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Intranasal LAG3 antibody infusion induces a rapid antidepressant effect via the hippocampal ERK1/2-BDNF signaling pathway in chronically stressed mice 鼻内注射 LAG3 抗体可通过海马 ERK1/2-BDNF 信号通路对慢性应激小鼠产生快速抗抑郁作用。
IF 4.6 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-08-15 DOI: 10.1016/j.neuropharm.2024.110118
Yunli Fang , Hainan Pan , Haojie Zhu , Hanxiao Wang , Minxiu Ye , Jie Ren , Jie Peng , Jinxin Li , Xu Lu , Chao Huang

The decline of microglia in the dentate gyrus is a new phenomenon that may explain the pathogenesis of depression, and reversing this decline has an antidepressant effect. The development of strategies that restore the function of dentate gyrus microglia in under stressful conditions is becoming a new focus. Lymphocyte-activating gene-3 (LAG3) is an immune checkpoint expressed by immune cells including microglia. One of its functions is to suppress the expansion of immune cells. In a recent study, chronic systemic administration of a LAG3 antibody that readily penetrates the brain was reported to reverse chronic stress-induced hippocampal microglia decline and depression-like behaviors. We showed here that a single intranasal infusion of a LAG3 antibody (In-LAG3 Ab) reversed chronic unpredictable stress (CUS)-induced depression-like behaviors in a dose-dependent manner, which was accompanied by an increase in brain-derived neurotrophic factor (BDNF) in the dentate gyrus. Infusion of an anti-BDNF antibody into the dentate gyrus, construction of knock-in mice with the BDNF Val68Met allele, or treatment with the BDNF receptor antagonist K252a abolished the antidepressant effect of In-LAG3 Ab. Activation of extracellular signal-regulated kinase1/2 (ERK1/2) is required for the reversal effect of In-LAG3 Ab on CUS-induced depression-like behaviors and BDNF decrease in the dentate gyrus. Moreover, both inhibition and depletion of microglia prevented the reversal effect of In-LAG3 Ab on CUS-induced depression-like behaviors and impairment of ERK1/2-BDNF signaling in the dentate gyrus. These results suggest that In-LAG3 Ab exhibits an antidepressant effect through microglia-mediated activation of ERK1/2 and synthesis of BDNF in the dentate gyrus.

齿状回小胶质细胞功能衰退是一种新现象,可能解释了抑郁症的发病机制,而逆转这种衰退具有抗抑郁作用。开发在压力条件下恢复齿状回小胶质细胞功能的策略正成为一个新的焦点。淋巴细胞活化基因-3(LAG3)是包括小胶质细胞在内的免疫细胞表达的一种免疫检查点。其功能之一是抑制免疫细胞的扩张。在最近的一项研究中,据报道,长期全身性服用易于穿透大脑的 LAG3 抗体可逆转慢性应激诱导的海马小胶质细胞衰退和抑郁样行为。我们的研究表明,单次鼻内注射 LAG3 抗体(In-LAG3 Ab)能以剂量依赖性的方式逆转慢性不可预测应激(CUS)诱导的抑郁样行为,同时齿状回中的脑源性神经营养因子(BDNF)也有所增加。向齿状回注入抗 BDNF 抗体、构建 BDNF Val68Met 等位基因基因敲入小鼠或用 BDNF 受体拮抗剂 K252a 治疗都会取消 In-LAG3 Ab 的抗抑郁作用。In-LAG3 Ab对CUS诱导的抑郁样行为和齿状回中BDNF减少的逆转效应需要细胞外信号调节激酶1/2(ERK1/2)的激活。此外,抑制和消耗小胶质细胞都能阻止 In-LAG3 Ab 对 CUS 诱导的抑郁样行为和齿状回中 ERK1/2-BDNF 信号转导损伤的逆转作用。这些结果表明,In-LAG3 Ab通过小胶质细胞介导的齿状回中ERK1/2的激活和BDNF的合成发挥抗抑郁作用。
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引用次数: 0
Neurolipidomics in schizophrenia: A not so well-oiled machine 精神分裂症的神经脂质组学:运转不灵的机器。
IF 4.6 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-08-15 DOI: 10.1016/j.neuropharm.2024.110117
Carlos Manuel Zapata-Martín del Campo , Garth L. Nicolson , Adonis Sfera

