A New Treatment for Depression?

By Jane Farrell

Researchers have discovered a chemical that could be an innovative tool to control depression, a severe and chronic psychiatric disease that affects 350 million people worldwide.

The research, from the Bruce Hammock laboratory at the University of California, Davis, was published in the journal Proceedings of the National Academy of Sciences, involves studies of an inhibitor of soluble epoxide hydrolase in rodents. Soluble epoxide hydrolase, or sEH, is emerging as a therapeutic target that acts on a number of inflammatory or inflammation-linked diseases.

“The research in animal models of depression suggests that sEH plays a key role in modulating inflammation, which is involved in depression,” said Hammock, a distinguished professor of entomology with a joint appointment at the UC Davis Comprehensive Cancer Center. “Inhibitors of sEH protect natural lipids in the brain that reduce inflammation and neuropathic pain. Thus, these inhibitors could be potential therapeutic drugs for depression.”

Researchers from Hammock’s laboratory, collaborating with depression expert Kenji Hashimoto and colleagues at the Chiba University Center for Forensic Mental Health, Japan, examined the role of the potent sEH inhibitor known as TPPU, in a rodent model of depression, “social defeat.”

They found that TPPU displayed rapid effects in both inflammation and social-defeat-stress models of depression. Expression of sEH protein was higher in key brain regions of chronically stressed mice than in control mice, they found.

“Most drugs for psychiatric diseases target how neurons communicate; here we are targeting the wellness and environment of the neurons,” said UC Davis researcher Christophe Morisseau.

In further explaining the significance of the findings, UC Davis researcher Karen Wagner said: “The rapid antidepressant action of the sEH inhibitor in these murine (mouse) models of depression is truly noteworthy because current antidepressants used in humans and animal models take weeks to have full effects.”

The researchers also discovered that postmortem brain samples of patients with psychiatric diseases, including depression, bipolar disorder and schizophrenia, showed a higher expression of sEH than controls.

The researchers found that pretreatment with TPPU prevented the onset of depression-like behaviors in mice after induced inflammation or repeated social-defeat stress. Mice lacking the sEH gene did not show depression-like behavior after repeated social-defeat stress.

“All these findings suggest that sEH plays a key role in the pathophysiology of depression and that epoxy fatty acids, and their mimics as well as sEH inhibitors, are potential therapeutic or prophylactic drugs for depression,” Hashimoto said.