The novel peptide LCGM-10 attenuates metabotropic glutamate receptor 5 activity and demonstrates behavioral effects in animal models

IF 2.6 3区医学 Q2 BEHAVIORAL SCIENCES

Frontiers in Behavioral Neuroscience Pub Date : 2024-02-07 DOI:10.3389/fnbeh.2024.1333258

Anton V. Malyshev, Vsevolod V. Pavshintcev, Nikita A. Mitkin, Iuliia A. Sukhanova, Vasilina R. Gedzun, Alexander S. Zlobin, Igor I. Doronin, Gennady A. Babkin, Tomi K. Sawyer

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Abstract

We employed a structural bioinformatics approach to develop novel peptides with predicted affinity to the binding site for negative allosteric modulators (NAMs) of metabotropic glutamate receptor 5 (mGluR5). Primary screening in zebrafish (Danio rerio) revealed a stimulatory effect of two peptides, LCGM-10 and LCGM-15. Target validation studies using calcium ion flux imaging and a luciferase reporter assay confirmed mGluR5 as the target. LCGM-10 showed greater potency than LCGM-15; it was comparable to that of the mGluR5 NAM 2-methyl-6-(phenylethynyl) pyridine (MPEP). Rodent behavioral screening in the open field and elevated plus maze revealed increased locomotor activity in both tests after acute LCGM-10 treatment, supported by further analysis of home cage spontaneous locomotor activity (SLA). The stimulating effect of a single LCGM-10 administration on SLA was evident up to 60 min after administration and was not accompanied by hypokinetic rebound observed for caffeine. According to our results, LCGM-10 has therapeutic potential to treat hypo- and dyskinesias of various etiologies. Further investigation of LCGM-10 effects in the delay discounting model of impulsive choice in rats revealed reduced trait impulsivity after single and chronic administrations, suggesting potential implication for attention deficit hyperactivity disorder, obsessive compulsive disorder, and addictions.

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新型多肽 LCGM-10 可抑制代谢型谷氨酸受体 5 的活性，并在动物模型中显示出行为效应

我们采用结构生物信息学方法开发了新型多肽，这些多肽与代谢型谷氨酸受体 5（mGluR5）的负变构调节剂（NAMs）结合部位具有亲和力。在斑马鱼（Danio rerio）中进行的初筛显示，LCGM-10 和 LCGM-15 这两种肽具有刺激作用。利用钙离子通量成像和荧光素酶报告实验进行的靶点验证研究确认了 mGluR5 为靶点。LCGM-10 比 LCGM-15 显示出更强的效力；与 mGluR5 NAM 2-甲基-6-（苯乙炔基）吡啶（MPEP）的效力相当。啮齿动物在开阔地和高架加迷宫中的行为筛选显示，急性 LCGM-10 治疗后，两种测试中的运动活动均有所增加，家笼自发运动活动（SLA）的进一步分析也证实了这一点。单次给药 LCGM-10 对 SLA 的刺激作用在给药后 60 分钟内都很明显，而且不会伴随咖啡因引起的运动减弱反弹。根据我们的研究结果，LCGM-10 具有治疗各种病因引起的运动功能低下和运动障碍的潜力。进一步研究 LCGM-10 在大鼠冲动选择延迟折现模型中的作用发现，单次和长期给药后大鼠的特质冲动性降低，这表明它对注意力缺陷多动障碍、强迫症和成瘾症有潜在的疗效。

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来源期刊

Frontiers in Behavioral Neuroscience BEHAVIORAL SCIENCES-NEUROSCIENCES

CiteScore

4.70

自引率

3.30%

发文量

506

审稿时长

6-12 weeks

期刊介绍： Frontiers in Behavioral Neuroscience is a leading journal in its field, publishing rigorously peer-reviewed research that advances our understanding of the neural mechanisms underlying behavior. Field Chief Editor Nuno Sousa at the Instituto de Pesquisa em Ciências da Vida e da Saúde (ICVS) is supported by an outstanding Editorial Board of international experts. This multidisciplinary open-access journal is at the forefront of disseminating and communicating scientific knowledge and impactful discoveries to researchers, academics, clinicians and the public worldwide. This journal publishes major insights into the neural mechanisms of animal and human behavior, and welcomes articles studying the interplay between behavior and its neurobiological basis at all levels: from molecular biology and genetics, to morphological, biochemical, neurochemical, electrophysiological, neuroendocrine, pharmacological, and neuroimaging studies.