-1电流，IC50接近其有效抗抑郁浓度。TREK-1在大脑中广泛表达，其在mPFC中的活动与调节抑郁样行为有关。早期生活压力会增加mPFC中TREK-1的表达，损害突触可塑性和神经回路的形成，从而导致情绪障碍。进一步研究表明，(2R,6R)-HNK增强mPFC锥体神经元的放电频率，上调突触可塑性相关蛋白，包括CREB和PSD95。至关重要的是，在mPFC中锥体神经元特异性敲除TREK-1的小鼠中，(2R,6R)-HNK的抗抑郁作用被消除，证实了TREK-1抑制在介导(2R,6R)-HNK作用中的重要作用。我们的研究结果确定TREK-1是(2R,6R)-HNK快速抗抑郁作用的关键靶点，为抑郁症治疗机制和新疗法的开发提供了新的见解。

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引用次数: 0

Epigenetic control of stress and environmental enrichment interplay on anxiety and prefrontal cortex BDNF expression 应激和环境富集的表观遗传控制对焦虑和前额叶皮层BDNF表达的影响。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2026-02-01 Epub Date: 2025-10-23 DOI: 10.1016/j.neuropharm.2025.110733

Nívea Karla de Gusmão Taveiros Silva , Gabriel Araújo Costa , Marina Gomes de Almeida , Priscila Marianno , Ariádne Elisa Belo da Silva , Veridiana Petenati Da Rovare , Mariana Beu Rae , Rosangela Aparecida dos Santos Eichler , Priti Chivers , Alexis Bailey , Rosana Camarini

Despite widespread recognition of the detrimental effects of chronic stress in developing stress-related psychopathologies, the interplay between environmental enrichment (EE) and chronic stress, along with their underlying mechanisms, remains poorly understood. Chronic stress disrupts brain-derived neurotrophic factor (BDNF) signalling pathways in the prefrontal cortex (PFC) and promotes epigenetic modifications that contribute to the pathogenesis of depression and anxiety disorders. Environmental enrichment (EE) has also been investigated for its effects on BDNF expression and epigenetic regulation, with evidence suggesting a possible role in modulating vulnerability to stress-related psychopathologies. Here, we investigated the impact of subthreshold chronic unpredictable mild stress (CMS) on mice pre-housed in EE conditions, examining anxiety-like behaviour, corticosterone levels, PFC Bdnf expression, BDNF protein levels, and DNA methylation profiles. We also explored whether the effects of CMS on EE-housed mice are mediated by DNA methylation mechanisms. CMS precipitated anxiety-like behaviour in EE-housed mice, but not in non-enriched controls. This phenotype was attenuated by systemic administration of the DNA methylation inhibitor 5-aza-2′-deoxycytidine, suggesting an epigenetic mechanism. While prolonged EE alone elevated plasma corticosterone levels, this was suppressed when EE was combined with CMS. EE followed by CMS downregulated Bdnf exons I, II, IV, and IX mRNA expression in the PFC. No changes in DNA methylation profile were detected at exon IX. While no effect was detected on BDNF protein levels, 5-azaC reduced BDNF specifically in EE-housed mice. These findings shed light on the emotional behavioural consequences and the molecular and epigenetic mechanisms underlying the interplay between CMS and EE.

尽管人们普遍认识到慢性应激在发展压力相关精神病理学方面的有害影响，但环境富集（EE）与慢性应激之间的相互作用及其潜在机制仍然知之甚少。慢性应激破坏前额皮质（PFC）中的脑源性神经营养因子（BDNF）信号通路，并促进导致抑郁和焦虑症发病机制的表观遗传修饰。环境富集（EE）也被研究了其对BDNF表达和表观遗传调控的影响，有证据表明它可能在调节应激相关精神病理的易感性中起作用。在这里，我们研究了阈下慢性不可预测轻度应激（CMS）对预先饲养在EE条件下的小鼠的影响，检查了焦虑样行为、皮质酮水平、PFC Bdnf表达、Bdnf蛋白水平和DNA甲基化谱。我们还探讨了CMS对ee小鼠的影响是否通过DNA甲基化机制介导。CMS在ee饲养的小鼠中诱发了焦虑样行为，但在未富集的对照组中没有。这种表型可以通过全身给予DNA甲基化抑制剂5-aza-2'-脱氧胞苷而减弱，这提示了一种表观遗传机制。虽然长时间EE单独升高血浆皮质酮水平，但当EE联合CMS时，这一水平被抑制。EE和CMS均下调pfc中Bdnf外显子I、II、IV和IX mRNA的表达，但外显子IX处DNA甲基化谱未见变化。虽然对BDNF蛋白水平没有影响，但5-azaC在ee饲养的小鼠中特异性地降低了BDNF。这些发现揭示了情绪行为后果以及CMS和EE之间相互作用的分子和表观遗传机制。

