Neuropharmacology最新文献_第5页

Methyltransferase METTL3 regulates neuropathic pain through m6A methylation modification of SOCS1 甲基转移酶 METTL3 通过 SOCS1 的 m6A 甲基化修饰调节神经性疼痛。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2024-09-30 DOI: 10.1016/j.neuropharm.2024.110176

Liping Wu , Peng Ning , Yingye Liang , Tianyi Wang , Lingnv Chen , Dongming Lu , Hongliang Tang

The mechanisms of neuropathic pain (NP) are considered multifactorial. Alterations in the suppressor of cytokine signaling 1 (SOCS1) play a critical role in neural damage and inflammation. Epigenetic RNA modifications, specifically N6-methyladenosine (m6A) methylation, have increasingly been observed to impact the nervous system. Nevertheless, there is a scarcity of studies investigating the connection between m6A methylation and SOCS1 in the molecular mechanisms of NP. This study investigates the roles and potential mechanisms of the m6A methyltransferase like 3 (METTL3) and SOCS1 in female rats with spinal nerve ligation (SNL)-induced NP. It was found that in NP, both METTL3 and overall m6A levels were downregulated, leading to the activation of pro-inflammatory cytokines, such as interleukin-1β, interleukin 6, and tumor necrosis factor-α. Notably, The SOCS1 mRNA is significantly enriched with m6A methylation modifications, with the most prevalent m6A methyltransferase METTL3 stabilizing the downregulation of SOCS1 by targeting m6A methylation modifications at positions 151, 164, and 966.Exogenous supplementation of METTL3 improved NP-related neuroinflammation and behavioral dysfunctions, but these effects could be reversed by the absence of SOCS1. Additionally, the depletion of endogenous SOCS1 promoted NP progression by inducing the toll-like receptor 4 (TLR4) signaling pathway. The dysregulation of METTL3 and the resulting m6A modification of SOCS1 form a crucial epigenetic regulatory loop that promotes the progression of NP. Targeting the METTL3/SOCS1 axis might offer new insights into potential therapeutic strategies for NP.

神经病理性疼痛（NP）的机制被认为是多因素的。细胞因子信号转导抑制因子 1（SOCS1）的变化在神经损伤和炎症中起着至关重要的作用。人们越来越多地观察到表观遗传 RNA 修饰，特别是 N6-甲基腺苷（m6A）甲基化对神经系统的影响。然而，很少有研究调查 m6A 甲基化和 SOCS1 在 NP 分子机制中的联系。本研究探讨了类似 m6A 甲基转移酶 3（METTL3）和 SOCS1 在脊神经结扎（SNL）诱导的雌性 NP 大鼠中的作用和潜在机制。研究发现，在 NP 中，METTL3 和总体 m6A 水平均下调，导致白细胞介素-1β、白细胞介素 6 和肿瘤坏死因子-α 等促炎细胞因子的激活。值得注意的是，SOCS1 mRNA 明显富含 m6A 甲基化修饰，最普遍的 m6A 甲基转移酶 METTL3 通过靶向 151、164 和 966 位的 m6A 甲基化修饰，稳定了 SOCS1 的下调。此外，内源性 SOCS1 的耗竭通过诱导收费样受体 4（TLR4）信号通路促进了 NP 的进展。METTL3 的失调和由此导致的 SOCS1 的 m6A 修饰形成了一个关键的表观遗传调控环，促进了 NP 的进展。以 METTL3/SOCS1 轴为靶点可能会为 NP 的潜在治疗策略提供新的见解。

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引用次数: 0

Methamphetamine-induced impairment of memory and fleeting neuroinflammation: Profiling mRNA changes in mouse hippocampus following short-term and long-term exposure 甲基苯丙胺诱发的记忆损伤和短暂的神经炎症：分析小鼠海马体在短期和长期暴露后的 mRNA 变化。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2024-09-30 DOI: 10.1016/j.neuropharm.2024.110175

