Martín-Hernández David, Bris Álvaro G, MacDowell Karina S, García-Bueno Borja, Madrigal José L M, Leza Juan C, Caso Javier R
Department of Pharmacology, School of Medicine, Universidad Complutense de Madrid, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Investigación Sanitaria Hospital 12 de Octubre (Imas12), Instituto de Investigación Neuroquímica (UCM), Avda. Complutense s/n, 28040, Madrid, Spain.
Department of Pharmacology, School of Medicine, Universidad Complutense de Madrid, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Investigación Sanitaria Hospital 12 de Octubre (Imas12), Instituto de Investigación Neuroquímica (UCM), Avda. Complutense s/n, 28040, Madrid, Spain.
Neuropharmacology. 2016 Apr;103:79-91. doi: 10.1016/j.neuropharm.2015.11.029. Epub 2015 Dec 12.
Patients with major depression who are otherwise medically healthy have activated inflammatory pathways in their organism. It has been described that depression is not only escorted by inflammation but also by induction of multiple oxidative/nitrosative stress pathways. Nevertheless, there are finely regulated mechanisms involved in preserving cells from damage, such as the antioxidant nuclear transcription factor Nrf2. We aim to explore in a depression-like model the Nrf2 pathway in the prefrontal cortex (PFC) and the hippocampus of rats and to analyze whether antidepressants affect the antioxidant activity of the Nrf2 pathway. Male Wistar rats were exposed to chronic mild stress (CMS) and some of them were treated with desipramine, escitalopram or duloxetine. We studied the expression of upstream and downstream elements of the Nrf2 pathway and the oxidative damage induced by the CMS. After CMS, there is an inhibition of upstream and downstream elements of the Nrf2 pathway in the PFC (e.g. PI3K/Akt, GPx…). Moreover, antidepressant treatments, particularly desipramine and duloxetine, are able to recover some of these elements and to reduce the oxidative damage induced by the CMS. However, in the hippocampus, Nrf2 pathways are not that affected and antidepressants do not have many actions. In conclusion, Nrf2 pathway is differentially regulated by antidepressants in the PFC and hippocampus. The Nrf2 pathway is involved in the oxidative/nitrosative damage detected in the PFC and antidepressants have a therapeutic action through this pathway. However, it seems that Nrf2 is not involved in the effects caused by CMS in the hippocampus.
在其他方面身体健康的重度抑郁症患者体内存在炎症途径激活的情况。据描述，抑郁症不仅伴随着炎症，还伴随着多种氧化/亚硝化应激途径的诱导。然而，存在一些精细调控的机制来保护细胞免受损伤，比如抗氧化核转录因子Nrf2。我们旨在通过抑郁症样模型探究大鼠前额叶皮质（PFC）和海马体中的Nrf2途径，并分析抗抑郁药是否会影响Nrf2途径的抗氧化活性。将雄性Wistar大鼠暴露于慢性轻度应激（CMS）下，其中一些大鼠用去甲丙咪嗪、艾司西酞普兰或度洛西汀进行治疗。我们研究了Nrf2途径的上游和下游元件的表达以及CMS诱导的氧化损伤。CMS后，PFC中Nrf2途径的上游和下游元件受到抑制（例如PI3K/Akt、谷胱甘肽过氧化物酶……）。此外，抗抑郁药治疗，尤其是去甲丙咪嗪和度洛西汀，能够恢复其中一些元件并减少CMS诱导的氧化损伤。然而，在海马体中，Nrf2途径受影响较小，抗抑郁药的作用不大。总之，Nrf2途径在PFC和海马体中受到抗抑郁药的不同调节。Nrf2途径参与了在PFC中检测到的氧化/亚硝化损伤，抗抑郁药通过该途径发挥治疗作用。然而，Nrf2似乎与CMS在海马体中引起的效应无关。
