Gene deficiency and pharmacological inhibition of soluble epoxide hydrolase confers resilience to repeated social defeat stress

Depression is a severe and chronic psychiatric disease, affecting 350 million subjects worldwide. Although multiple antidepressants have been used in the treatment of depressive symptoms, their beneficial effects are limited. The soluble epoxide hydrolase (sEH) plays a key role in the inflammation that is involved in depression. Thus, we examined here the role of sEH in depression. In both inflammation and social defeat stress models of depression, a potent sEH inhibitor, TPPU, displayed rapid antidepressant effects. Expression of sEH protein in the brain from chronically stressed (susceptible) mice was higher than of control mice. Furthermore, expression of sEH protein in postmortem brain samples of patients with psychiatric diseases, including depression, bipolar disorder, and schizophrenia, was higher than controls. This finding suggests that increased sEH levels might be involved in the pathogenesis of certain psychiatric diseases. In support of this hypothesis, pretreatment with TPPU prevented the onset of depression-like behaviors after inflammation or repeated social defeat stress. Moreover, sEH KO mice did not show depression-like behavior after repeated social defeat stress, suggesting stress resilience. The sEH KO mice showed increased brain-derived neurotrophic factor (BDNF) and phosphorylation of its receptor TrkB in the prefrontal cortex, hippocampus, but not nucleus accumbens, suggesting that increased BDNF-TrkB signaling in the prefrontal cortex and hippocampus confer stress resilience. All of these findings suggest that sEH plays a key role in the pathophysiology of depression, and that epoxy fatty acids, their mimics, as well as sEH inhibitors could be potential therapeutic or prophylactic drugs for depression.Depression is the most severe and debilitating of the psychiatric illnesses. The World Health Organization estimates that more than 350 million individuals of all ages suffer from depression (1). Almost one million lives are lost annually because of suicide, which translates to 3,000 deaths daily (1). Although antidepressants are generally effective in the treatment of depression, it can still take weeks before patients feel the full antidepressant effects. However, approximately two-thirds of depressed patients fail to respond fully to pharmacotherapy. Furthermore, there is a high rate of relapse, and depressed patients have a high risk of committing suicide (2–4).Accumulating evidence suggests that inflammation plays a central role in the pathophysiology of depression (5–9). Meta-analyses showed higher blood levels of proinflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin 6 (IL-6), in drug-free depressed patients compared with healthy controls (10–13). Studies using postmortem brain samples showed elevated gene expression of proinflammatory cytokines in the frontal cortex of people with a history of depression (14, 15). Taking these data together, we find that it is likely that both peripheral and central inflammations are associated with depression and that antiinflammatory drugs, such as cyclooxygenase inhibitors, could ameliorate depressive symptoms in depressed patients (16, 17).Epoxyeicosatrienoic acids (EETs), which are produced from arachidonic acid by the action of cytochrome P450s, have potent antiinflammatory actions. These mediators are broken down into the corresponding diols by soluble epoxide hydrolase (sEH), and inhibition of sEH enhances the beneficial effects of EETs (18–21). It is also reported that sEH inhibitors have potent antiinflammatory effects in a number of animal models (18–20, 22, 23). Although sEH has been associated with the onset of anorexia nervosa (24), the role of sEH in the pathophysiology of depression has not been studied to date.The purpose of this study was to examine the role of sEH in the pathophysiology of depression using a potent sEH inhibitor and sEH knockout (KO) mice. Furthermore, we examined the role of brain-derived neurotrophic factor (BDNF) and its receptor TrkB signaling in selected brain regions, because BDNF-TrkB signaling plays a key role in the pathophysiology of depression (25–30).