New research partially funded by NIEHS suggests an enzyme in the brain plays a key role in Parkinson’s disease (PD). Scientists demonstrated that inhibiting an enzyme known as soluble epoxide hydrolase (sEH) can help curb the inflammation associated with the development and progression of PD.
The team from the University of California-Davis (UCD), worked closely with colleagues in Japan and China. Their research appeared May 7 in the Proceedings of the National Academy of Sciences.
The project was led by Kenji Hashimoto, Ph.D., at Chiba University Center for Forensic Mental Health in Japan, and Bruce Hammock, Ph.D., from UCD. Hammock is a longtime NIEHS grantee and directs the NIEHS-funded Superfund Research Program (SRP) at UCD.
Key regulatory enzyme
Hammock explained that sEH is a key regulatory enzyme involved in the metabolism of fatty acids. “[In] our previous research, we found that sEH inhibitors treat neuropathic and inflammatory pain in humans and companion animals,” he said. “Now we're finding that these inhibitors play a key role in Parkinson's disease.”
In studies involving mice, the scientists found that sEH plays an important role in the inflammation associated with both progression of PD and the mechanisms that lead to the disease. They tested a potent sEH inhibitor and a mouse model that was genetically modified not to produce sEH. The two approaches produced similar results.
“By establishing this causal chain of events … we can better predict environmental chemicals that could predispose people to Parkinson's disease and possibly even treat the disease,” Hammock suggested.
“The Hammock lab studied foreign compound metabolism, which led to the work on the role of epoxide hydrolases in pain and inflammation,” noted Heather Henry, Ph.D., from the NIEHS Hazardous Substances Branch. “Now, 30 years into research at the UC Davis SRP, they report its potential role in reducing inflammation in Parkinson’s. It seems this is only the beginning of understanding how broadly applicable their discoveries are.”
“[Both] the sEH inhibitor [and] deletion of the sEH gene protected against MPTP-induced neurotoxicity in mouse brain,” Hashimoto said. MPTP is a relative of cyperquat and paraquat herbicides.
Hashimoto pointed out that medications to treat PD symptoms do not prevent the progression of the disease. “Therefore, the development of new drugs possessing disease-modifying or neuroprotective properties is critical,” he said.
sEH implicated in cell death
“While we know that a certain group of brain cells that produce dopamine are selectively destroyed in Parkinson's patients, what triggers this brain cell death remains poorly understood,” said Cesar Borlongan, Ph.D., from the University of South Florida. Borlongan was not involved in the study.
“In small and large animal models of Parkinson's disease, and further confirmed in a group of PD patients, [sEH] is highly elevated in specific regions of the brain implicated in dopamine cell death,” he observed.
The authors reported that the enzyme was also highly expressed in the brains of patients with a disease called dementia of Lewy bodies. That form of dementia, like PD, involves deposits of a protein called alpha-synuclein, in multiple regions of the brain.
According to Hammock, sEH inhibitors will soon enter human clinical trials supported by the Blueprint Program of the National Institute of Neurological Disorders and Stroke. “These drugs could provide relief for patients with a wide variety of inflammatory diseases,” he suggested. Hammock is CEO of a Davis-based company, EicOsis, that is developing the sEH inhibitors.
“sEH can break down some of the natural fatty acids in the body that reduce inflammation, high blood pressure, and pain symptoms,” explained Daniel Shaughnessy, Ph.D., from NIEHS. “Bruce and his colleague Alan Buckpitt [Ph.D.] saw the potential of inhibiting sEH as therapy for inflammation-related conditions.”
The researchers received a Small Business Innovation Research (SBIR) grant from NIEHS to develop sEH inhibitors for treating neuropathic pain. Shaughnessy is the NIEHS program lead for SBIR grants.
Citation: Ren Q, Ma M, Yang J, Nonaka R, Yamaguchi A, Ishikawa KI, Kobayashi K, Murayama S, Hwang SH, Saiki S, Akamatsu W, Hattori N, Hammock BD, Hashimoto K. 2018. Soluble epoxide hydrolase plays a key role in the pathogenesis of Parkinson's disease. Proc Natl Acad Sci U S A; doi:10.1073/pnas.1802179115 [Online 7 May 2018].
(This story is based on a UCD press release by Kathy Keatley Garvey.)