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引用次数: 0

α-Asaronol, a low-toxicity α-asarone metabolite, suppresses seizures in zebrafish Dravet syndrome via positive modulation of GABAA receptors and LDH inhibition α-细辛醇是一种低毒性α-细辛酮代谢物，通过正调节GABAA受体和LDH抑制斑马鱼Dravet综合征的癫痫发作。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2026-02-01 Epub Date: 2025-10-24 DOI: 10.1016/j.neuropharm.2025.110727

Ying Sun , Yajun Bai , Xirui He , Jing Xie , Huijun Kang , Zhiling Zhu , Yujun Bai , Xiaotong Cui , Pu Jia , Ye Zhao , Shixiang Wang , Kechun Liu , Meng Jin , Guangzhi Shan , Tai-Ping Fan , Xiaohui Zheng

Dravet syndrome (DS), a rare and severe developmental encephalopathy in children classified as a refractory epilepsy syndrome, presents significant challenges in therapeutic development with urgent unmet needs. α-Asaronol (α-AOL), a terminal hydroxylated metabolite of α-asarone (α-A) and an active constituent of Acorus plants, has demonstrated potent anti-seizure effects in mouse and zebrafish models based on preliminary studies. However, its therapeutic potential for DS remains unexplored. Given the pediatric focus of this research, parallel investigation of its primary metabolites (α-OA and α-TMCA) is imperative to ensure safety. This study aims to (1) validate the general anti-seizure activities of α-OA and α-TMCA, (2) evaluate their comparative efficacy against DS alongside α-AOL, and (3) elucidate underlying mechanisms. We systematically assessed anti-seizure activities using pentylenetetrazol-induced seizure models in zebrafish and mice, followed by rigorous evaluation in a zebrafish DS model (scn1Lab^−/− mutants). Mechanistic pathways were investigated through GABA_A receptor modulation, energy metabolism regulation, and molecular docking analyses. Results revealed dose-dependent anti-seizure efficacy across all models, with potency ranking α-AOL > α-A > α-OA ≫ α-TMCA. Notably, α-AOL exhibited superior efficacy in scn1Lab^−/− mutants compared to α-asarone and reference drugs stiripentol and cannabidiol. Mechanistic studies identified dual pathways for α-AOL: potentiation of GABA_A receptor currents (EC₅₀ = 34.0 μmol/L) and inhibition of neuronal lactate dehydrogenase activity. These findings establish terminal oxidation of α-asarone as a critical metabolic pathway enhancing anti-seizure efficacy while reducing toxicity, positioning α-AOL as a promising lead compound for DS therapeutics.

Dravet综合征（DS）是一种罕见和严重的儿童发育性脑病，被归类为难治性癫痫综合征，在治疗开发方面面临重大挑战，迫切需要满足。α-细辛醇（α-AOL）是α-细辛酮（α-A）的末端羟基化代谢物，是菖柏属植物的活性成分，在小鼠和斑马鱼模型中显示出强大的抗癫痫作用。然而，其治疗退行性椎体滑移的潜力仍未被探索。鉴于本研究的儿科重点，平行研究其主要代谢物（α-OA和α-TMCA）是必要的，以确保安全性。本研究旨在(1)验证α-OA和α-TMCA的一般抗癫痫活性，(2)评估它们与α-AOL对DS的比较疗效，(3)阐明其作用机制。我们在斑马鱼和小鼠中使用戊四唑诱导的癫痫模型系统地评估了抗癫痫活性，随后在斑马鱼DS模型（scn1Lab-/- mutants）中进行了严格的评估。通过GABAA受体调节、能量代谢调节和分子对接分析，探讨其机制途径。结果显示，所有模型的抗癫痫效果均呈剂量依赖性，效价依次为α-AOL >α-A >α-OA >>α-TMCA。值得注意的是，α-AOL对scn1Lab-/-突变体的疗效优于α-asarone和参比药物stiripentool和大麻二酚。机制研究发现α-AOL的双重通路：增强GABAA受体电流（EC50 = 34.0 μmol/L）和抑制神经元乳酸脱氢酶活性。这些发现表明α-asarone的末端氧化是一种关键的代谢途径，可以增强抗癫痫疗效，同时降低毒性，将α-AOL定位为一种有前景的DS治疗先导化合物。