Laiqiang Wu , Xiaorui Liu , Qingchen Jiang , Ming Li , Min Liang , Shuai Wang , Rui Wang , Linlan Su , Tong Ni , Nan Dong , Li Zhu , Fanglin Guan , Jie Zhu , Wen Zhang , Min Wu , Yanjiong Chen , Teng Chen , Biao Wang

Methamphetamine (METH) has been implicated in inducing memory impairment, but the precise mechanisms underlying this effect remain unclear. Current research often limits itself to singular models or focuses on individual gene or protein functions, which hampers a comprehensive understanding of the underlying mechanisms. In this study, we established three METH mouse exposure models, extracted hippocampal nuclei, and utilized RNA sequencing to analyze changes in mRNA expression profiles. Our results indicate that METH significantly impairs the learning and memory capabilities of mice. Additionally, we observed that METH-induced inflammatory responses occur in the early phase and do not further exacerbate with repeated injections. However, RNA sequencing revealed the persistent enrichment of inflammatory pathway molecules, which correlated with worsened behaviors. This suggests that although METH-induced neuroinflammation plays a critical role in learning and memory impairment, the continued enrichment of inflammatory pathway molecules is associated with behavioral outcomes. These findings provide crucial evidence for the potential application of immune intervention in METH-related disorders.

甲基苯丙胺（METH）被认为会诱发记忆损伤，但这种效应的确切机制仍不清楚。目前的研究往往局限于单一的模型，或侧重于单个基因或蛋白质的功能，这阻碍了对潜在机制的全面了解。在本研究中，我们建立了三种 METH 暴露小鼠模型，提取了海马核，并利用 RNA 测序分析了 mRNA 表达谱的变化。我们的研究结果表明，METH 会严重损害小鼠的学习和记忆能力。此外，我们还观察到，METH 诱导的炎症反应发生在早期阶段，并不会随着重复注射而进一步加剧。然而，RNA 测序发现炎症通路分子持续富集，这与行为恶化有关。这表明，尽管 METH 诱导的神经炎症在学习和记忆损伤中起着关键作用，但炎症通路分子的持续富集与行为结果有关。这些发现为免疫干预在 METH 相关疾病中的潜在应用提供了重要证据。

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引用次数: 0

Reversal of neurodevelopmental impairment and cognitive enhancement by pharmacological intervention with the polyphenol polydatin in a Down syndrome model 在唐氏综合征模型中使用多酚多苷进行药物干预，可逆转神经发育障碍并增强认知能力。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2024-09-27 DOI: 10.1016/j.neuropharm.2024.110170

Marco Emili , Fiorenza Stagni , Carla Russo , Laura Angelozzi , Sandra Guidi , Renata Bartesaghi

Intellectual disability (ID) is the unavoidable hallmark of Down syndrome (DS), a genetic condition due to triplication of chromosome 21. ID in DS is largely attributable to neurogenesis and dendritogenesis alterations taking place in the prenatal/neonatal period, the most critical time window for brain development. There are currently no treatments for ID in DS. Considering the timeline of brain development, treatment aimed at improving the neurological phenotypes of DS should be initiated as early as possible and use safe agents. The goal of this study was to establish whether it is possible to improve DS-linked neurodevelopmental defects through early treatment with polydatin, a natural polyphenol. We used the Ts65Dn mouse model of DS and focused on the hippocampus, a brain region fundamental for long-term memory. We found that in Ts65Dn mice of both sexes treated with polydatin from postnatal (P) day 3 to P15 there was full restoration of neurogenesis, neuron number, and dendritic development. These effects were accompanied by normalization of Cyclin D1 and DSCAM levels, which may account for the rescue of neurogenesis and dendritogenesis, respectively. Importantly, in Ts65Dn mice treated with polydatin from P3 to adolescence (∼P50) there was full restoration of hippocampus-dependent memory, indicating a pro-cognitive outcome of treatment. No adverse effects were observed on the body and brain weight. The efficacy and safety of polydatin in a model of DS prospect the possibility of its use during early life stages for amelioration of DS-linked neurodevelopmental alterations.

