Laboratory of Pharmacology, School of Pharmaceutical Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan; Medicinal Research Laboratories, School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
Laboratory of Pharmacology, School of Pharmaceutical Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan; Medicinal Research Laboratories, School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
Behav Brain Res. 2020 Apr 6;383:112506. doi: 10.1016/j.bbr.2020.112506. Epub 2020 Jan 23.
Gabapentinoids, which are the common analgesics, are also thought to be an effective treatment for anxiety disorder, which is one of several psychiatric disorders triggered and exacerbated by stress. The aim of the present study was to investigate whether mirogabalin, a recently launched gabapentinoid, protects multiple brain functions against repeated restraint stress. Adult male ddY mice were restrained for 7 days (repeated restraint stress: 2 h/day) or for 30 min (single restraint stress). Mirogabalin (intraperitoneal, intracerebroventricular or intrahippocampal injection) was administered prior to the restraint stress. Y-maze, elevated-plus maze and c-Fos immunohistochemistry were performed to evaluate learning function, anxiety levels and hippocampal neuronal activities, respectively, after the 7th day of the repeated restraint stress. Intestinal function was evaluated in terms of defecation, which was scored after the 5th day of repeated restraint stress and by the number of fecal pellets excreted after a single session of restraint stress. Repeated restraint stress induced memory dysfunction, anxiety-like behavior, an abnormal defecation score and increased hippocampal c-Fos expression. These changes were prevented by systemic administration of mirogabalin. Abnormal defecation was also induced by single restraint stress, and was inhibited by both systemic and central administration of mirogabalin, suggesting that the effect on the intestinal function was also mediated via the central nervous system. Enhancement of c-Fos expression by repeated stress was decreased by intrahippocampal injection of mirogabalin. Together, these observations suggest that mirogabalin protects multiple brain functions from repeated stress, which may be mediated by inhibition of hippocampal neuron hyperactivation.
加巴喷丁类药物是常见的镇痛药，也被认为是治疗焦虑症的有效方法，焦虑症是由压力引发和加剧的几种精神疾病之一。本研究旨在探讨新型加巴喷丁类药物米罗加巴林是否能保护多种大脑功能免受重复束缚应激的影响。成年雄性 ddY 小鼠接受 7 天的束缚（重复束缚应激：每天 2 小时）或 30 分钟的束缚（单次束缚应激）。在束缚应激之前，通过腹腔内、脑室内或海马内注射米罗加巴林进行给药。在第 7 天重复束缚应激后，通过 Y 迷宫、高架十字迷宫和 c-Fos 免疫组织化学评估学习功能、焦虑水平和海马神经元活性。在第 5 天重复束缚应激后和单次束缚应激后，通过粪便评分和粪便颗粒数评估肠道功能。重复束缚应激导致记忆功能障碍、焦虑样行为、异常排便评分和海马 c-Fos 表达增加。这些变化可通过全身给予米罗加巴林来预防。单次束缚应激也会引起异常排便，且全身和中枢给予米罗加巴林均可抑制这种变化，这表明其对肠道功能的影响也是通过中枢神经系统介导的。重复应激引起的 c-Fos 表达增强可通过海马内注射米罗加巴林而减少。综上所述，这些观察结果表明米罗加巴林可保护多种大脑功能免受重复应激的影响，其机制可能是通过抑制海马神经元的过度激活。