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引用次数: 0

Neuromedin U in paraventricular nucleus enhances adipose afferent reflex and sympathoexcitation via the activation of receptor-ERK signaling pathway in rats with obesity-related hypertension 室旁核神经素U通过激活受体- erk信号通路增强肥胖相关性高血压大鼠脂肪传入反射和交感神经兴奋。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2026-02-01 Epub Date: 2025-10-26 DOI: 10.1016/j.neuropharm.2025.110750

Qian Wang , Han-Xu Zhu , Qing Gao , Chen-Xi Xia , Wen-Juan Cao , Ai-Dong Chen , Ye-Bo Zhou , Lei-Lei Chen

Background

Neuromedin U (NMU) is an important neuropeptide. The paraventricular nucleus (PVN) is an important central nucleus for regulating the adipose afferent reflex (AAR). In this study, we aimed to investigate the acute effects of NMU in PVN on AAR, sympathetic nerve activity (SNA), blood pressure (BP) and heart rate (HR) in the rats with obesity-related hypertension (OH) induced by a high-fat diet for 16 weeks.

Methods

Electrophysiological experiment was used to assess AAR with renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) responses to the injection of capsaicin into right inguinal white adipose tissue of anesthetized rats.

Results

Western blotting results showed that the protein level of NMU receptor 2 (NMUR2) and N-methyl-D-aspartate receptor 1 (NMDAR1) subunit of the glutamate receptor in the PVN of OH rats were significantly up-regulated when compared to the control rats. Elisa and electrophysiological results indicated that acute NMU microinjection into the PVN significantly increased excitatory neurotransmitter glutamate level and strengthened the basal SNA and the enhanced AAR in OH rats, which were effectively inhibited by NMUR2 antagonist R-PSOP, MAPK/ERK activation inhibitor U0126 and NMDA receptor antagonist D-AP5, respectively. Moreover, NMU in the PVN induced a greater increase in ERK phosphorylation.

Conclusion

Taken together, our data reveal that NMU in the PVN further promotes sympathetic over-activation, enhances AAR and elevates BP and HR. The activation of receptor-mediated ERK activation in the PVN and the resultant promotion of the increase in glutamate level mediate NMU's action on SNA and AAR in OH condition.

背景：NMU是一种重要的神经肽。室旁核（PVN）是调节脂肪传入反射（AAR）的重要中枢核。本研究旨在探讨NMU对高脂饮食诱导的肥胖相关性高血压（OH）大鼠急性期AAR、交感神经活性（SNA）、血压（BP）和心率（HR）的影响。方法：采用电生理方法观察麻醉大鼠右侧腹股沟白色脂肪组织注射辣椒素后，肾脏交感神经活动（RSNA）和平均动脉压（MAP）对AAR的影响。结果：Western blot结果显示，与对照组相比，OH大鼠PVN中谷氨酸受体NMU受体2 （NMUR2）和n -甲基- d -天冬氨酸受体1 （NMDAR1）亚基蛋白水平显著上调。Elisa和电生理结果显示，急性NMU微注射PVN可显著提高OH大鼠兴奋性神经递质谷氨酸水平，增强基础SNA和增强的AAR，而NMUR2拮抗剂R-PSOP、MAPK/ERK活化抑制剂U0126和NMDA受体拮抗剂D-AP5分别能有效抑制这些作用。此外，PVN中的NMU诱导了ERK磷酸化的更大增加。结论：综上所述，我们的数据表明，NMU在PVN进一步促进交感神经过度激活，增强AAR，升高BP和HR。在OH条件下，PVN中受体介导的ERK激活的激活以及由此导致的谷氨酸水平的增加介导了NMU对SNA和AAR的作用。

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引用次数: 0

Repeated administration of the synthetic cannabinoid AKB48 induces serotonergic neuroadaptation in male and female mice: behavioural and immunohistochemical evidence 反复给药合成大麻素AKB48诱导雄性和雌性小鼠血清素能神经适应：行为和免疫组织化学证据

