The effects of sEH inhibitor on depression‐like behavior and neurogenesis in male mice

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Depression is one of the leading causes of suicide and disability. The disease afflicts more than 350 million people worldwide (Ledford, 2014). Depression symptoms include pessimistic mood, anhedonia, difficulty concentrating, and sleep disorder (Krishnan and Nestler, 2008). Although the molecular, cellular, and neurocircuitry changes underlying depression have been well studied, the biological mechanisms remain unclear.
Clinically, current antidepressants take as long as 2–8 weeks of administration before they are effective (Bunney et al., 2015); In addition, about 30–50% of patients with depression do not respond to traditional treatments (Hodes et al., 2015). Thus, there is an urgent need for novel fast‐acting, highly effective antidepressant drugs.
A potential target for antidepressants that may influence the hippocampus is soluble epoxide hydolase (sEH). The sEH is an enzyme that metabolizes epoxyeicosatrienoic acids (EETs) into dihydroxyeicosatrienoic acids (DHETs). EETs are products of the cytochrome P450 epoxygenase pathway in arachidonic acid metabolism and have broad biological functions, such as anti‐hypertensive, anti‐inflammatory, proangiogenic and anti‐apoptotic functions.(Bianco et al., 2009; Spector, 2009). Since inhibition of sEH would prevent the metabolism of EETs and thus enhance their biological activities, sEHIs has been extensively studied as an anti‐hypertensive and anti‐inflammatory drug. Recent reports have shown that EETs and sEH inhibitor (sEHIs) also function as neuroprotectives. The sEHIs significantly reduced cortical infarct, and the rate of cell death in ischemic tissue (Imig et al., 2011; Shaik et al., 2013). Direct administration of sEHI or EETs also delayed the onset of PTZ‐induced seizures (Inceoglu et al., 2013). Moreover, co‐exposure of sEHI and 14,15‐EET promoted axon outgrowth in cultured cortical neurons(Abdu et al., 2011).
In the present study, we examine the antidepressant effect of sEHI TPPU in mice and its effect on hippocampal neurogenesis. We determined that TPPU elicits antidepressant effects, partially through regulation of the BDNF pathway.
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