Department of Molecular and Celular Signaling, Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), Santander, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Santander, Spain; Department of Physiology and Pharmacology, Faculty of Medicine, University of Cantabria, Santander, Spain.
Institut de Recherches Internationales Servier, Pôle d'Innovation Thérapeutique Neuropsychiatrie, Suresnes Cedex, France.
Prog Neuropsychopharmacol Biol Psychiatry. 2019 Jul 13;93:205-213. doi: 10.1016/j.pnpbp.2019.04.005. Epub 2019 Apr 10.
S 47445 is a positive allosteric modulator of glutamate AMPA-type receptors that possesses procognitive, neurotrophic and enhancing synaptic plasticity properties. Its chronic administration promotes antidepressant- and anxiolytic-like effects in different rodent models of depression. We have evaluated the behavioral effects of S 47445 in the bilateral olfactory bulbectomy mice model (OB) and the adaptive changes in those proteins associated to brain neuroplasticity (BDNF and mTOR pathway). Following OB surgery, adult C57BL/6J male mice were chronically administered S 47445 (1, 3 and 10 mg/kg/day; i.p.) and fluoxetine (18 mg/kg/day; i.p.), and then behaviorally tested in the open field test. Afterwards, the expression levels of BDNF, mTOR, phospho-mTOR, 4EBP1 and phospho-4EBP1 were evaluated in hippocampus and prefrontal cortex. Both drugs reduced the OB-induced locomotor activity, a predictive outcome of antidepressant efficacy, with a similar temporal pattern of action. S 47445, but not fluoxetine, showed an anxiolytic effect as reflected by an increased central activity. Chronic administration of S 47445 reversed OB-induced changes in BDNF and phopho-mTOR expression in hippocampus but not in prefrontal cortex. The chronic administration of S 47445 induced antidepressant- and anxiolytic-like effects at low-medium doses (1 and 3 mg/kg/day, i.p.) associated with the reversal of OB-induced changes in hippocampal BDNF and mTOR signaling pathways.
S 47445 是一种谷氨酸 AMPA 型受体的正变构调节剂，具有认知促进、神经营养和增强突触可塑性的特性。其慢性给药可在不同的抑郁啮齿动物模型中促进抗抑郁和抗焦虑样作用。我们评估了 S 47445 在双侧嗅球切除术小鼠模型（OB）中的行为效应，以及与脑神经可塑性相关的那些蛋白的适应性变化（BDNF 和 mTOR 通路）。在 OB 手术后，成年 C57BL/6J 雄性小鼠接受 S 47445（1、3 和 10mg/kg/天；腹腔内注射）和氟西汀（18mg/kg/天；腹腔内注射）的慢性给药，然后在开阔场试验中进行行为测试。之后，在海马体和前额叶皮层评估 BDNF、mTOR、磷酸化 mTOR、4EBP1 和磷酸化 4EBP1 的表达水平。两种药物均减少了 OB 引起的运动活动，这是抗抑郁疗效的预测结果，具有相似的作用时间模式。S 47445 但不是氟西汀，表现出抗焦虑作用，表现为中央活动增加。S 47445 的慢性给药逆转了 OB 诱导的海马体 BDNF 和 phopho-mTOR 表达的变化，但在前额叶皮层没有。S 47445 的慢性给药在低中剂量（1 和 3mg/kg/天，腹腔内注射）诱导抗抑郁和抗焦虑样作用，与海马体 BDNF 和 mTOR 信号通路中 OB 诱导的变化逆转相关。
