- Author: Kathy Keatley Garvey
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.”
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 was higher 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.
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 epoxyfatty acids, and their mimics as well as sEH inhibitors, are potential therapeutic or prophylactic drugs for depression,” Hashimoto said.
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. 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.”
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.
The 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 (NIEHS) R01 ES002710, NIEHS Superfund Research Program grant P42 ES004699, and NIH U24 DK097154 West Coast Comprehensive Metabolomics Center.
Hammock and Professor Bruce German, UC Davis recently received a National Institutes of Health grant in collaboration with Pei-an Shih, UC San Diego Department of Psychiatry, to investigate the role of bioactive lipids in a related psychiatric disorder, anorexia nervosa.