Most patients with schizophrenia (SCZ) do not exhibit violent behaviors and are more likely to be victims rather than perpetrators of violent acts. However, a subgroup of forensic detainees with SCZ exhibit tendencies to engage in criminal violations. Although numerous models have been proposed, ranging from substance use, serotonin transporter gene, and cognitive dysfunction, the molecular underpinnings of violence in SCZ patients remains elusive.

Lithium and clozapine have established anti-aggression properties and recent studies have linked low cholesterol levels and ultraviolet (UV) radiation with human aggression, while vitamin D3 reduces violent behaviors. A recent study found that vitamin D3, omega-3 fatty acids, magnesium, and zinc lower aggression in forensic population.

In this review article, we take a closer look at aryl hydrocarbon receptor (AhR) and the dysfunctional lipidome in neuronal membranes, with emphasis on cholesterol and vitamin D3 depletion, as sources of aggressive behavior. We also discuss modalities to increase the fluidity of neuronal double layer via membrane lipid replacement (MLR) and natural or synthetic compounds.

大多数精神分裂症(SCZ)患者不会表现出暴力行为,他们更有可能成为暴力行为的受害者而非实施者。然而,在法医拘留的精神分裂症患者中,有一小部分人表现出从事违法犯罪行为的倾向。尽管从药物使用、5-羟色胺转运体基因和认知功能障碍等方面提出了许多模型,但SCZ患者暴力行为的分子基础仍然难以捉摸。锂和氯氮平具有抗攻击性,最近的研究表明,低胆固醇水平和紫外线(UV)辐射与人类攻击行为有关,而维生素 D3 可减少暴力行为。最近的一项研究发现,维生素 D3、ω-3 脂肪酸、镁和锌可降低法医人群的攻击性。在这篇综述文章中,我们将仔细研究神经元膜中的芳基烃受体(AhR)和功能失调的脂质体,重点是胆固醇和维生素 D3 的消耗,它们是攻击行为的来源。我们还讨论了通过膜脂置换(MLR)和天然或合成化合物增加神经元双层流动性的方法。
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引用次数: 0
Medial prefrontal cortex circuitry and social behaviour in autism 自闭症患者的内侧前额叶皮层回路和社交行为。
IF 4.6 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-08-14 DOI: 10.1016/j.neuropharm.2024.110101
Diego H. Mediane , Shinjini Basu , Emma N. Cahill , Paul G. Anastasiades

Autism spectrum disorder (ASD) has proven to be highly enigmatic due to the diversity of its underlying genetic causes and the huge variability in symptom presentation. Uncovering common phenotypes across people with ASD and pre-clinical models allows us to better understand the influence on brain function of the many different genetic and cellular processes thought to contribute to ASD aetiology. One such feature of ASD is the convergent evidence implicating abnormal functioning of the medial prefrontal cortex (mPFC) across studies. The mPFC is a key part of the 'social brain' and may contribute to many of the changes in social behaviour observed in people with ASD. Here we review recent evidence for mPFC involvement in both ASD and social behaviours. We also highlight how pre-clinical mouse models can be used to uncover important cellular and circuit-level mechanisms that may underly atypical social behaviours in ASD.

