Lei Ting, Dong Dan, Song Meiying, Sun Yanfei, Liu Xiaofeng, Zhao Hua
Neuroscience Research Center, First Hospital of Jilin University, Changchun, 130021, PR China.
Department of Physiology, College of Basic Medical Sciences, Jilin University, Changchun, 130021, PR China.
Neuropsychopharmacology. 2020 Sep;45(10):1717-1724. doi: 10.1038/s41386-020-0652-9. Epub 2020 Mar 8.
The specific GluN2B antagonist rislenemdaz (Ris; a.k.a. MK-0657 and CERC-301) is in phase II clinical trial as an antidepressive drug, but the working mechanism for its antidepressant effects is not clearly understood. Given the important role of the lateral habenula (LHb) in the pathogenesis of depression and the fact that GluN2B-containing N-methyl-D-aspartate receptors and brain-derived neurotrophic factor (BDNF) are expressed in the LHb, we conducted a study to examine whether the LHb mediates Ris' antidepressant effects in a chronic restraint stress (CRS)-induced depressive-like mouse model. In this study, Ris was administered systemically or locally into the LHb. Short hairpin RNAs were used to knockdown BDNF in the LHb. Depressive-like behaviors were assessed with the open field test, forced swimming test, tail suspension test, and sucrose preference test. Expression of GluN2B, BDNF, and c-Fos in the LHb were analyzed with western blotting and immunohistochemistry under condition with Ris administered systemically or with BDNF knockdown in the LHb. We found that both systemic and intra-LHb administration of Ris alleviated CRS-induced despair-like behavior and that systemic Ris reduced LHb expression of GluN2B, BDNF, and c-Fos (a neuronal activity marker). Specific knockdown of BDNF in the LHb prevented CRS-induced despair-like behavior, while preventing CRS-induced increases in BDNF and c-Fos expression in the LHb. Together these results suggest that Ris may exert its antidepressant effects through affecting the LHb such as downregulating BDNF expression in the LHb.
特异性GluN2B拮抗剂利司来奈达唑（Ris；又名MK-0657和CERC-301）作为一种抗抑郁药物正处于II期临床试验阶段，但其抗抑郁作用的作用机制尚不清楚。鉴于外侧缰核（LHb）在抑郁症发病机制中的重要作用，以及含GluN2B的N-甲基-D-天冬氨酸受体和脑源性神经营养因子（BDNF）在LHb中表达这一事实，我们开展了一项研究，以检验在慢性束缚应激（CRS）诱导的抑郁样小鼠模型中，LHb是否介导Ris的抗抑郁作用。在本研究中，Ris通过全身给药或局部注射到LHb中。短发夹RNA用于敲低LHb中的BDNF。采用旷场试验、强迫游泳试验、悬尾试验和蔗糖偏好试验评估抑郁样行为。在全身给予Ris或敲低LHb中BDNF的条件下，通过蛋白质免疫印迹法和免疫组织化学法分析LHb中GluN2B、BDNF和c-Fos的表达。我们发现，全身给药和向LHb内注射Ris均可减轻CRS诱导的绝望样行为，且全身给予Ris可降低LHb中GluN2B、BDNF和c-Fos（一种神经元活性标志物）的表达。特异性敲低LHb中的BDNF可预防CRS诱导的绝望样行为，同时预防CRS诱导的LHb中BDNF和c-Fos表达增加。这些结果共同表明，Ris可能通过影响LHb发挥其抗抑郁作用，如下调LHb中BDNF的表达。
