A chemical discovered in the Bruce Hammock laboratory at the University of California, Davis, may offer a promising new approach to treating depression, a chronic psychiatric disorder that affects an estimated 350 million people worldwide.
Published March 14 in the Proceedings of the National Academy of Sciences, the study reports that inhibiting soluble epoxide hydrolase (sEH) produces rapid antidepressant-like effects in rodent models. sEH is an enzyme linked to inflammation, and growing evidence indicates that inflammation contributes to the development and persistence of depressive disorders.
“Our animal research suggests that sEH is a major regulator of inflammatory pathways that influence mood,” said Bruce Hammock, distinguished professor of entomology at UC Davis and a co-author of the study. “Inhibitors of sEH protect bioactive lipids in the brain that help reduce inflammation and neuropathic pain. Those same mechanisms may make sEH inhibitors useful as antidepressant or preventive treatments.”
The UC Davis team, working with depression specialist Kenji Hashimoto and colleagues at Chiba University Center for Forensic Mental Health in Japan, tested a potent sEH inhibitor called TPPU in mice using both inflammation-induced and social defeat stress models of depression. Social defeat is a validated rodent model that mimics aspects of chronic psychosocial stress experienced in human mood disorders.
Key findings from the study include:
- TPPU produced rapid antidepressant-like effects in both the inflammation model and the repeated social-defeat model.
- Mice chronically susceptible to social stress showed increased sEH protein expression in critical brain regions compared with control animals.
- Postmortem brain tissue from people diagnosed with psychiatric disorders—depression, bipolar disorder, and schizophrenia—revealed higher sEH expression than tissue from control subjects, suggesting elevated sEH may be linked to disease pathology.
- Pretreating mice with TPPU prevented the emergence of depression-like behaviors after inflammatory challenge or repeated social-defeat stress.
- Mice genetically lacking the sEH gene (sEH knockout mice) displayed resilience to repeated social-defeat stress, failing to develop depression-like behaviors.
- Resilient sEH knockout mice exhibited increased levels of brain-derived neurotrophic factor (BDNF) and greater phosphorylation of its receptor TrkB in the prefrontal cortex and hippocampus, but not the nucleus accumbens—pointing to enhanced BDNF-TrkB signaling in those regions as a likely mechanism of stress resilience.
Novel therapeutic direction
“Most psychiatric medications act directly on neuronal signaling,” said UC Davis researcher Christophe Morisseau. “This work represents a different strategy: improving the neuronal environment by reducing neuroinflammation and protecting beneficial lipid signaling molecules.” Karen Wagner, another UC Davis investigator, emphasized the clinical relevance: “The rapid antidepressant effect seen with an sEH inhibitor in mouse models is notable because existing antidepressants typically require weeks to achieve full benefit.”
Independent commentary from Robert E. Hales, distinguished professor of clinical psychiatry at UC Davis School of Medicine, highlighted the urgent need for new treatments. “Major depressive disorder has a lifetime prevalence around 16 percent, and nearly two-thirds of patients do not respond adequately to current medications,” Hales said. “These results support the potential of sEH inhibitors such as TPPU as a novel class of therapeutics to prevent or treat depression.”
Implications and next steps
Collectively, the findings point to sEH as a compelling target for drug development. By preserving epoxy fatty acids—natural lipids that counteract inflammation—sEH inhibitors or lipid mimics could provide rapid symptom relief and possibly long-term resilience against stress-induced mood disorders. The observation of elevated sEH in human postmortem brain samples strengthens the translational significance of the animal data, but clinical studies will be required to confirm safety and efficacy in people.
The paper lists additional contributors from Chiba University and UC Davis, and notes that inventors on related UC patents include Morisseau, Jun Yang and Wagner. Some of these patents are licensed by EicOsis Human Health, a company founded by Hammock to develop treatments for neuropathic and inflammatory pain.
Funding
The work received funding from Japan’s Ministry of Education, Culture, Sports, Science and Technology, the Japan Society for the Promotion of Science, and U.S. grants from the National Institute of Environmental Health Sciences and related NIH programs. Hammock and collaborators also recently received an NIH grant to study bioactive lipids in anorexia nervosa.
Abstract
Gene deficiency and pharmacological inhibition of soluble epoxide hydrolase confers resilience to repeated social defeat stress
This study evaluates the role of soluble epoxide hydrolase (sEH) in depression. In both inflammation-induced and social-defeat models, the sEH inhibitor TPPU produced rapid antidepressant-like effects. Chronically stressed mice showed increased brain sEH expression, and postmortem brain samples from patients with depression, bipolar disorder, and schizophrenia also displayed elevated sEH. Pretreatment with TPPU prevented depression-like behaviors after inflammatory challenge or repeated social defeat, and sEH knockout mice were resilient to repeated social defeat. Resilient mice exhibited increased BDNF and TrkB phosphorylation in the prefrontal cortex and hippocampus, implicating enhanced BDNF-TrkB signaling in stress resilience. These results indicate sEH plays a key role in the pathophysiology of depression and suggest that epoxy fatty acids, their mimics, and sEH inhibitors are potential therapeutic or preventive strategies.
Authors include Qian Ren, Min Ma, Tamaki Ishima, Ji-chun Zhang, Chun Yang, Wei Yao, Chao Dong and Mei Han (Chiba University), and Jun Yang, Christophe Morisseau, Karen M. Wagner, and Bruce D. Hammock (UC Davis), with Kenji Hashimoto as a leading collaborator. The study was published in PNAS on March 14, 2016.
Source: Bruce Hammock — UC Davis
Image Credit: The image is in the public domain.