自闭症谱系障碍(ASD)由于其潜在遗传原因的多样性和症状表现的巨大差异性,已被证明是一种高度神秘的疾病。通过发现患者和临床前模型的共同表型,我们可以更好地理解被认为是自闭症病因的多种不同遗传和细胞过程对大脑功能的影响。ASD 的一个特点是,在各项研究中都有证据表明内侧前额叶皮层 (mPFC) 功能异常。内侧前额叶皮层是 "社交脑 "的关键部分,可能是导致 ASD 患者社交行为发生改变的原因之一。在此,我们回顾了 mPFC 参与 ASD 和社会行为的最新证据。我们还强调了如何利用临床前小鼠模型来揭示可能导致 ASD 患者非典型社交行为的重要细胞和回路机制。
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引用次数: 0
Influence of β2-adrenergic selective agonist formoterol on the motor unit of a mouse model of a congenital myasthenic syndrome with complete VAChT deletion β2-脱能选择性激动剂福莫特罗对伴有完全 VAChT 脱失的遗传性肌萎缩综合征猴子模型运动单元的影响。
IF 4.6 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-08-14 DOI: 10.1016/j.neuropharm.2024.110116
Leonardo Rossi , Bárbara I. Mota , Priscila A.C. Valadão , Matheus P.S. Magalhães-Gomes , Bruna S. Oliveira , Silvia Guatimosim , Luiz C.C. Navegantes , Aline S. Miranda , Marco A.M. Prado , Vânia F. Prado , Cristina Guatimosim

Congenital Myasthenic Syndromes (CMS) are a set of genetic diseases that affect the neuromuscular transmission causing muscular weakness. The standard pharmacological treatment aims at ameliorating the myasthenic symptom by acetylcholinesterase inhibitors. Most patients respond well in the short and medium term, however, over time the beneficial effects rapidly fade, and the efficacy of the treatment diminishes. Increasing evidence shows that β2-adrenergic agonists can be a suitable choice for the treatment of neuromuscular disorders, including CMS, as they promote beneficial effects in the neuromuscular system. The exact mechanism on which they rely is not completely understood, although patients and animal models respond well to the treatment, especially over extended periods. Here, we report the use of the long-lasting specific β2-adrenergic agonist formoterol in a myasthenic mouse model (mnVAChT-KD), featuring deletion of VAChT (Vesicular Acetylcholine Transporter) specifically in the α-motoneurons. Our findings demonstrate that formoterol treatment (300 μg/kg/day; sc) for 30 days increased the neuromuscular junction area, induced skeletal muscle hypertrophy and altered fibre type composition in myasthenic mice. Interestingly, β2-adrenergic agonists have shown efficacy even in the absence of ACh (acetylcholine). Our data provide important evidence supporting the potential of β2-adrenergic agonists in treating neuromuscular disorders of pre-synaptic origin and characterized by disruptions in nerve-muscle communication, through a direct and beneficial action within the motor unit.

先天性肌无力综合征(CMS)是一组影响神经肌肉传导、导致肌肉无力的遗传疾病。标准药物治疗的目的是通过乙酰胆碱酯酶抑制剂改善肌无力症状。大多数患者在短期和中期内反应良好,但随着时间的推移,有益作用会迅速消失,疗效也会减弱。越来越多的证据表明,β2-肾上腺素能激动剂可作为治疗包括 CMS 在内的神经肌肉疾病的合适选择,因为它们能促进神经肌肉系统的有益作用。尽管患者和动物模型对这种疗法反应良好,尤其是在长期治疗中,但它们所依赖的确切机制尚未完全明了。在此,我们报告了在肌无力小鼠模型(mnVAChT-KD)中使用长效特异性 β2-肾上腺素能激动剂福莫特罗的情况。我们的研究结果表明,福莫特罗治疗(300 μg/kg/天;sc)30 天可增加肌无力小鼠的神经肌肉接头面积、诱导骨骼肌肥大并改变纤维类型组成。有趣的是,即使在没有乙酰胆碱(ACh)的情况下,β2-肾上腺素能激动剂也有疗效。我们的数据提供了重要的证据,支持β2-肾上腺素能激动剂通过在运动单元内发挥直接和有益的作用,治疗突触前源性神经肌肉疾病的潜力。
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引用次数: 0
Enhanced interleukin-16-CD4 signaling in CD3 T cell mediates neuropathic pain via activating astrocytes in female mice CD3 T 细胞中白细胞介素-16-CD4 信号的增强通过激活雌性小鼠的星形胶质细胞介导神经性疼痛
IF 4.6 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-08-11 DOI: 10.1016/j.neuropharm.2024.110115
Xuan Zhu , Xiang Li , Siyi Liu , Yun-Han Zhao , Xue-Ru Liu , Xing-Yu Liu , Rongrong Yao , Lixia Tian , Xin-Qi Liu , Fanjun Meng , Lingli Liang

