University of Lille, CNRS, UMR 8576, UGSF, Unité de Glycobiologie Structurale et Fonctionnelle, Lille, France; International Associated Laboratory (LIA) "Prenatal Stress and Neurodegenerative Diseases", University of Lille, CNRS UMR8576, Sapienza University of Rome, IRCCS Neuromed, France.
Dept. Pharmacology and Human Physiology, Sapienza University of Rome, Italy.
Neuropharmacology. 2018 Jun;135:284-296. doi: 10.1016/j.neuropharm.2018.03.018. Epub 2018 Mar 23.
S 47445 is a positive modulator of glutamate AMPA-type receptors, possessing neurotrophic and enhancing synaptic plasticity effects as well as pro-cognitive and anti-stress properties. Here, the drug was assessed in the perinatal stress (PRS) rat model, known to have a high predictive validity with monoaminergic antidepressants. The effects of a chronic treatment (i.p.) with S 47445 were investigated on risk-taking, motivational and cognitive behavior. S 47445 (1 and 10 mg/kg) increased the exploration of the elevated-plus maze and light/dark box as well as the time spent grooming in the splash test, and improved social memory in PRS rats. Also, the effects of S 47445 were examined on the synaptic neurotransmission. The reduced depolarization-evoked glutamate release induced by PRS was corrected with S 47445 (10 mg/kg). Remarkably, the reduction in glutamate release induced by PRS and corrected by S 47445 chronic treatment was correlated with all the behavioral changes. S 47445 at 10 mg/kg also normalized the lower levels of synaptic vesicle-associated proteins in ventral hippocampus in PRS rats. Finally, S 47445 reversed the decrease of mGlu5 receptors, GR and OXTR induced by PRS. Collectively, in an animal model of stress-related disorders, S 47445 corrected the imbalance between excitatory and inhibitory neurotransmission by regulating glutamate-evoked release that is predictive of PRS behavioral alterations, and also normalized the reduction of trafficking of synaptic vesicles induced by PRS. These results support the interest of glutamatergic-based therapeutic strategies to alleviate stress-related disorders.
S47445 是一种谷氨酸 AMPA 型受体的正变构调节剂，具有神经营养和增强突触可塑性作用，以及认知促进和抗应激特性。在这里，该药物在围产期应激（PRS）大鼠模型中进行了评估，该模型具有与单胺类抗抑郁药高度预测相关性的特点。研究了慢性腹腔注射 S47445 对冒险行为、动机和认知行为的影响。S47445（1 和 10mg/kg）增加了高架十字迷宫和明暗箱的探索，以及飞溅测试中的梳理时间，并改善了 PRS 大鼠的社会记忆。此外，还研究了 S47445 对突触神经传递的影响。PRS 诱导的去极化诱发谷氨酸释放减少被 S47445（10mg/kg）纠正。值得注意的是，PRS 诱导的谷氨酸释放减少和 S47445 慢性治疗纠正与所有行为变化相关。S47445（10mg/kg）还使 PRS 大鼠腹侧海马中突触囊泡相关蛋白水平降低恢复正常。最后，S47445 逆转了 PRS 诱导的 mGlu5 受体、GR 和 OXTR 的减少。总之，在应激相关障碍的动物模型中，S47445 通过调节谷氨酸诱发的释放来纠正兴奋性和抑制性神经递质之间的不平衡，该释放可预测 PRS 行为改变，还可使 PRS 诱导的突触囊泡转运减少恢复正常。这些结果支持基于谷氨酸的治疗策略缓解应激相关障碍的兴趣。
