Soluble Epoxide Hydrolase Inhibition to Face Neuroinflammation in Parkinson’s Disease: A New Therapeutic Strategy

Abstract

Neuroinflammation is a crucial process associated with the pathogenesis of neurodegenerative diseases, including Parkinson’s disease (PD). Several pieces of evidence suggest an active role of lipid mediators, especially epoxy-fatty acids (EpFAs), in the genesis and control of neuroinflammation; 14,15-epoxyeicosatrienoic acid (14,15-EET) is one of the most commonly studied EpFAs, with anti-inflammatory properties. Soluble epoxide hydrolase (sEH) is implicated in the hydrolysis of 14,15-EET to its corresponding diol, which lacks anti-inflammatory properties. Preventing EET degradation thus increases its concentration in the brain through sEH inhibition, which represents a novel pharmacological approach to foster the reduction of neuroinflammation and by end neurodegeneration. Recently, it has been shown that sEH levels increase in brains of PD patients. Moreover, the pharmacological inhibition of the hydrolase domain of the enzyme or the use of sEH knockout mice reduced the deleterious effect of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration. This paper overviews the knowledge of sEH and EETs in PD and the importance of blocking its hydrolytic activity, degrading EETs in PD physiopathology. We focus on imperative neuroinflammation participation in the neurodegenerative process in PD and the putative therapeutic role for sEH inhibitors. In this review, we also describe highlights in the general knowledge of the role of sEH in the central nervous system (CNS) and its participation in neurodegeneration. We conclude that sEH is one of the most promising therapeutic strategies for PD and other neurodegenerative diseases with chronic inflammation process, providing new insights into the crucial role of sEH in PD pathophysiology as well as a singular opportunity for drug development.

The Role of Epoxyeicosatrienoic Acids in Cardiac Remodeling

“…In 1981, Capdevila et al (1981) firstly reported that AA could be metabolized to EETs by CYP in the liver. Since then, plenty of studies have demonstrated that EETs played important roles in several diseases, such as kidney diseases ( Hye Khan et al, 2016 ; Deng et al, 2017 ; Wang et al, 2019 ), neurodegenerative diseases ( Atone et al, 2020 ; Pallas et al, 2020 ), rheumatic arthritis ( Hoxha, 2018 ; Hoxha and Zappacosta, 2020 ), and especially CVD ( Xu et al, 2011 ; Chen and Wang, 2013 ).…”

Targeting Mitochondrial Impairment in Parkinson's Disease: Challenges and Opportunities

“…There are multiple lines of evidence suggesting that soluble epoxide hydrolase (sEH) deficiency or inhibition can attenuate parkinsonism in MPTP-treated mice (Qin et al, 2015;Pallas et al, 2020). For example, deficiency and inhibition of sEH attenuates the loss of TH-positive cells and improves rotarod performance (Qin et al, 2015).…”

“…Thus, sEH inhibition might be a powerful tool to protect dopaminergic neurons in PD (Qin et al, 2015). In addition to having anti-inflammatory properties, EETs may have numerous benefits such as antioxidant effects, a reduction in mitochondrial dysfunction and apoptosis and improved cerebral blood flow (Pallas et al, 2020).…”

Cytochrome P450 Metabolism of Polyunsaturated Fatty Acids and Neurodegeneration

“…The neuroinflammation can be controlled by either suppressing the expression and release of pro-inflammatory mediators such as iNOS, Iba1, TNF-a, or increasing anti-inflammatory cytokines, including IL-10 by polarized microglia, which is greatly affected by endogenous Ep-PUFAs, in particular EETs [ 136 , 138 , 139 ]. Several studies have shown that deletion or inhibition of sEH induces production of anti-inflammatory cytokines such as IL-10, while reducing pro-inflammatory mediators including IFN-γ, and decreasing TNF-α localization and circulation [ 176 , 211 , 212 ].…”