智力障碍（ID）是唐氏综合征（DS）不可避免的特征，而唐氏综合征是一种因 21 号染色体三倍体而导致的遗传病。唐氏综合征的智力障碍主要是由于产前/新生儿期的神经发生和树突发生改变造成的，而这一时期正是大脑发育最关键的时期。目前尚无治疗 DS 先天性脑发育症的方法。考虑到大脑发育的时间表，旨在改善 DS 神经表型的治疗应尽早开始，并使用安全的药物。本研究的目的是确定是否有可能通过使用天然多酚多拉丁（polydatin）进行早期治疗来改善与DS相关的神经发育缺陷。我们使用了Ts65Dn DS小鼠模型，并重点研究了海马区--一个对长期记忆至关重要的脑区。我们发现，从出生后第 3 天到出生后第 15 天，使用多酚类药物治疗的雌雄 Ts65Dn 小鼠的神经发生、神经元数量和树突发育都得到了完全恢复。伴随这些影响的是细胞周期蛋白 D1 和 DSCAM 水平的正常化，这可能是神经发生和树突形成得到挽救的原因。重要的是，Ts65Dn小鼠在P3至青春期（∼P50）期间接受多铂治疗后，海马依赖性记忆完全恢复，这表明治疗具有促进认知的效果。没有观察到对身体和大脑重量的不良影响。多拉丁在DS模型中的有效性和安全性为在生命早期阶段使用多拉丁来改善与DS相关的神经发育改变提供了可能。

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引用次数: 0

The psychedelic drug DOI reduces heroin motivation by targeting 5-HT2A receptors in a heroin and alcohol co-use model 在海洛因和酒精共同使用模型中，迷幻药DOI通过靶向5-HT2A受体降低海洛因动机。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2024-09-26 DOI: 10.1016/j.neuropharm.2024.110163

Joel Bonilla , Giuseppe Giannotti , Nathaniel P. Kregar , Jasper A. Heinsbroek , David E. Olson , Jamie Peters

There has been a recent renewed interest in the potential use of psychedelic drugs as therapeutics for certain neuropsychiatric disorders, including substance use disorders. The psychedelic drug 2,5-dimethoxy-4-iodoamphetamine (DOI) has demonstrated therapeutic efficacy in preclinical models of opioid use disorder (OUD). Alcohol is commonly co-used in individuals with OUD, but preclinical models that recapitulate this comorbidity are lacking. We developed a polydrug model wherein male and female rats were allowed to self-administer intravenous heroin and oral alcohol (or saccharin control solution) over weeks of behavioral training, and then we conducted a series of progressive ratio tests to assess the animals' motivational state for heroin and alcohol. In this model, motivation for heroin is higher than alcohol, and DOI (0.4 mg/kg) administered prior to testing significantly reduced heroin motivation measured as the animals’ break point, or maximum effort the animal is willing to expend to obtain a single infusion of heroin. The 5-HT2A receptor antagonist MDL 100,907 (0.3 mg/kg), but not the 5-HT2C receptor antagonist SB-242084 (0.5 mg/kg), blocked the therapeutic effect of DOI on heroin motivation. No significant effects on alcohol break points were observed, nor did MDL 100,907 or SB-242084 have any effect on break points on their own. These data support the view that psychedelic drugs like DOI may have therapeutic effects on opioid use in individuals with OUD and comorbid alcohol use, by acting as a 5-HT2A receptor agonist.

