Blocking an enzyme associated with inflammation and disease progression in Parkinson’s patients may by a promising way of treating this neurodegenerative disorder, new research suggests.
The study, “Soluble epoxide hydrolase plays a key role in the pathogenesis of Parkinson’s disease,” was published in the journal Proceedings of the National Academy of Sciences (PNAS).
Inflammation, impaired mitochondria (the cell’s power plants) and oxidative stress are know to exist in affected brain regions of Parkinson’s patients.
Epoxy fatty acids (EpFAs) — molecules produced from the oxidation of unsaturated fatty acids — have shown potent anti-inflammatory properties in animal models. Inhibiting the enzyme that breaks down these compounds, called soluble epoxide hydrolase (sEH), further enhances their beneficial effects.
Previous research has also shown that sEH plays a key role in depressive symptomsreported in Parkinson’s patients.
Using mouse models of the disease, researchers evaluated the potential of either inhibiting or genetically deleting sEH — specifically in the striatum, the brain region involved in Parkinson’s disease. They also investigated sEH protein levels in postmortem brain samples of patients with Lewy body dementia, a progressive dementia related to Alzheimer’s. A similar dementia can afflict Parkinson’s patients.
Repeated oral administration of TTPU — an sEH inhibitor — improved levels of dopamine, a neurotransmitter, and associated metabolites in mice.
Deleting the gene that codes for sEH also protected the brains of these mice against induced neurotoxicity, while increasing sEH production had the opposite effect.
Higher sEH activity was observed in the brains of mice models of Parkinson’s, specifically in the striatum, and levels of this enzyme positively correlated with those of a specific form of the protein alpha-synuclein, which is the main component of Lewy bodies in Parkinson’s and the dementia patients.
In both Parkinson’s mice and the dementia patients, sEH levels in the striatum were higher than in healthy controls.
The team next tested pluripotent stem cells — able to generate almost any cell type — derived from a patient carrying PARK2, one of the familial forms of Parkinson’s and caused by a mutation in the PRKN gene.
Treating these stem cell-derived neurons with TPPU prevented the loss of domaninergic cells. Levels of sEH messenger RNA, which contains the genetic information to produce the sEH protein, were also seen to be higher in the patient stem cell-derived neurons than in healthy controls.
“Collectively, these findings suggest that sEH plays a key role in the pathogenesis of [Parkinson’s] and that sEH inhibitors may prove to be promising prophylactic or therapeutic drugs,” the researchers wrote.
They added that, although the findings in the familial Parkinson’s case warrant additional studies in other familial or sporadic patients, transplanted human stem cells may be a promising way of better understanding disease mechanisms and its treatment.
https://parkinsonsnewstoday.com/2018/05/16/enzyme-linked-to-parkinsons-inflammation-progression-may-be-treatment-target-study-suggests/
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