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.2025.110758

Giorgia Corli , Fabrizio De Luca , Sabrine Bilel , Marta Bassi , Elisa Roda , Rosa Maria Gaudio , Liana Fattore , Carlo Alessandro Locatelli , Matteo Marti

Background and purpose

In the last years, Synthetic Cannabinoids (SCBs) have established themselves as one of the largest and most popular groups of Novel Psychoactive Substances (NPS), being frequently detected in biological samples of patients involved in intoxication and death cases. To date, compelling evidence on the potential interaction between SCBs and non-cannabinoid neurotransmission systems has emerged, with reference to a high-level overlap between endocannabinoid and serotoninergic system. Their long-term effect on serotoninergic pathways is still to be elucidated.

Experimental approach

Using a behavioural and immunohistochemical approach, we investigated the neuroplasticity at 5-HT_2A serotoninergic receptors and serotonin transporter in the cerebellum and cortex induced by repeated AKB48 administration in male and female mice. Further, pharmacological response to the serotoninergic compounds 2C-I or 25I-NBOMe has been studied.

Key results

The repeated exposure to AKB48 results in a worsening effect on the visual sensorimotor, sensory gating, and motor reactivity response to synthetic hallucinogens, that appears to be generally more prolonged in male with respect to AKB48-treated female mice. Interestingly, the effect has been related to cerebellar and cortical neuroplasticity at serotoninergic neurotransmission system, that involves both 5-HT_2A and SERT, that occurs more markedly and rapidly in female with respect to male mice.

Conclusion and implications

This data highlight the interaction between SCBs and psychedelic drugs that may be relevant to their long-term effects and psychiatric sequelae potentially related to their consumption.

在过去的几年中，合成大麻素（SCBs）已经成为最大和最受欢迎的新型精神活性物质（NPS）群体之一，经常在涉及中毒和死亡病例的患者的生物样本中检测到。迄今为止，关于scb和非大麻素神经传递系统之间潜在相互作用的令人信服的证据已经出现，涉及内源性大麻素和5 -羟色胺能系统之间的高度重叠。它们对血清素能通路的长期影响仍有待阐明。实验方法：采用行为学和免疫组织化学方法，研究了反复给药AKB48对雌雄小鼠小脑和皮层5-HT2A 5-羟色胺能受体和5-羟色胺转运体的神经可塑性。此外，对血清素能化合物2C-I或25i - nome的药理学反应也进行了研究。反复暴露于AKB48导致视觉感觉运动、感觉门控和对合成致幻剂的运动反应反应的恶化，与AKB48处理的雌性小鼠相比，雄性小鼠的这种影响通常更长。有趣的是，这种效应与5-HT2A和SERT的5-羟色胺能神经传递系统的小脑和皮层神经可塑性有关，雌性小鼠比雄性小鼠发生得更明显、更迅速。结论和意义这些数据强调了scb和迷幻药物之间的相互作用，这可能与它们的长期影响和精神后遗症有关。

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引用次数: 0

Caffeine Citrate does not reduce brain injury following inflammation-amplified hypoxia ischaemia or hypoxia ischaemia in the Newborn Piglet Model 在新生仔猪模型中，咖啡因柠檬酸盐不会减少炎症扩张性缺氧缺血或缺氧缺血后的脑损伤。

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.2025.110763

George Maple , Christopher Meehan , Ilenia d’Angelo , Yujin Kim , Ellie Campbell , Katie Tucker , Kennosuke Tsuda , Louise Han , Georgina Norris , Alison Mintoft , Francisco Torrealdea , Alan Bainbridge , John Barks , Raymand Pang , Nicola J. Robertson