最近，人们再次对迷幻药作为治疗某些神经精神疾病（包括药物使用障碍）的潜在药物产生了兴趣。迷幻药 2,5-二甲氧基-4-碘苯丙胺（DOI）已在阿片类药物使用障碍（OUD）的临床前模型中显示出疗效。酗酒是 OUD 患者的常见并发症，但目前还缺乏能再现这种并发症的临床前模型。我们开发了一种多药模型，让雄性和雌性大鼠在数周的行为训练中自行静脉注射海洛因和口服酒精（或糖精对照溶液），然后进行一系列渐进比值测试，以评估动物对海洛因和酒精的动机状态。在该模型中，动物对海洛因的动机高于对酒精的动机，而在测试前注射 DOI（0.4 毫克/千克）可显著降低动物对海洛因的动机，该动机是以动物的断点（即动物为获得单次输注的海洛因而愿意付出的最大努力）来衡量的。5-HT2A 受体拮抗剂 MDL 100,907 （0.3 毫克/千克）阻断了 DOI 对海洛因动机的治疗作用，但 5-HT2C 受体拮抗剂 SB-242084 （0.5 毫克/千克）没有阻断这种作用。对酒精断点没有观察到明显的影响，MDL 100,907 或 SB-242084 本身对断点也没有影响。这些数据支持这样一种观点，即 DOI 等迷幻药可作为 5-HT2A 受体激动剂，对患有 OUD 并合并酗酒的人使用阿片类药物具有治疗作用。

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引用次数: 0

Inhibition of KIF5b-mediated Nav1.8 transport by ropivacaine contributes to axonal regeneration following sciatic nerve injury in rats 罗哌卡因抑制 KIF5b 介导的 Nav1.8 转运有助于大鼠坐骨神经损伤后的轴突再生。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2024-09-25 DOI: 10.1016/j.neuropharm.2024.110169

Yongchen Cui , Qinjun Chu , Xiaogao Jin , Yong Li , Kaiyuan Guo , Guangming Zhang , Zhe Zhao , Junfeng Zhang

Peripheral nerve injury (PNI), typically caused by traumatic accidents or medical events, is currently one of the most common diseases that leads to limb disability. After PNI, tetrodotoxin-resistant voltage-gated sodium channel Nav1.8 is upregulated at the lesion site. Our earlier study suggested that ropivacaine promotes axon regrowth by regulating Nav1.8-mediated macrophage signaling. Nevertheless, the mechanism of ropivacaine in regulation of Nav1.8 expression remains incompletely understood. Kinesin family 5b (KIF5b) was reported to mediate the Nav1.8 axonal transport from dorsal root ganglia (DRGs) to lesion site. Herein, we investigated whether ropivacaine promotes axon regeneration through inhibition of KIF5b-mediated Nav1.8 transport. Reduced levels of KIF5b and Nav1.8 in DRGs coincide with their increase at the lesion site. Nav1.8 mRNA was significantly increased at the lesion site but not in DRGs. Surprisingly, ropivacaine reversed the alterations of Nav1.8 and KIF5b protein expression without affecting Nav1.8 mRNA level. Due to KIF5b overexpression in DRGs, Nav1.8 protein level was significantly decreased in DRGs and increased at the lesion site. We also found KIF5b overexpression significantly impaired behavioral functions, reduced the recovery index of compound muscle action potential (CMAP) amplitude, inhibited axonal regrowth, slowed M1 macrophage infiltration and shift to M2 phenotype, and delayed myelin debris clearance. Notably, all aforementioned results caused by KIF5b overexpression were alleviated by ropivacaine. Furthermore, we demonstrated that inhibition of Nav1.8 transport by A-803467 produced mitigating effects on the impairment of regenerative capacity induced by KIF5b overexpression similar to ropivacaine. These results suggest that ropivacaine promotes axonal regeneration at least partially by inhibiting KIF5b-mediated Nav1.8 forward transport.