Immune cells and interleukins play a crucial role in female-specific pain signaling. Interleukin 16 (IL-16) is a cytokine primarily associated with CD4+ T cell function. While previous studies have demonstrated the important role of spinal CD4+ T cells in neuropathic pain, the specific contribution of IL-16 to neuropathic pain remains unclear. In this study, by using a spinal nerve ligation (SNL)-induced neuropathic pain mice model, we found that SNL induced an increase in IL-16 mRNA levels, which persisted for a longer duration in female mice compared to male mice. Immunofluorescence analysis further confirmed enhanced IL-16- and CD4-positive signals in the spinal dorsal horn following SNL surgery in female mice. Knockdown of spinal IL-16 by siRNA or inhibition of CD4 by FGF22-IN-1, a CD4 inhibitor, attenuated established mechanical and thermal pain hypersensitivity induced by SNL. Furthermore, female mice injected with IL-16 intrathecally exhibited significant spontaneous pain, mechanical and thermal hyperalgesia, all of which could be alleviated by FGF22-IN-1 or a CD3 antibody. Additionally, IL-16 induced astrocyte activation but not microglial activation in the spinal dorsal horn of female mice. Meanwhile, astrocyte activation could be suppressed by the CD3 antibody. These results provide compelling evidence that IL-16 promotes astrocyte activation via CD4 on CD3+ T cells, which is critical for maintaining neuropathic pain in female mice.

免疫细胞和白细胞介素在女性特异性疼痛信号传导中起着至关重要的作用。白细胞介素 16(IL-16)是一种主要与 CD4+ T 细胞功能相关的细胞因子。虽然之前的研究已经证明了脊髓 CD4+ T 细胞在神经病理性疼痛中的重要作用,但 IL-16 对神经病理性疼痛的具体贡献仍不清楚。在本研究中,通过使用脊神经结扎(SNL)诱导的神经病理性疼痛小鼠模型,我们发现 SNL 会诱导 IL-16 mRNA 水平的增加,与雄性小鼠相比,雌性小鼠 IL-16 mRNA 水平的增加持续时间更长。免疫荧光分析进一步证实,雌性小鼠接受 SNL 手术后,脊髓背角 IL-16 和 CD4 阳性信号增强。通过 siRNA 敲除脊髓 IL-16 或通过 CD4 抑制剂 FGF22-IN-1 抑制 CD4,可减轻 SNL 引起的机械和热痛觉过敏。此外,雌性小鼠鞘内注射 IL-16 后会表现出明显的自发痛、机械痛和热痛觉过敏,而 FGF22-IN-1 或 CD3 抗体可减轻所有这些症状。此外,IL-16 能诱导雌性小鼠脊髓背角的星形胶质细胞活化,但不能诱导小胶质细胞活化。同时,CD3 抗体可抑制星形胶质细胞的活化。这些结果提供了令人信服的证据,证明IL-16通过CD3+ T细胞上的CD4促进星形胶质细胞活化,这对维持雌性小鼠的神经性疼痛至关重要。
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引用次数: 0
Alcohol, flexible behavior, and the prefrontal cortex: Functional changes underlying impaired cognitive flexibility 酒精、灵活行为和前额叶皮层:认知灵活性受损背后的功能变化。
IF 4.6 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-08-10 DOI: 10.1016/j.neuropharm.2024.110114
Kathryn E. Nippert , Courtney P. Rowland , Elena M. Vazey , David E. Moorman