There is a need to develop alternative therapies for neonatal encephalopathy (NE) in term babies. Caffeine citrate exposure saw benefit in preclinical models of hypoxia-ischaemia (HI). We assessed the safety and cytoprotective efficacy of caffeine citrate in an inflammation-amplified (IA-HI) and HI newborn piglet model based on the probability of treatment superiority (Pr_(sup)) of magnetic resonance spectroscopy, amplitude integrated encephalography (aEEG/EEG) and immunohistochemistry outcomes. Eighteen newborn piglets were randomised to saline, 20/10/10 mg/kg or 60/30/30 mg/kg caffeine citrate following IA-HI. A further twenty piglets were randomised to saline or 40/10/10 mg/kg caffeine citrate following HI. Caffeine plasma concentrations were within range following a 20/10/10 mg/kg dosage but were lower than putative target levels following a 40/10/10 mg/kg dosage. Caffeine concentrations exceeded toxic levels following a 60/30/30 mg/kg dosage. Following IA-HI, 20/10/10 or 60/30/30 mg/kg caffeine citrate treatment failed to reduce white matter (WM) (Pr_(sup) 39.3 %, 52.5 %) and basal ganglia and thalamic (BGT) (Pr_(sup) 35.0 %, 50.3 %) lactate/N-acetylaspartate (Lac/NAA), preserve the phosphocreatine/exchange phosphate pool (PCr/Epp) ratio (Pr_(sup) 44.2 %, 62.0 %), or improve aEEG/EEG recovery (Pr_(sup) 22.4 %, 21.7 %). A 60/30/30 mg/kg dose demonstrated increased cell death, indicating toxicity. Following HI, 40/10/10 mg/kg caffeine citrate treatment failed to reduce WM (Pr_(sup) 58.3 %) and BGT (Pr_(sup) 48.0 %) Lac/NAA, preserve the PCr/Epp ratio (Pr_(sup) 72.8 %), or improve aEEG/EEG recovery (Pr_(sup) 48.0 %), with seizures more refractory. However, there was a modest benefit in male caffeine-treated piglets following HI. The lack of neuroprotection observed following caffeine citrate treatment after both IA-HI and HI suggests further preclinical studies are required before clinical translation for term babies with NE.

有必要开发替代治疗新生儿脑病（NE）在足月婴儿。咖啡因柠檬酸盐暴露在缺氧缺血性（HI）的临床前模型中有益处。我们根据磁共振波谱、振幅综合脑电图（aEEG/EEG）和免疫组织化学结果的治疗优势概率（Pr(sup)），评估了枸橼酸咖啡因在炎症放大（IA-HI）和HI新生仔猪模型中的安全性和细胞保护功效。18头新生仔猪在IA-HI后随机分为生理盐水、20/10/10 mg/kg或60/30/30 mg/kg枸橼酸咖啡因。另外20头仔猪在HI后随机分配生理盐水或40/10/10 mg/kg枸橼酸咖啡因。在20/10/10 mg/kg剂量下，咖啡因血浆浓度在范围内，但在40/10/10 mg/kg剂量下，咖啡因血浆浓度低于假定的目标水平。咖啡因浓度在60/30/30 mg/kg剂量下超过毒性水平。IA-HI后，20/10/10或60/30/30 mg/kg柠檬酸咖啡因处理均未能降低白质（WM）（Pr(sup) 39.3%, 52.5%）、基底节区和丘脑区（BGT）（Pr(sup) 35.0%, 50.3%）乳酸/ n -乙酰天冬氨酸（Lac/NAA），保持磷酸肌酸/交换磷酸池（PCr/Epp）比值（Pr(sup) 44.2%, 62.0%），或改善aEEG/EEG恢复（Pr(sup) 22.4%, 21.7%）。60/30/30 mg/kg剂量显示细胞死亡增加，表明有毒性。HI后，40/10/10 mg/kg枸橼酸咖啡因治疗未能降低WM （Pr(sup) 58.3%）和BGT (Pr(sup) 48.0%) Lac/NAA，保持PCr/Epp比值（Pr(sup) 72.8%），或改善aEEG/EEG恢复（Pr(sup) 48.0%），癫痫发作更加难治性。然而，在HI之后，雄性咖啡因处理仔猪有适度的益处。在IA-HI和HI后，枸橼酸咖啡因治疗后观察到缺乏神经保护，这表明在临床转化为NE足月婴儿之前，需要进一步的临床前研究。

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引用次数: 0

Corrigendum to “Protective role of madecassoside from Centella asiatica against protein L-isoaspartyl methyltransferase deficiency-induced neurodegeneration” [Neuropharmacology 109834 (2023) DOI: 10.1016/j.neuropharm.2023.109834] “积雪草草皂苷对蛋白质l -异天冬氨酸甲基转移酶缺乏症诱导的神经变性的保护作用”[神经药理学109834 (2023)DOI: 10.1016/j.n neuromedicine .2023.109834]的更正。