周围神经损伤（PNI）通常由创伤性事故或医疗事件引起，是目前导致肢体残疾的最常见疾病之一。周围神经损伤后，耐河豚毒素的电压门控钠通道 Nav1.8 在损伤部位上调。我们早前的研究表明，罗哌卡因可通过调节 Nav1.8 介导的巨噬细胞信号来促进轴突再生。然而，罗哌卡因调控 Nav1.8 表达的机制仍不完全清楚。据报道，驱动蛋白家族 5b （KIF5b）介导了 Nav1.8 从背根神经节（DRGs）到病变部位的轴突运输。在此，我们研究了罗哌卡因是否能通过抑制 KIF5b 介导的 Nav1.8 转运促进轴突再生。KIF5b和Nav1.8在DRG中的水平降低与它们在病变部位的水平升高相吻合。Nav1.8 mRNA 在病变部位显著增加，但在 DRG 中却没有增加。令人惊讶的是，罗哌卡因逆转了 Nav1.8 和 KIF5b 蛋白表达的改变，但不影响 Nav1.8 mRNA 水平。由于 KIF5b 在 DRGs 中过表达，Nav1.8 蛋白水平在 DRGs 中显著降低，而在病变部位则显著升高。我们还发现，KIF5b过表达会明显损害行为功能，降低复合肌动作电位（CMAP）振幅的恢复指数，抑制轴突再生，减缓M1巨噬细胞浸润和向M2表型的转变，延迟髓鞘碎片的清除。值得注意的是，罗哌卡因能缓解 KIF5b 过表达引起的所有上述结果。此外，我们还证明，A-803467抑制Nav1.8转运对KIF5b过表达引起的再生能力损害的缓解作用与罗哌卡因相似。这些结果表明，罗哌卡因至少部分是通过抑制 KIF5b 介导的 Nav1.8 转运来促进轴突再生的。

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引用次数: 0

Increased levels of Escherichia-Shigella and Klebsiella in the gut contribute to the responsivity of placebo analgesia 肠道中的志贺氏菌和克雷伯氏菌水平升高，导致了安慰剂镇痛的反应性。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2024-09-25 DOI: 10.1016/j.neuropharm.2024.110168

Siqi Yang , Yuanyuan Wang , Zifeng Wu, Di Wang, Xinying Zhang, Suwan Hu, Qi Zhang, Yuchen Bu, Cunming Liu, Chaoli Huang, Chun Yang

Placebo analgesia is observed in both humans and animals. Given the complexity of placebo analgesia involving a variety of neurobiological, psychological, and psychosocial processes, further investigation into its underlying mechanisms is essential. Gut microbiota has been implicated in the responsivity of placebo analgesia, but its precise role remains unknown and warrants further investigations. Here, we conducted a conditioning training model with chronic inflammatory pain induced by complete Freund's adjuvant (CFA) in mice, associating parecoxib with different cues. Hierarchical clustering analysis of placebo analgesia behaviors was employed to classify mice into responders and non-responders phenotypes. Approximately 40% of CFA mice undergoing conditioning training exhibited placebo analgesia. Notably, placebo analgesia responders displayed reduced anxiety-like behaviors. 16S rRNA results revealed a distinct composition of gut microbiota composition among the control, placebo analgesia non-responders and responders groups. Notably, levels of Escherichia Shigella and Klebsiella in the gut were increased considerably in the placebo analgesia responders as compared to both control and non-responders groups. In conclusion, placebo analgesia responders demonstrated marked analgesia, reduced anxiety-like behaviors, and increased levels of Escherichia-Shigella and Klebsiella, implying a potential linkage between gut microbiota and placebo analgesia.