Cognitive flexibility enables individuals to alter their behavior in response to changing environmental demands, facilitating optimal behavior in a dynamic world. The inability to do this, called behavioral inflexibility, is a pervasive behavioral phenotype in alcohol use disorder (AUD), driven by disruptions in cognitive flexibility. Research has repeatedly shown that behavioral inflexibility not only results from alcohol exposure across species but can itself be predictive of future drinking. Like many high-level executive functions, flexible behavior requires healthy functioning of the prefrontal cortex (PFC). The scope of this review addresses two primary themes: first, we outline tasks that have been used to investigate flexibility in the context of AUD or AUD models. We characterize these based on the task features and underlying cognitive processes that differentiate them from one another. We highlight the neural basis of flexibility measures, focusing on the PFC, and how acute or chronic alcohol in humans and non-human animal models impacts flexibility. Second, we consolidate findings on the molecular, physiological and functional changes in the PFC elicited by alcohol, that may contribute to cognitive flexibility deficits seen in AUD. Collectively, this approach identifies several key avenues for future research that will facilitate effective treatments to promote flexible behavior in the context of AUD, to reduce the risk of alcohol related harm, and to improve outcomes following AUD.

认知灵活性使个体能够根据不断变化的环境需求改变自己的行为,从而在动态世界中实现最佳行为。无法做到这一点,即所谓的行为缺乏灵活性,是酒精使用障碍(AUD)中普遍存在的行为表型,其驱动因素是认知灵活性的破坏。研究一再表明,行为缺乏灵活性不仅是跨物种酒精暴露的结果,其本身还能预测未来的饮酒情况。与许多高级执行功能一样,灵活的行为需要前额叶皮质(PFC)的健康运作。本综述涉及两个主要主题:首先,我们概述了在 AUD 或 AUD 模型中用于研究灵活性的任务。我们根据这些任务的特征以及区别于其他任务的基本认知过程来描述这些任务。我们强调了灵活性测量的神经基础,重点是前脑功能区,以及人类和非人类动物模型的急性或慢性酒精如何影响灵活性。其次,我们整合了有关酒精引起的前脑功能区分子、生理和功能变化的研究成果,这些变化可能会导致 AUD 中出现的认知灵活性缺陷。总之,这种方法为今后的研究确定了几条关键途径,有助于采取有效的治疗方法,促进 AUD 患者的灵活行为,降低酒精相关伤害的风险,并改善 AUD 后的治疗效果。
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引用次数: 0
Long-term saturated fat-enriched diets impair hippocampal learning and memory processes in a sex-dependent manner 长期富含饱和脂肪的饮食会以性别依赖的方式损害海马学习和记忆过程。
IF 4.6 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-08-10 DOI: 10.1016/j.neuropharm.2024.110108
Ana Belén Sanz-Martos , María Roca , Adrián Plaza , Beatriz Merino , Mariano Ruiz-Gayo , Nuria del Olmo

Consumption of saturated fat-enriched diets during adolescence has been closely associated with the reduction of hippocampal synaptic plasticity and the impairment of cognitive function. Nevertheless, the effect of long-term intake of these foods has not yet been studied. In the present study, we have investigated the effect of a treatment, lasting for 40 weeks, with a diet enriched in saturated fat (SOLF) on i) spatial learning and memory, ii) hippocampal synaptic transmission and plasticity, and iii) hippocampal gene expression levels in aged male and female mice. Our findings reveal that SOLF has a detrimental impact on spatial memory and synaptic plasticity mechanisms, such as long-term potentiation (LTP), and downregulates Gria1 expression specifically in males. In females, SOLF downregulates the gene expression of Gria1/2/3 and Grin1/2A/2B glutamate receptor subunits as well as some proinflammatory interleukins. These findings highlight the importance of considering sex-specific factors when assessing the long-term effects of high-fat diets on cognition and brain plasticity.

