Abelaira Helena M, Réus Gislaine Z, Ignácio Zuleide M, Dos Santos Maria Augusta B, de Moura Airam B, Matos Danyela, Demo Júlia P, da Silva Júlia B I, Michels Monique, Abatti Mariane, Sonai Beatriz, Dal Pizzol Felipe, Carvalho André F, Quevedo João
Laboratório de Neurociências, Programa de Pós-Graduação em Ciências da Saúde, Unidade Acadêmica de Ciências da Saúde, Universidade do Extremo Sul Catarinense, Criciúma, Brazil.
Laboratório de Neurociências, Programa de Pós-Graduação em Ciências da Saúde, Unidade Acadêmica de Ciências da Saúde, Universidade do Extremo Sul Catarinense, Criciúma, Brazil.
J Psychiatr Res. 2017 Apr;87:81-87. doi: 10.1016/j.jpsychires.2016.12.002. Epub 2016 Dec 3.
Recent studies show that activation of the mTOR signaling pathway is required for the rapid antidepressant actions of glutamate N-methyl-D-aspartate (NMDA) receptor antagonists. A relationship between mTOR kinase and the endoplasmic reticulum (ER) stress pathway, also known as the unfolded protein response (UPR) has been shown. We evaluate the effects of ketamine administration on the mTOR signaling pathway and proteins of UPR in the prefrontal cortex (PFC), hippocampus, amygdala and nucleus accumbens, after the inhibiton of mTOR signaling in the PFC. Male adult Wistar rats received pharmacological mTOR inhibitor, rapamycin (0.2 nmol), or vehicle into the PFC and then a single dose of ketamine (15 mg/kg, i.p.). The immunocontent of mTOR, eukaryotic initiation factor 4E-binding protein 1 (4E-BP1), eukaryotic elongation factor 2 kinase (eEF2K) homologous protein (CHOP), PKR-like ER kinase (PERK) and inositol-requiring enzyme 1 (IRE1) - alpha were determined in the brain. The mTOR levels were reduced in the rapamycin group treated with saline and ketamine in the PFC; p4EBP1 levels were reduced in the rapamycin group treated with ketamine in the PFC and nucleus accumbens; the levels of peEF2K were increased in the PFC in the vehicle group treated with ketamine and reduced in the rapamycin group treated with ketamine. The PERK and IRE1-alpha levels were decreased in the PFC in the rapamycin group treated with ketamine. Our results suggest that mTOR signaling inhibition by rapamycin could be involved, at least in part, with the mechanism of action of ketamine; and the ketamine antidepressant on ER stress pathway could be also mediated by mTOR signaling pathway in certain brain structures.
最近的研究表明，谷氨酸N-甲基-D-天冬氨酸（NMDA）受体拮抗剂的快速抗抑郁作用需要mTOR信号通路的激活。mTOR激酶与内质网（ER）应激通路（也称为未折叠蛋白反应（UPR））之间的关系已被证实。我们在抑制前额叶皮质（PFC）中的mTOR信号后，评估氯胺酮给药对PFC、海马体、杏仁核和伏隔核中mTOR信号通路及UPR相关蛋白的影响。成年雄性Wistar大鼠在PFC中接受药理学mTOR抑制剂雷帕霉素（0.2 nmol）或赋形剂，然后腹腔注射单剂量氯胺酮（15 mg/kg）。测定大脑中mTOR、真核起始因子4E结合蛋白1（4E-BP1）、真核延伸因子2激酶（eEF2K）同源蛋白（CHOP）、PKR样内质网激酶（PERK）和肌醇需求酶1（IRE1）-α的免疫含量。在PFC中，用生理盐水和氯胺酮处理的雷帕霉素组中mTOR水平降低；在PFC和伏隔核中，用氯胺酮处理的雷帕霉素组中p4EBP1水平降低；在用氯胺酮处理的赋形剂组的PFC中，peEF2K水平升高，而在用氯胺酮处理的雷帕霉素组中降低。在用氯胺酮处理的雷帕霉素组的PFC中，PERK和IRE1-α水平降低。我们的结果表明，雷帕霉素抑制mTOR信号可能至少部分参与氯胺酮的作用机制；氯胺酮对ER应激通路的抗抑郁作用也可能在某些脑结构中由mTOR信号通路介导。
