Modulation of the enzyme soluble epoxide hydrolase as a therapeutic target against neurodegenerative diseases

Abstract

Neurodegenerative diseases cursing with chronic inflammatory conditions represent a major health problem due to the global increase in life expectancy and age-related diseases. Thus, there is an urgent need for new approaches to mitigate neuroinflammation. Epoxyeicosatrienoic acids (EETs) are endogenous mediators that have several potentially protective functions including anti-inflammatory effects. EETs beneficial effects disappear when the enzyme soluble Epoxide Hydrolase (sEH) metabolizes them to the corresponding dihydroxyeicosatrienoic acids. Therefore, sEH enzyme is emerging as a promising pharmacological target, because its inhibition allows increasing EETs and keeping them active. The aim of the present study was to determine the half maximal inhibitory concentration (IC50) of a newly synthetized sEH inhibitor (sEHi) series, agents A01, A02, A03, A04, A05 and A06, and study their toxicity and anti-inflammatory effects. Neuroblastoma SH-SY5Y cell cultures were used to the IC50 calculation and the safety level of each sEHi. To study the anti-inflammatory effects, lipopolysaccharide stimulated microglial-like BV2 cells were used to obtain conditioned media with the proinflammatory mediators. Modulatory effects on the inflammatory pathways iNOS and NFĸB, and the release of cytokines were explored using techniques of Western Blot, immunocytochemistry and ELISA. All agents showed higher inhibitory potency than the reference compound 1-(1-propionylpiperidin-4-yl)- 3-[4-(trifluoromethoxy)phenyl]urea (TPPU) and generally low cytotoxicity. They also showed promising anti-inflammatory properties. In this way, the newly synthesized sEHi agents could be a new therapy against the neuroinflammation present in neurodegenerative diseases as Alzheimer’s disease, and in other neurological diseases with an inflammatory component.