青少年时期摄入富含饱和脂肪的饮食与海马突触可塑性降低和认知功能受损密切相关。然而,长期摄入这些食物的影响尚未得到研究。在本研究中,我们调查了持续 40 周的富含饱和脂肪(SOLF)饮食对雌雄老年小鼠的以下方面的影响:i)空间学习和记忆;ii)海马突触传递和可塑性;iii)海马基因表达水平。我们的研究结果表明,SOLF 对空间记忆和突触可塑性机制(如长期电位(LTP))有不利影响,并特别下调雄性小鼠的 Gria1 表达。在女性中,SOLF会下调Gria1/2和Grin1/2A/2B谷氨酸受体亚基以及一些促炎性白细胞介素的基因表达。这些发现凸显了在评估高脂饮食对认知和大脑可塑性的长期影响时,考虑性别特异性因素的重要性。
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引用次数: 0
Deguelin inhibits the glioblastoma progression through suppressing CCL2/NFκB signaling pathway Deguelin 通过抑制 CCL2/NFκB 信号通路抑制胶质母细胞瘤的进展。
IF 4.6 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-08-10 DOI: 10.1016/j.neuropharm.2024.110109
Yiming Qian , Jianhong Dong , Wei Zhang , Xiumin Xue , Zhenrong Xiong , Weiquan Zeng , Qian Wang , Ziwei Fan , Zhenxing Zuo , Zhihui Huang , Yuanyuan Jiang

Glioblastoma multiforme (GBM) is the most common primary intracranial tumor with characteristics of high aggressiveness and poor prognosis. Deguelin, a component from the bark of Leguminosae Mundulea sericea (African plant), displays antiproliferative effects in some tumors, however, the inhibitory effect and mechanism of deguelin on GBM were still poorly understood. At first, we found that deguelin reduced the viability of GBM cells by causing cell cycle arrest in G2/M phase and inducing their apoptosis. Secondly, deguelin inhibited the migration of GBM cells. Next, RNA-seq analysis identified that CCL2 (encoding chemokine CCL2) was downregulated significantly in deguelin-treated GBM cells. As reported, CCL2 promoted the cell growth, and CCL2 was associated with regulating NFκB signaling pathway, as well as involved in modulating tumor microenvironment (TME). Furthermore, we found that deguelin inactivated CCL2/NFκB signaling pathway, and exougous CCL2 could rescue the anti-inhibitory effect of deguelin on GBM cells via upregulating NFκB. Finally, we established a syngeneic intracranial orthotopic GBM model and found that deguelin regressed the tumor growth, contributed to an anti-tumorigenic TME and inhibited angiogenesis of GBM by suppressing CCL2/NFκB in vivo. Taken together, these results suggest the anti-GBM effect of deguelin via inhibiting CCL2/NFκB pathway, which may provide a new strategy for the treatment of GBM.

