目的:N-甲基-D-天冬氨酸(NMDA)受体(NMDAR)已被证明与快速抗抑郁作用密切相关。这里,GW043作为靶向NMDAR的新化合物,我们探讨了其抗抑郁作用及其作用机制。
方法:我们的研究利用电生理技术来证实GW043对NMDAR电流的影响。此外,我们通过高通量受体-配体结合实验评估了GW043的选择性.使用啮齿动物行为模型检查GW043的抗抑郁特性,包括强迫游泳测试(FST),尾部悬挂测试(TST),慢性不可预测的轻度压力(CUMS)。通过蛋白质印迹分析获得了对GW043发病机制的洞察,BrdU染色,高尔基染色,和电生理技术。
结果:电生理学研究表明GW043作为NMDAR的部分激动剂发挥作用。行为实验证实了GW043在啮齿动物中的抗抑郁作用。机制研究表明,GW043通过LTP和BDNF-mTOR通路调节突触可塑性,因此导致新生儿神经元数量的增加和随后的抗抑郁作用。
结论:我们的发现表明,GW043作为NMDAR的部分激动剂,可以通过调节突触可塑性来逆转大鼠的抑郁样行为,表明其作为抗抑郁药的潜力。
The N-methyl-D-aspartate (NMDA) receptor (NMDAR) has been proven to be strongly correlated with rapid antidepressant effects. Here, GW043, as a new compound targeting NMDAR, we explored its antidepressant effects and its mechanism of action.
Our study utilized electrophysiological techniques to confirm the effect of GW043 on NMDAR currents. Additionally, we assessed the selectivity of GW043 through high-throughput receptor-ligand binding experiments. The antidepressant properties of GW043 were examined using rodent behavioral models including the Forced Swim Test (FST), Tail Suspension Test (TST), and Chronic Unpredictable Mild Stress (CUMS). Mechanistic insight into GW043\'s onset was gained through western blot analysis, BrdU staining, Golgi staining, and electrophysiological techniques.
Electrophysiological studies indicated that GW043 acts as a partial agonist of NMDAR. Behavioral experiments confirmed the antidepressant effect of GW043 in rodents. Mechanistic investigations revealed that GW043 modulates synaptic plasticity through the LTP and BDNF-mTOR pathways, consequently leading to an increase in the number of newborn neurons and subsequent antidepressant effects.
Our findings disclose that GW043, as a partial agonist of NMDAR, can reverse depression-like behaviors in rats by modulating synaptic plasticity, indicating its potential as an antidepressant agent.