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.2025.110735

Zicheng Ling , Sirui Zhou , Yancheng Zhou , Wanyu Zhong , Zhonghao Su , Zhenxia Qin

引用次数: 0

Ticagrelor as a dual RAS modulator and mitochondrial stabilizer: A multifaceted neurotherapeutic strategy in Huntington's disease 替格瑞洛作为双重RAS调节剂和线粒体稳定剂：亨廷顿病的多方面神经治疗策略。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2026-02-01 Epub Date: 2025-10-20 DOI: 10.1016/j.neuropharm.2025.110726

Ola E. Mohamed , Rabab H. Sayed , Dalaal M. Abdallah , Doaa Abou El-ezz , Amany El-Brairy , Hanan S. El-Abhar

The pathobiology of Huntington's disease (HD) is far from complete. Although limited, patients have been reported to exhibit altered platelet function, enhanced ENT1, and changes in renin–angiotensin system (RAS), all of which may impact cognitive function. Ticagrelor has demonstrated neuroprotective effects in stroke and parkinsonism models through mechanisms that extend beyond its therapeutic benefits as a P2Y12 receptor antagonist and ENT1 inhibitor. In this study, we investigated the potential efficiency Ticagrelor post-treatment on motor defects in a 3-nitropropionic acid (3-NP)-induced HD-like model. Symptomatic HD rats were daily treated for a week with Ticagrelor, the MAS receptor (MAS-R) antagonist A-779, or Ticagrelor + A-779. Ticagrelor amended body weight loss, motor function in open field and rotarod tests, and striatal histopathological alterations induced by 3-NP. On the striatal molecular level, Ticagrelor downregulated prorenin receptor mRNA expression but upregulated that of the MAS-R. Additionally, it decreased striatal contents of prorenin/renin and angiotensin II (Ang II), while increasing those of angiotensin-converting enzyme 2 and Ang-(1–7). Ticagrelor also hindered the phosphorylation/activation of the inositol trisphosphate receptor (IP3R), dynamin-related protein-1 (DRP-1), and PTEN-induced putative kinase 1 protein (PINK1) expressions. Additionally, it boosted the voltage-dependent anion channel-1 (VDAC-1) and Mitofusin-2 (Mnf-2) striatal contents. A-779 partially reverted Ticagrelor impact on all amendments except for prorenin receptor and p-IP3R. However, prorenin/renin correlated markedly with IP3R, DRP-1, and PINK1, but inversely with VDAC-1 and Mfn-2. In conclusion, Ticagrelor demonstrates promising neurotherapeutic effects in HD partially via the activation of MAS-R, inhibition of prorenin/renin/prorenin receptor, and improvement of mitochondrial homeostasis.

亨廷顿舞蹈病（HD）的病理生物学还远未完成。尽管有限，但有报道称患者表现出血小板功能改变、ENT1增强和肾素-血管紧张素系统（RAS）改变，所有这些都可能影响认知功能。替格瑞洛已在中风和帕金森模型中显示出神经保护作用，其机制超出了其作为P2Y12受体拮抗剂和ENT1抑制剂的治疗益处。在这项研究中，我们研究了替格瑞洛后处理对3-硝基丙酸（3-NP）诱导的hd样模型运动缺陷的潜在效率。有症状的HD大鼠每天用替格瑞洛、MAS受体（MAS- r）拮抗剂a -779或替格瑞洛+ a -779治疗一周。替格瑞洛改善了开阔场地和旋转试验中的体重减轻、运动功能以及3-NP诱导的纹状体组织病理学改变。在纹状体分子水平上，替格瑞洛下调prorenin受体mRNA的表达，上调MAS-R的表达。降低纹状体中原肾素/肾素和血管紧张素II （Ang II）的含量，增加血管紧张素转换酶2和Ang-的含量（1-7）。替格瑞洛还阻碍了肌醇三磷酸受体（IP3R）、动力蛋白相关蛋白-1 （DRP-1）和pten诱导的推定激酶1蛋白（PINK1）表达的磷酸化/激活。此外，它还增加了电压依赖性阴离子通道-1 （VDAC-1）和Mitofusin-2 （Mnf-2）纹状体的含量。A-779部分逆转了替格瑞洛对除prorenin受体和p-IP3R外的所有修正的影响。然而，prorenin/renin与IP3R、DRP-1和PINK1呈显著相关，而与VDAC-1和Mfn-2呈负相关。综上所述，替格瑞洛通过激活MAS-R、抑制prorenin/renin/prorenin受体和改善线粒体稳态，在HD中显示出有希望的神经治疗效果。

