Although guanosine is an endogenous nucleoside that displays antidepressant-like properties in several animal models, the mechanism underlying its antidepressant-like effects is not well characterized. The present study aimed at investigating the involvement of ERK/GSK-3β and Nrf2/HO-1 signaling pathways in the antidepressant-like effect of guanosine in the mouse tail suspension test (TST). The immobility time in the TST was taken as an indicative of antidepressant-like responses and the locomotor activity was assessed in the open-field test. Biochemical analyses were performed by Western blotting in the hippocampus and prefrontal cortex (PFC). The combined treatment with sub-effective doses of guanosine (0.01 mg/kg, p.o.) and lithium chloride (a non-selective GSK-3β inhibitor, 10 mg/kg, p.o.) or AR-A014418 (selective GSK-3β inhibitor, 0.01 μg/site, i.c.v.) produced a synergistic antidepressant-like effect in the TST. The antidepressant-like effect of guanosine (0.05 mg/kg, p.o.) was completely prevented by the treatment with MEK1/2 inhibitors U0126 (5 μg/site, i.c.v.), PD98059 (5 μg/site, i.c.v.), or zinc protoporphyrin IX (ZnPP) (HO-1 inhibitor, 10 μg/site, i.c.v). Guanosine administration (0.05 mg/kg, p.o.) increased the immunocontent of β-catenin in the nuclear fraction and Nrf2 in the cytosolic fraction in the hippocampus and PFC. The immunocontent of HO-1 was also increased in the hippocampus and PFC. Altogether, the results provide evidence that the antidepressant-like effect of guanosine in the TST involves the inhibition of GSK-3β, as well as activation of MAPK/ERK and Nrf2/HO-1 signaling pathways, highlighting the relevance of these molecular targets for antidepressant responses.

中文翻译：

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鸟苷的抗抑郁样作用取决于GSK-3β的抑制以及MAPK / ERK和Nrf2 /血红素加氧酶-1信号通路的激活。

虽然鸟苷是一种内源性核苷，在几种动物模型中均显示出抗抑郁样的特性，但其抗抑郁样效果的潜在机制尚不十分清楚。本研究旨在在小鼠尾部悬吊试验（TST）中研究ERK /GSK-3β和Nrf2 / HO-1信号通路与鸟苷抗抑郁样作用的关系。在TST中的不动时间被认为是抗抑郁样反应的指标，并且在开放视野试验中评估了运动活性。通过Western印迹法对海马和前额叶皮层（PFC）进行生化分析。亚有效剂量的鸟苷（0.01 mg / kg，口服）和氯化锂（非选择性GSK-3β抑制剂，10 mg / kg，口服）或AR-A014418（选择性GSK-3β抑制剂，0的联合治疗） 。在TST中，每1微克（icv）产生协同的抗抑郁药样作用。通过用MEK1 / 2抑制剂U0126（5μg/位，icv），PD98059（5μg/位，icv）或原卟啉锌IX的治疗，完全阻止了鸟嘌呤（0.05 mg / kg，po）的抗抑郁样作用。 （ZnPP）（HO-1抑制剂，10μg/位，icv）。施用鸟苷（0.05 mg / kg，口服）可增加海马和PFC的核级分中β-catenin的免疫含量，并改善胞质中Nrf2的免疫含量。海马和PFC中HO-1的免疫含量也增加。总之，这些结果提供了证据表明鸟嘌呤在TST中具有抗抑郁样作用，包括抑制GSK-3β以及激活MAPK / ERK和Nrf2 / HO-1信号通路，