Camargo Anderson, Rodrigues Ana Lúcia S
Neuroscience Postgraduate Program, Center of Biological Sciences, Universidade Federal de Santa Catarina, Florianópolis, Brazil.
Department of Biochemistry, Center of Biological Sciences, Universidade Federal de Santa Catarina, Florianópolis, Brazil.
Chronic Stress (Thousand Oaks). 2019 Jun 26;3:2470547019858083. doi: 10.1177/2470547019858083. eCollection 2019 Jan-Dec.
The available medications for the treatment of major depressive disorder have limitations, particularly their limited efficacy, delayed therapeutic effects, and the side effects associated with treatment. These issues highlight the need for better therapeutic agents that provide more efficacious and faster effects for the management of this disorder. Ketamine, an N-methyl-D-aspartate receptor antagonist, is the prototype for novel glutamate-based antidepressants that has been shown to cause a rapid and sustained antidepressant effect even in severe refractory depressive patients. Considering the importance of these findings, several studies have been conducted to elucidate the molecular targets for ketamine's effect. In addition, efforts are under way to characterize ketamine-like drugs. This review focuses particularly on evidence that endogenous glutamatergic neuromodulators may be able to modulate mood and to elicit fast antidepressant responses. Among these molecules, agmatine and creatine stand out as those with more published evidence of similarities with ketamine, but guanosine and ascorbic acid have also provided promising results. The possibility that these neuromodulators and ketamine have common neurobiological mechanisms, mainly the ability to activate mechanistic target of rapamycin and brain-derived neurotrophic factor signaling, and synthesis of synaptic proteins in the prefrontal cortex and/or hippocampus is presented and discussed.
用于治疗重度抑郁症的现有药物存在局限性，尤其是其疗效有限、治疗效果延迟以及与治疗相关的副作用。这些问题凸显了对更好治疗药物的需求，这些药物能为该疾病的管理提供更有效且起效更快的效果。氯胺酮，一种N-甲基-D-天冬氨酸受体拮抗剂，是新型谷氨酸盐类抗抑郁药的原型，已被证明即使在重度难治性抑郁症患者中也能产生快速且持续的抗抑郁作用。鉴于这些发现的重要性，已经开展了多项研究以阐明氯胺酮作用的分子靶点。此外，正在努力对类氯胺酮药物进行特性描述。本综述特别关注内源性谷氨酸能神经调节剂可能能够调节情绪并引发快速抗抑郁反应的证据。在这些分子中，胍丁胺和肌酸因与氯胺酮有更多已发表的相似性证据而格外突出，但鸟苷和抗坏血酸也取得了有前景的结果。本文提出并讨论了这些神经调节剂与氯胺酮具有共同神经生物学机制的可能性，主要是激活雷帕霉素作用靶点和脑源性神经营养因子信号传导，以及在前额叶皮质和/或海马体中合成突触蛋白的能力。