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引用次数: 0

Physostigmine modulates hippocampal GABAergic neurotransmission via α7 nicotinic acetylcholine receptors 毒豆碱通过α7烟碱乙酰胆碱受体调节海马gaba能神经传递

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2026-02-01 Epub Date: 2025-10-24 DOI: 10.1016/j.neuropharm.2025.110736

Andy Hernández-Abrego, Elizabeth Vázquez-Gómez, Jassiel Mejía-Piedras, Jesús García-Colunga

GABAergic synaptic transmission is modulated by nicotinic acetylcholine receptors (nAChRs) and both are regulated by several substances, including antidepressants and acetylcholinesterase inhibitors. They may therefore be involved in disorders such as depression. Physostigmine (an acetylcholinesterase inhibitor), besides inducing depressive behaviors, is an agonist and positive allosteric modulator of nAChRs; however, its effects on both GABAergic transmission and α7 nAChRs are not clear. Here we explore the pharmacological actions of physostigmine on both GABAergic transmission and α7 nAChRs in the hippocampus by using voltage-clamp technique. We found in rat hippocampal CA1 stratum radiatum interneurons that, a) physostigmine increased the frequency of spontaneous and miniature inhibitory postsynaptic currents (sIPSCs and mIPSCs), which was reversed by mecamylamine (a non-selective nAChR antagonist) and by methyllycaconitine (a selective α7 nAChR antagonist); but not by dihydro-β-erythroidine (a selective α4β2 nAChR antagonist), b) methyllycaconitine alone decreased the frequency of sIPSCs, c) the antidepressant fluoxetine decreased the frequency of sIPSCs that was potentiated by physostigmine, and had no effect after methyllycaconitine application, d) physostigmine potentiated the ionic current induced by choline without modifying its decay time constant, and was inhibited by fluoxetine. Finally, in hippocampal CA1 pyramidal neurons, physostigmine decreased the frequency of sIPSCs, which was reverted by fluoxetine. In conclusion, physostigmine increases GABAergic synaptic transmission in hippocampal CA1 stratum radiatum interneurons acting as a type I positive allosteric modulator on tonic endogenous activated α7 nAChRs. These effects of physostigmine might be counteracted by fluoxetine, through inhibition of α7 nAChRs.

gaba能突触传递由烟碱乙酰胆碱受体（nAChRs）调节，两者均受几种物质调节，包括抗抑郁药和乙酰胆碱酯酶抑制剂。因此，它们可能与抑郁症等疾病有关。毒豆碱（一种乙酰胆碱酯酶抑制剂）除诱导抑郁行为外，还是nachr的激动剂和正变构调节剂；但其对gaba能传递和α7 nachr的影响尚不清楚。本研究采用电压钳技术，探讨了毒豆黄碱对海马gaba能传递和α7 nachr的药理作用。我们发现，在大鼠海马CA1辐射层中间神经元中，a)蛇毒碱增加了自发和微型抑制性突触后电流（sIPSCs和mIPSCs）的频率，这被甲胺（一种非选择性nAChR拮抗剂）和甲基莱卡头碱（一种选择性α7 nAChR拮抗剂）逆转；二氢β-红血碱（α4β2 nAChR的选择性拮抗剂）对sIPSCs的发生无明显影响，b)单用甲基莱卡乌碱可降低sIPSCs的发生频率，c)抗抑郁药氟西汀可降低被残碱增强的sIPSCs的发生频率，但在使用残碱后没有作用，d)残碱可增强胆碱诱导的离子电流，但不改变其衰减时间常数，氟西汀可抑制残碱诱导的离子电流。最后，在海马CA1锥体神经元中，褐豆碱降低了sIPSCs的频率，氟西汀可以逆转这一现象。综上所述，毒豆碱可增加海马CA1辐射层间神经元gaba能突触传递，并可作为强直内源性活化α7 nachr的I型正变构调节剂。氟西汀可能通过抑制α7 nachr来抵消褐豆碱的这些作用。

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引用次数: 0