Pharmacological investigations to discover new therapeutic strategies for depression

Abstract

Agitated depression is defined as the major depressive disorder with restlessness and motor excitement. Patients suffering from agitated depression can harm themselves and might get involved in harmful behavior. In this piece of work, an attempt was made to explore the potential link between kynurenine pathway and Keap-1/Nrf2/ARE pathway as well as the potential pharmacotherapeutic role of Nrf2 activators in agitated depression. Clinical studies found increased inflammation and alteration in the antioxidant enzymes in depressive patients with suicidal tendencies. Accumulating evidences showed that downregulation of Keap-1/Nrf2/ARE system plays a key role in development of depression through increased oxidative stress and inflammation. Olfactory bulbectomized mice model of depression that mimic the pathogenesis of agitated depression was validated for this research work. Further, potential role of kynurenine pathway in pathophysiology of agitated depression and the pharmacotherapeutic potential of naturally occurring Nrf2 activators were evaluated for the antidepressant property in olfactory bulbectomized mice model of agitated depression. The present research work confirmed the substantial role of QA in inducing oxidative stress and inflammation in agitated depression via downregulating Keap-1/Nrf2/ARE pathway along with other mechanisms. Nrf2 activators (naringenin, nordihydroguaiaretic acid and carnosic acid) reversed the behavioral, biochemical and molecular alterations leading to agitated depression by upregulating Keap-1/Nrf2/ARE pathway. Therefore, Nrf2 activators can be explored further for the development of a novel class of therapeutics for treatment of agitated depression. newline