在人类和动物身上都能观察到安慰剂镇痛。鉴于安慰剂镇痛的复杂性，它涉及多种神经生物学、心理学和社会心理过程，因此进一步研究其潜在机制至关重要。肠道微生物群与安慰剂镇痛的反应性有关，但其确切作用仍不清楚，需要进一步研究。在此，我们利用完全弗氏佐剂（CFA）诱导的慢性炎症性疼痛对小鼠进行了条件训练模型，将帕瑞昔布与不同的线索联系起来。采用安慰剂镇痛行为的层次聚类分析将小鼠分为应答者和非应答者表型。接受条件反射训练的CFA小鼠中约有40%表现出安慰剂镇痛。值得注意的是，安慰剂镇痛应答者的焦虑样行为有所减少。16S rRNA 结果显示，对照组、安慰剂镇痛无反应组和反应组的肠道微生物群组成各不相同。值得注意的是，与对照组和非应答组相比，安慰剂镇痛应答者肠道中志贺氏菌和克雷伯氏菌的水平显著增加。总之，安慰剂镇痛应答者表现出明显的镇痛、焦虑样行为减少以及志贺氏菌和克雷伯氏菌水平升高，这意味着肠道微生物群与安慰剂镇痛之间存在潜在联系。

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引用次数: 0

Ketamine reverses chronic corticosterone-induced behavioral deficits and hippocampal synaptic dysfunction by regulating eIF4E/BDNF signaling 氯胺酮通过调节eIF4E/BDNF信号转导逆转慢性皮质酮诱导的行为缺陷和海马突触功能障碍

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2024-09-24 DOI: 10.1016/j.neuropharm.2024.110156

Canyu Yang , Tahir Ali , Axiang Li , Ruyan Gao , Xiaoming Yu , Shupeng Li , Tao Li

Major depressive disorder (MDD) is a debilitating illness with a high global burden. While Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, offers rapid-acting antidepressant effects, its mechanism remains incompletely understood. Recent research suggests that dysregulation of mRNA translation via the Eukaryotic initiation factor 4E (eIF4E) pathway might contribute to depression pathophysiology. This study investigates whether Ketamine modulates eIF4E signaling in the hippocampus during its antidepressant action. Herein, adult male mice were exposed to Corticosterone, a well-established model for anxiety and depression, followed by behavioral testing and biochemical analysis. Corticosterone induced depression-like symptoms and disrupted synaptic function, including reduced TrkB/BDNF and eIF4E/MNK1/p-eIF2α/ubiquitin signaling. Ketamine treatment reversed these deficits. Notably, the eIF4E/MNK1 signaling inhibitor, eFT508, blocked Ketamine's antidepressant effect, leading to a return of depression-like phenotype and impaired synaptic signaling. Importantly, these effects were reversed by 7,8-DHF, a BDNF/TrkB signaling agonist. Mice treated with Corticosterone, Ketamine, and eFT508 and subsequently exposed to 7,8-DHF displayed normalized depression-like behaviors and restored synaptic signaling, including increased eIF4E phosphorylation and MNK1 expression. Besides, 7,8-DHF treatment enhanced p-eIF2α levels compared to the eFT508-treated group. These findings suggest that Ketamine exerts its antidepressant action through the regulation of the eIF4E/BDNF signaling pathway in the hippocampus. This study provides novel insights into the molecular mechanisms underlying Ketamine's therapeutic effects and highlights the potential of targeting this pathway for future MDD treatment strategies.

重度抑郁障碍（MDD）是一种使人衰弱的疾病，给全球带来沉重负担。氯胺酮是一种N-甲基-D-天冬氨酸（NMDA）受体拮抗剂，具有速效抗抑郁作用，但其作用机制仍未完全明了。最近的研究表明，通过真核生物起始因子 4E（eIF4E）途径对 mRNA 翻译的失调可能会导致抑郁症的病理生理学。本研究探讨氯胺酮在抗抑郁作用过程中是否会调节海马中的eIF4E信号转导。在本研究中，成年雄性小鼠暴露于皮质酮（一种成熟的焦虑和抑郁模型），然后进行行为测试和生化分析。皮质酮会诱发类似抑郁症的症状，并破坏突触功能，包括减少TrkB/BDNF和eIF4E/MNK1/p-eIF2α/泛素信号传导。氯胺酮治疗可逆转这些缺陷。值得注意的是，eIF4E/MNK1信号转导抑制剂eFT508阻断了氯胺酮的抗抑郁作用，导致抑郁样表型恢复和突触信号转导受损。重要的是，BDNF/TrkB 信号激动剂 7,8-DHF 可以逆转这些影响。小鼠经皮质酮、氯胺酮和 eFT508 处理后，再接触 7,8-DHF 会显示出正常的抑郁样行为，并恢复突触信号传导，包括增加 eIF4E 磷酸化和 MNK1 表达。此外，与 eFT508 处理组相比，7,8-DHF 处理提高了 p-eIF2α 的水平。这些研究结果表明，氯胺酮通过调节海马中的eIF4E/BDNF信号通路发挥抗抑郁作用。这项研究为氯胺酮治疗效果的分子机制提供了新的见解，并强调了针对这一途径的未来 MDD 治疗策略的潜力。

