Jasmonic acid and methyl jasmonate attenuate neuroinflammation via crosstalk with the prostaglandin E2/receptor EP2 signaling axis

Abstract

The jasmonates are a class of oxylipin phytohormones known to exhibit anti-inflammatory, antioxidant, and anti-cancer effects in mammalian cells. We investigated the ability of three jasmonate compounds (jasmonic acid, methyl jasmonate, and 12-OPDA) and two structurally distinct jasmonate precursors (alpha-linolenic acid and palmitic acid) to attenuate inflammation in an in vitro model of neurodegenerative disease, for which the mechanisms of action have not been well identified. The study modeled chronic neuroinflammation in SH-SY5Y neuroblastoma cells using exogenous prostaglandin E2 (PGE2) treatment. Prostaglandin E2 caused concentration-dependent levels of inflammation and SH-SY5Y cell death, which were attenuated by the jasmonates and their precursors. To this end, structural similarities between the jasmonates and PGE2 were correlated with increased potency of their anti-inflammatory effects. Downstream biomarkers of signaling through the pro-inflammatory E prostanoid receptor subtype 2 (EP2) were then quantified using enzyme-linked immunosorbent assay methods. Of the compounds tested, only jasmonic acid and methyl jasmonate attenuated inflammation in the SH-SY5Y cells via crosstalk with the PGE2/EP2 signaling axis. Additionally, structural models and molecular binding simulations serve as evidence for our hypothesis that JA and MeJA achieve this crosstalk through competitive inhibition of the receptor EP2. This novel finding has implications in the study of neurodegenerative diseases for which the disease pathology is related to chronic neuroinflammation, including Alzheimers Disease (AD), Parkinsons Disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS). In addition, these findings add to the understanding of the relationship between pro-inflammatory prostaglandin E2 signaling and disease severity.