Zhao Jinghua, Liu Xuejie, Chang Daiyue, Zhang Xintong, Lian Huimin, Du Xueman, Gao Li
Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, College of Veterinary Medicine, Northeast Agriculture University, Harbin 150030, China.
ACS Chem Neurosci. 2020 Mar 4;11(5):752-762. doi: 10.1021/acschemneuro.9b00669. Epub 2020 Feb 13.
About 16% of the world's population has major depressive disorder. Traditional antidepressants have slow effect rates and low response rates. Many studies have shown that low doses of ketamine can produce rapid and effective antidepressant effects. However, its mechanism of action needs further exploration. Lipopolysaccharide (LPS) was used to establish a depression model in rats and PC12 nerve cells were used for experiments. (2,4)-Dimethoxybenzylidene anabaseine dihydrochloride (GTS-21), a specific agonist of α7 nicotinic acetylcholine receptors (α7 nAChRs), was used to compare the rapid antidepressant effect of ketamine. Different doses of α7 nAChR antagonist methyllycaconatine (MLA) and α7 nAChR-siRNA were used to interfere with the protective effects of ketamine on neuroinflammation in rats and PC12 cells, respectively. MLA intervention downregulated the anti-inflammatory effects of ketamine and decreased the effects of ketamine on behavior, synaptic plasticity, and Nissl bodies in the neuronal cells. Moreover, the dose of MLA was positively correlated with the inhibitory effect in rat hippocampi and the protective effects of GTS-21 were consistent with ketamine. These results demonstrated that low-dose ketamine could produce neuroprotective effects by activating the α7 nAChR-mediated cholinergic anti-inflammatory pathway (CAP) in depression, resulting in a rapid antidepressant effect.
世界上约16%的人口患有重度抑郁症。传统抗抑郁药起效慢且有效率低。许多研究表明，低剂量氯胺酮可产生快速有效的抗抑郁作用。然而，其作用机制有待进一步探索。采用脂多糖（LPS）建立大鼠抑郁模型，并使用PC12神经细胞进行实验。使用α7烟碱型乙酰胆碱受体（α7 nAChRs）的特异性激动剂（2,4）-二甲氧基亚苄基安那abaseine二盐酸盐（GTS-21）来比较氯胺酮的快速抗抑郁作用。分别使用不同剂量的α7 nAChR拮抗剂甲基黄连碱（MLA）和α7 nAChR-siRNA来干扰氯胺酮对大鼠和PC12细胞神经炎症的保护作用。MLA干预下调了氯胺酮的抗炎作用，并降低了氯胺酮对神经元细胞行为、突触可塑性和尼氏体的影响。此外，MLA的剂量与大鼠海马体中的抑制作用呈正相关，且GTS-21的保护作用与氯胺酮一致。这些结果表明，低剂量氯胺酮可通过激活抑郁症中α7 nAChR介导的胆碱能抗炎途径（CAP）产生神经保护作用，从而产生快速抗抑郁效果。