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引用次数: 0

Epigenetic mechanisms of bone cancer pain 骨癌疼痛的表观遗传机制

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2024-09-20 DOI: 10.1016/j.neuropharm.2024.110164

Chaobo Ni , Liping Chen , Bohan Hua, Zixin Han, Longsheng Xu, Qinghe Zhou, Ming Yao, Huadong Ni

The management and treatment of bone cancer pain (BCP) remain significant clinical challenges, imposing substantial economic burdens on patients and society. Extensive research has demonstrated that BCP induces changes in the gene expression of peripheral sensory nerves and neurons, which play crucial roles in the onset and maintenance of BCP. However, our understanding of the epigenetic mechanisms of BCP underlying the transcriptional regulation of pro-nociceptive (such as inflammatory factors and the transient receptor potential family) and anti-nociceptive (such as potassium channels and opioid receptors) genes remains limited. This article reviews the epigenetic regulatory mechanisms in BCP, analyzing the roles of histone modifications, DNA methylation, and noncoding RNAs (ncRNAs) in the expression of pro-nociceptive and anti-nociceptive genes. Finally, we provide a comprehensive view of the functional mechanisms of epigenetic regulation in BCP and explore the potential of these epigenetic molecules as therapeutic targets for BCP.

骨癌疼痛（BCP）的管理和治疗仍然是重大的临床挑战，给患者和社会造成了巨大的经济负担。大量研究表明，骨癌痛会诱导外周感觉神经和神经元的基因表达发生变化，这在骨癌痛的发生和维持中起着至关重要的作用。然而，我们对 BCP 促痛觉基因（如炎症因子和瞬时受体电位家族）和抗痛觉基因（如钾通道和阿片受体）转录调控的表观遗传学机制的了解仍然有限。本文回顾了 BCP 的表观遗传调控机制，分析了组蛋白修饰、DNA 甲基化和非编码 RNA（ncRNA）在促痛觉基因和抗痛觉基因表达中的作用。最后，我们全面介绍了 BCP 中表观遗传调控的功能机制，并探讨了这些表观遗传分子作为 BCP 治疗靶点的潜力。

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引用次数: 0

Flavors of GPCR signaling bias GPCR 信号偏差的味道。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2024-09-19 DOI: 10.1016/j.neuropharm.2024.110167

Mohammad Seyedabadi , Vsevolod V. Gurevich

GPCRs are inherently flexible molecules existing in an equilibrium of multiple conformations. Binding of GPCR agonists shifts this equilibrium. Certain agonists can increase the fraction of active-like conformations that predispose the receptor to coupling to a particular signal transducer or a select group of transducers. Such agonists are called biased, in contrast to balanced agonists that facilitate signaling via all transducers the receptor couples to. These biased agonists preferentially channel the signaling of a GPCR to particular G proteins, GRKs, or arrestins. Preferential activation of particular G protein or arrestin subtypes can be beneficial, as it would reduce unwanted on-target side effects, widening the therapeutic window. However, biasing GPCRs has two important limitations: a) complete bias is impossible due to inherent flexibility of GPCRs; b) receptor-independent functions of signal transducer proteins cannot be directly affected by GPCR ligands or differential receptor barcoding by GRK phosphorylation.