多形性胶质母细胞瘤(GBM)是最常见的原发性颅内肿瘤,具有侵袭性强、预后差的特点。非洲豆科植物Mundulea sericea树皮中的一种成分Deguelin对某些肿瘤具有抗增殖作用,但Deguelin对GBM的抑制作用和机制仍不甚明了。首先,我们发现鹿角菜苷通过使细胞周期停滞在 G2/M 期并诱导细胞凋亡来降低 GBM 细胞的活力。其次,deguelin抑制了GBM细胞的迁移。接着,RNA-seq分析发现,CCL2(编码一种重要的趋化因子CCL2)在deguelin处理的GBM细胞中显著下调。据报道,CCL2通过NFκB信号通路促进GBM细胞的活力和迁移,抑制GBM细胞的凋亡,并调节GBM肿瘤微环境(TME),从而促进GBM的进展。此外,我们还发现CCL2可以挽救deguelin通过NFκB信号通路对GBM细胞的抗抑制作用。最后,我们建立了颅内同种异位 GBM 模型,发现 deguelin 可抑制肿瘤生长,通过抑制 CCL2/NFκB 促进免疫抑制 TME 并抑制体内 GBM 的血管生成。综上所述,这些结果表明,deguelin可通过抑制CCL2/NFκB途径发挥抗GBM作用,这可能为治疗GBM提供了一种新策略。
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引用次数: 0
MSK1 is required for the experience- and ampakine-dependent enhancement of spatial reference memory and reversal learning and for the induction of Arc and BDNF MSK1是经验和安巴碱依赖性增强空间参照记忆和逆转学习的必要条件。
IF 4.6 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-08-10 DOI: 10.1016/j.neuropharm.2024.110110
Lorenzo Morè , Lucia Privitera , Marcia Lopes , J. Simon C. Arthur , Julie C. Lauterborn , Sonia A.L. Corrêa , Bruno G. Frenguelli
There is considerable interest in the development of nootropics, pharmacological agents that can improve cognition across a range of both cognitive modalities and cognitive disabilities. One class of cognitive enhancers, the ampakines, has attracted particular attention by virtue of improving cognition associated with animal models of neurodevelopmental, neurodegenerative, and psychiatric conditions, as well as in age-related cognitive impairment. Ampakines elevate CNS levels of BDNF, and it is through this elevation that their beneficial actions are believed to occur. However, what transduces the elevation of BDNF into long-lasting cognitive enhancement is not known. We have previously shown that MSK1, by virtue of its ability to regulate gene transcription, converts the elevation of BDNF associated with environmental enrichment into molecular, synaptic, cognitive and genomic adaptations that underlie enrichment-induced enhanced synaptic plasticity and learning and memory, a property that MSK1 retains across the lifespan. To establish whether MSK1 similarly converts ampakine-induced elevations of BDNF into cognitive enhancement we tested an ampakine (CX929) in male WT mice and in male mice in which the kinase activity of MSK1 was inactivated. We found that MSK1 is required for the ampakine-dependent improvement in spatial reference memory and cognitive flexibility, and for the elevations of BDNF and the plasticity-related protein Arc associated with ampakines and experience. These observations implicate MSK1 as a key enabler of the beneficial effects of ampakines on cognitive function, and furthermore identify MSK1 as a hub for BDNF-elevating nootropic strategies.
人们对能改善各种认知模式和认知障碍的药理制剂--促智剂的开发产生了浓厚的兴趣。其中一类认知增强剂--安非他酮类药物--因能改善与神经发育、神经退行性和精神疾病动物模型相关的认知能力,以及与年龄相关的认知障碍,而引起了人们的特别关注。安帕金类药物能提高中枢神经系统的 BDNF 水平,人们认为正是通过这种提高,安帕金类药物才发挥了有益的作用。然而,是什么将 BDNF 的升高转化为持久的认知能力增强尚不清楚。我们之前已经证明,MSK1 凭借其调控基因转录的能力,将与环境富集相关的 BDNF 升高转化为分子、突触、认知和基因组适应性,这些适应性是富集诱导的突触可塑性增强以及学习和记忆增强的基础,MSK1 的这一特性在人的一生中都会保持。为了确定 MSK1 是否同样能将安帕金诱导的 BDNF 升高转化为认知增强,我们在雄性 WT 小鼠和 MSK1 激酶活性发生突变的雄性小鼠体内测试了安帕金(CX929)。我们发现,安非他明依赖性地改善空间参照记忆和认知灵活性,以及与安非他明和经验相关的 BDNF 和可塑性相关蛋白 Arc 的升高,都需要 MSK1。这些观察结果表明,MSK1是安非他明类药物对认知功能产生有益影响的关键因素,并进一步确定了MSK1是提高BDNF的促智策略的枢纽。
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引用次数: 0
Zelquistinel acts at an extracellular binding domain to modulate intracellular calcium inactivation of N-methyl-d-aspartate receptors Zelquistinel 作用于细胞外结合域,调节 N-甲基-D-天冬氨酸受体的细胞内钙失活。
IF 4.6 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-08-06 DOI: 10.1016/j.neuropharm.2024.110100
Xiao-lei Zhang , Yong-Xin Li , Nils Berglund , Jeffrey S. Burgdorf , John E. Donello , Joseph R. Moskal , Patric K. Stanton

