Departamento de Ciências Biológicas, Programa de Pós-Graduação em Ciências Biológicas, Universidade Federal de Ouro Preto (UFOP), Ouro Preto, Brazil.
Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil.
Sci Rep. 2020 May 21;10(1):8429. doi: 10.1038/s41598-020-65300-w.
The treatment of major depressive disorder (MDD) is still a challenge. In the search for novel antidepressants, glutamatergic neuromodulators have been investigated as possible fast-acting antidepressants. Innovative studies suggest that the purine cycle and/or the purinergic signaling can be dysregulated in MDD, and the endogenous nucleoside guanosine has gained attention due to its extracellular effects. This study aimed to verify if guanosine produces fast-onset effects in the well-validated, reliable and sensitive olfactory bulbectomy (OBX) model of depression. The involvement of the mTOR pathway, a key target for the fast-onset effect of ketamine, was also investigated. Results show that a single i.p. injection of guanosine, or ketamine, completely reversed the OBX-induced anhedonic-like behavior 24 or 48 h post treatment, as well as the short-term recognition memory impairment 48 h post treatment. The antidepressant-like effects of guanosine and ketamine were completely abolished by rapamycin. This study shows, for the first time, that guanosine, in a way similar to ketamine, is able to elicit a fast antidepressant response in the OBX model in mice. The results support the notion that guanosine represents a new road for therapeutic improvement in MDD.
治疗重度抑郁症（MDD）仍然是一个挑战。在寻找新型抗抑郁药的过程中，谷氨酸能神经调节剂已被研究为可能的快速抗抑郁药。创新性研究表明，MDD 中嘌呤循环和/或嘌呤能信号可能失调，内源性核苷鸟苷因其细胞外作用而受到关注。本研究旨在验证鸟苷是否在经过充分验证、可靠和敏感的嗅球切除术（OBX）抑郁模型中产生快速作用。还研究了 mTOR 途径的参与，该途径是氯胺酮快速作用的关键靶点。结果表明，腹腔内注射鸟苷或氯胺酮可完全逆转 OBX 诱导的快感缺失样行为，分别在治疗后 24 或 48 小时，以及短期识别记忆障碍，在治疗后 48 小时。雷帕霉素完全消除了鸟苷和氯胺酮的抗抑郁样作用。本研究首次表明，鸟苷以类似于氯胺酮的方式，能够在 OBX 模型中引发快速的抗抑郁反应。结果支持这样一种观点，即鸟苷代表了治疗 MDD 的新途径。