GPCR 本身是一种灵活的分子，处于多种构象的平衡状态。GPCR 激动剂的结合会改变这种平衡。某些激动剂可以增加活性构象的比例，从而使受体与特定的信号转导物或一组特定的信号转导物发生耦合。这种激动剂被称为偏性激动剂，与之相反的是，平衡激动剂会促进受体通过与之偶联的所有转换器发出信号。这些偏性激动剂会优先将 GPCR 的信号传递给特定的 G 蛋白、GRK 或抑制素。优先激活特定的 G 蛋白或抑制素亚型可能是有益的，因为这样可以减少不必要的靶向副作用，扩大治疗窗口。然而，偏向 GPCR 有两个重要的局限性：a) 由于 GPCR 固有的灵活性，不可能完全偏向；b) 信号转导蛋白与受体无关的功能不能直接受到 GPCR 配体或 GRK 磷酸化的不同受体条码的影响。

引用次数: 0

Anisomycin alleviates cognitive impairments and pathological features in 3xTg-AD mice Anisomycin 可减轻 3xTg-AD 小鼠的认知障碍和病理特征。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2024-09-18 DOI: 10.1016/j.neuropharm.2024.110159

Juan-Juan Jiao , Yang Hu , Yu-Jia Cui , Chun-Mei Tuo , Yi-Xuan Wang , Xin-Yi Li , Yi Zhang , Mei-Na Wu

Neuroinflammation plays a pivotal role in the pathogenesis of Alzheimer's disease (AD). Anisomycin is a pyrrolidine antibiotic isolated from Streptomyces griseolus, which is an efficient anti-inflammatory agent that functions both in vivo and in vitro. However, it is not clear whether anisomycin can exert neuroprotective effect in AD. In the present study, anisomycin was intragastrically administrated to female triple-transgenic AD (3xTg-AD) model mice, then Morris water maze test was used to observe the long-term spatial memory of mice, the in vivo hippocampal field potential recording was performed to evaluate the synaptic plasticity, the Western blot and immunofluorescence were employed to detect pathological changes, and the bioinformatics analysis was used to predict the potential target of anisomycin exerting effects in AD. The results showed that anisomycin ameliorated the long-term spatial memory deficits, improved LTP depression and increased the expression of PSD-95, reduced the Aβ and tau pathologies, and alleviated the activation of microglia and astrocytes in the brains of 3xTg-AD mice. In addition, the results from bioinformatics analysis showed that the potential target of anisomycin focused on inflammatory pathway. These results indicated that anisomycin exerts neuroprotective effects in 3xTg-AD mice by alleviating neuroinflammation, but the potential mechanism of anisomycin exerting neuroprotective effects needs to be further investigated.

神经炎症在阿尔茨海默病（AD）的发病机制中起着关键作用。Anisomycin 是一种从 Streptomyces griseolus 中分离出来的吡咯烷抗生素，是一种高效的抗炎药物，在体内和体外都能发挥作用。然而，目前尚不清楚安乃近霉素能否对AD产生神经保护作用。本研究给雌性三转基因AD（3xTg-AD）模型小鼠灌胃安乃近，然后用Morris水迷宫试验观察小鼠的长期空间记忆，用体内海马场电位记录评价突触可塑性，用Western印迹和免疫荧光检测病理变化，用生物信息学分析预测安乃近在AD中的潜在作用靶点。结果表明，在3xTg-AD小鼠脑中，安乃近能改善长期空间记忆障碍，改善LTP抑制，增加PSD-95的表达，减少Aβ和tau病理变化，缓解小胶质细胞和星形胶质细胞的活化。此外，生物信息学分析结果表明，安乃近霉素的潜在靶点集中在炎症通路。这些结果表明，安乃近霉素通过缓解神经炎症对3xTg-AD小鼠发挥了神经保护作用，但安乃近霉素发挥神经保护作用的潜在机制还有待进一步研究。

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