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New Chemical May Help Control Inflammation and Depression

A chemical discovered in the Bruce Hammock laboratory at the University of California, Davis, may be a new, innovative tool to control depression, a severe and chronic psychiatric disease that affects 350 million persons worldwide.

The research, published March 14 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.

New therapeutic approach:

“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 depressionlike behaviors in mice after induced inflammation or repeated social-defeat stress. Mice lacking the sEH gene did not show depressionlike 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.

Addresses a pressing need:

Robert E. Hales, distinguished professor of clinical psychiatry and the Joe P. Tupin Endowed Chair of the Department of Psychiatry and Behavioral Sciences at UC Davis School of Medicine, said new medication treatment approaches are needed to treat depression.

Image shows a woman with her head in her hands.

Researchers 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. Image is for illustrative purposes only.

Hales, who was not involved in the research, said the new paper represents “an important and novel approach to treating depression.”

“With lifetime prevalence rates of major depressive disorder being in the range of 16 percent and with nearly two-thirds of patients failing to respond to pharmacologic treatments, there is a pressing need to discover new medication treatment approaches,” Hales said. “Their findings lend support to the potential use of TPPU, a sEH inhibitor, as a new therapeutic medication to prevent and treat depression.”

About this psychology research

Other authors on the paper are: Qian Ren, Min Ma, Tamaki Ishima, Ji-chun Zhang, Chun Yang, Wei Yao, Chao Dong and Mei Han, Chiba University; and Jun Yang at UC Davis.

Morisseau, Yang and Wagner are inventors on University of California patents related to soluble epoxide hydrolase. Some of these patents have been licensed by EicOsis Human Health, a Davis company founded by Hammock to develop pharmaceuticals to alleviate neuropathic and inflammatory pain.

Funding: he research was funded by Grant-in-Aid for Scientific Research on Innovative Areas of the Ministry of Education, Culture, Sports, Science and Technology, Japan, to Kenji Hashimoto, (#24116006); and a Research Fellowship for Young Scientists of the Japan Society for the Promotion of Science (Tokyo, Japan) to Qian Ren.

Partial support was provided by the National Institute of Environmental Health Sciences R01 ES002710, NIEHS Superfund Research Program grant P42 ES004699 and NIH U24 DK097154 West Coast Comprehensive Metabolomics Center.

Hammock and Professor Bruce German of UC Davis recently received a National Institutes of Health grant in collaboration with Pei-an Shih of the UC San Diego Department of Psychiatry, to investigate the role of bioactive lipids in a related psychiatric disorder, anorexia nervosa.

Source: Bruce Hammock – UC Davis
Image Credit: The image is in the public domain.
Original Research: Full open access research for “Gene deficiency and pharmacological inhibition of soluble epoxide hydrolase confers resilience to repeated social defeat stress” by Qian Ren, Min Ma, Tamaki Ishima, Christophe Morisseau, Jun Yang, Karen M. Wagner, Ji-chun Zhang, Chun Yang, Wei Yao, Chao Dong, Mei Han, Bruce D. Hammock, and Kenji Hashimoto in PNAS. Published online March 14 2016 doi:10.1073/pnas.1601532113


Abstract

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.

“Gene deficiency and pharmacological inhibition of soluble epoxide hydrolase confers resilience to repeated social defeat stress” by Qian Ren, Min Ma, Tamaki Ishima, Christophe Morisseau, Jun Yang, Karen M. Wagner, Ji-chun Zhang, Chun Yang, Wei Yao, Chao Dong, Mei Han, Bruce D. Hammock, and Kenji Hashimoto in PNAS. Published online March 14 2016 doi:10.1073/pnas.1601532113

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