AsianScientist (Apr. 4, 2016) – Researchers from Japan and the US have discovered the beneficial effects of inhibiting the soluble epoxide hydrolase (sEH) protein in the inflamed brains of depressed mice. Their findings, which were published in the Proceedings of the National Academy of Science, could lead to improved therapeutic drugs for depression.
Depression is a severe and chronic psychiatric disease, affecting an estimated 350 million people worldwide. This disease, when moderate to severe, can be debilitating. According to the World Health Organization, it is the leading cause of disability worldwide, and also a major contributor to the overall global burden of disease.
Unfortunately, although antidepressants are generally effective, it can still take weeks before patients feel the full antidepressant effects, and approximately two-thirds of depressed patients fail to respond fully.
Seeking to address this problem, the researchers from Chiba University Center for Forensic Mental Health in Japan and the Bruce Hammock laboratory at the University of California in the US set out to examine the role that the protein sEH plays in the inflammation that is associated with depression.
While there is a growing body of research pointing to the potential of sEH inhibitors to treat anorexia nervosa and cardiovascular disease, for example, this study is the first to investigate this protein’s role in the pathogenesis, or development, of depression.
The researchers tested their hypothesis in two groups, mice with induced brain inflammation and mice that went through social defeat stress—stressful situations where they face off with dominant mice. They found that expression of sEH was higher in the brains of chronically stressed mice than in control mice.
Moreover, mice in which sEH was knocked out did not show depression-like behavior after repeated social defeat stress, indicating a level of stress resilience.
To see if this would be the same for humans, the research team went a step further and tested for sEH in postmortem brain samples of patients who suffered from psychiatric diseases such as depression, bipolar disorder, and schizophrenia. This yielded similar results, suggesting that increased sEH levels might be involved in the pathogenesis of certain psychiatric diseases.
The researchers also learned that a potent sEH inhibitor, TPPU, displayed rapid antidepressant effects in the brains of both the inflamed and chronically stressed mice. Furthermore, during their experiments, orally administered pretreatment with TPPU actually prevented the onset of depression-like behaviors after inflammation or repeated social defeat stress. The speed with which TPPU yielded results is notable, considering that conventional treatments take weeks to come into full effect.
Therefore, these data suggest that TPPU has both therapeutic and protective effects against sEH, and could lead to better drug treatments for depression in the future.
The article can be found at: Ren et al. (2016) Gene Deficiency and Pharmacological Inhibition of Soluble Epoxide Hydrolase Confers Resilience to Repeated Social Defeat Stress.
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