Instituto Teófilo Hernando, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain; Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain.
Psychoneuroendocrinology. 2013 Oct;38(10):2010-22. doi: 10.1016/j.psyneuen.2013.03.020. Epub 2013 Apr 23.
A causative relationship between inflammation and depression is gradually gaining consistency. Because Nrf2 participates in inflammation, we hypothesized that Nrf2 could play a role in depressive disorders. In this study, we have observed that Nrf2 deletion in mice results in: (i) a depressive-like behavior evaluated as an increase in the immobility time in the tail-suspension test and by a decrease in the grooming time in the splash test, (ii) reduced levels of dopamine and serotonin and increased levels of glutamate in the prefrontal cortex, (iii) altered levels of proteins associated to depression such as VEGF and synaptophysin and (iv) microgliosis. Furthermore, treatment of Nrf2 knockout mice with the anti-inflammatory drug rofecoxib reversed their depressive-like behavior, while induction of Nrf2 by sulforaphane, in an inflammatory model of depression elicited by LPS, afforded antidepressant-like effects. In conclusion, our results indicate that chronic inflammation due to a deletion of Nrf2 can lead to a depressive-like phenotype while induction of Nrf2 could become a new and interesting target to develop novel antidepressive drugs.
炎症和抑郁之间的因果关系逐渐得到一致认可。由于 Nrf2 参与炎症反应，我们假设 Nrf2 可能在抑郁障碍中发挥作用。在这项研究中，我们观察到 Nrf2 基因敲除小鼠表现出：（i）抑郁样行为，表现在悬尾试验中不动时间增加和浸水试验中梳理时间减少；（ii）前额叶皮层中多巴胺和血清素水平降低，谷氨酸水平升高；（iii）与抑郁相关的蛋白如 VEGF 和突触小体素水平改变；（iv）小胶质细胞增生。此外，用抗炎药物罗非昔布治疗 Nrf2 基因敲除小鼠可逆转其抑郁样行为，而在脂多糖诱导的抑郁炎症模型中，用萝卜硫素诱导 Nrf2 可产生抗抑郁样作用。总之，我们的研究结果表明，由于 Nrf2 的缺失导致的慢性炎症可能导致抑郁样表型，而诱导 Nrf2 可能成为开发新型抗抑郁药物的新的有趣靶点。
