- Author: Kathy Keatley Garvey
Researchers at the Huazhong University of Science and Technology, Wuhan China, used the drug developed at UC Davis to show that the neurofibrillary pathology of an Alzheimer's disease-related protein could be dramatically reduced. Their work was published in December in the Journal of Huazhong University of Science and Technology.
“They further demonstrated the mechanism of action of the UC Davis drug in blocking the oxidative stress-driven phosphorylation events associated with Alzheimer's disease,” Hammock said. The UC Davis drug stabilizes natural anti-inflammatory mediators by inhibiting an enzyme called soluble epoxide hydrolase (sEH) discovered at UC Davis and recently spotlighted in the Proceedings of the National Academy of Sciences and the National Institutes of Health's PubMed.
“I was thrilled to see this paper on tau phosphorylation from Huazhong University shows that our drug could block a key event and a key enzyme called GSK-3 beta thought critical in the development of Alzheimer's disease,” said Hammock, who holds a joint appointment in the UC Davis Department of Entomology and Nematology and the UC Davis Comprehensive Cancer Center.
“We were planning to do this study, but having another laboratory do it with our compound was even better,” he said. “Since our publication last year in PNAS that showed UC Davis soluble epoxide hydrolase inhibitors both prevented and reversed depression, we have been excited about trying to block the development of Alzheimer's disease.”
The PNAS paper, “Gene Deficiency and Pharmacological Inhibition of Soluble Epoxide Hydrolase Confers Resilience to Repeated Social Defeat Stress,” was co-authored by a 13-member research team led by Hammock and Kenji Hashimoto of Chiba University Center's Division of Clinical Neuroscience, Japan. They found 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 and several other disorders of the central nervous system. Co-authors of the paper included Hammock lab researchers Christophe Morisseau, Jun Yang and Karen Wagner.
Hammock credited several UC Davis colleagues for their work leading to the publications. Research from the labs of Liang Zhang and Qing Li at the University of Hawaii--Qing is a former UC Davis doctoral student--pointed out some of the mechanisms involved in cognitive decline which associate professor Aldrin Gomes of the UC Davis Department of Neurobiology, Physiology and Behavior and Fawaz Haj of the UC Davis Department of Nutrition “have shown to be blocked by the natural metabolites stabilized by the UC Davis drugs,” Hammock said.
One of the Hammock lab drugs is moving toward human clinical trials for neuropathic pain through a Davis-based company, EicOsis, LLC, and the financial support of the Blueprint Program through NIH's National Institute of Neurological Disorders and Stroke. Hammock founded the company to develop inhibitors to the soluble epoxide hydrolase, a key regulatory enzyme involved in the metabolism of fatty acids, to treat unmet medical needs in human and animals.
“The clinical back-up candidate at EicOsis penetrates the blood brain barrier and should be a perfect compound to test if this class of chemistry can prevent cognitive decline and Alzheimer's disease,” Hammock said.
The National Institute of Environmental Health Sciences, National Institutes of Health, funded the research.
Highly honored by his peers, Hammock is a fellow of the National Academy of Inventors, which honors academic invention and encourages translations of inventions to benefit society. He is a member of the U.S. National Academy of Sciences, a fellow of the Entomological Society of America, and the recipient of the Bernard B. Brodie Award in Drug Metabolism, sponsored by the America Society for Pharmacology and Experimental Therapeutics. He directs the campuswide Superfund Research Program, National Institutes of Health Biotechnology Training Program, and the National Institute of Environmental Health Sciences (NIEHS) Combined Analytical Laboratory.
- 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.