Stinels are a novel class of N-methyl-d-aspartate glutamate receptor (NMDAR) positive allosteric modulators. We explored mechanism of action and NR2 subtype specificity of the stinel zelquistinel (ZEL) in HEK 293 cells expressing recombinant NMDARs. ZEL potently enhanced NMDAR current at NR2A (EC50 = 9.9 ± 0.5 nM) and NR2C-containing (EC50 = 9.7 ± 0.6 nM) NMDARs, with a larger ceiling enhancement at NR2B-NMDAR (EC50 = 35.0 ± 0.7 nM), while not affecting NR2D-containing NMDARs. In cells expressing NR2A and NR2C-containing NMDARs, ZEL exhibited an inverted-U dose-response relation, with a low concentration enhancement and high concentration suppression of NMDAR currents. Extracellular application of ZEL potentiated NMDAR receptor activity via prolongation of NMDAR currents. Replacing the slow Ca2+ intracellular chelator EGTA with the fast chelator BAPTA blocked ZEL potentiation of NMDARs, suggesting an action on intracellular Ca2+-calmodulin-dependent inactivation (CDI). Consistent with this mechanism of action, removal of the NR1 intracellular C-terminus, or intracellular infusion of a calmodulin blocking peptide, blocked ZEL potentiation of NMDAR current. In contrast, BAPTA did not prevent high-dose suppression of current, indicating this effect has a different mechanism of action. These data indicate ZEL is a novel positive allosteric modulator that binds extracellularly and acts through a unique long-distance mechanism to reduce NMDAR CDI, eliciting enhancement of NMDAR current. The critical role that NMDARs play in long-term, activity-dependent synaptic plasticity, learning, memory and cognition, suggests dysregulation of CDI may contribute to psychiatric disorders such as depression, schizophrenia and others, and that the stinel class of drugs can restore NMDAR-dependent synaptic plasticity by reducing activity-dependent CDI.

Stinels是一类新型的N-甲基-D-天冬氨酸谷氨酸受体(NMDAR)正异构调节剂。我们在表达重组 NMDARs 的 HEK 293 细胞中探索了 Stinel zelquistinel (ZEL) 的作用机制和 NR2 亚型特异性。ZEL 能有效增强 NR2A(EC50=9.9 ± 0.5 nM)和含 NR2C(EC50=9.7 ± 0.6 nM)的 NMDAR 电流,对 NR2B-NMDAR 的上限增强更大(EC50=35.0 ± 0.7 nM),而对含 NR2D 的 NMDAR 无影响。在表达含 NR2A 和 NR2C 的 NMDAR 的细胞中,ZEL 表现出倒 U 型的剂量-反应关系,低浓度增强,高浓度抑制 NMDAR 电流。细胞外施用 ZEL 可通过延长 NMDAR 电流来增强 NMDAR 受体的活性。用快速螯合剂 BAPTA 取代慢速 Ca2+ 细胞内螯合剂 EGTA 可阻断 ZEL 对 NMDAR 的增效作用,这表明 ZEL 对细胞内 Ca2+ - 钙调素依赖性失活 (CDI) 起作用。与这一作用机制相一致的是,去除 NR1 细胞内的 C 端,或在细胞内注入钙调蛋白阻断肽,都会阻断 ZEL 对 NMDAR 电流的增效作用。与此相反,BAPTA 并不能阻止大剂量抑制电流,这表明这种效应具有不同的作用机制。这些数据表明,ZEL 是一种新型的正性异构调节剂,它能在细胞外结合,并通过独特的长程机制降低 NMDAR CDI,从而增强 NMDAR 电流。NMDAR 在长期、依赖活动的突触可塑性、学习、记忆和认知中发挥着关键作用,这表明 CDI 失调可能是抑郁症、精神分裂症等精神疾病的诱因,而 Stinel 类药物可以通过降低依赖活动的 CDI 来恢复突触可塑性。
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引用次数: 0
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Neuropharmacology
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