Inhibitor of hyaluronic acid synthesis 4-methylumbelliferone (4-MU) as a potential anti-inflammatory substance in acute neuroinflammation model in vivo.

Abstract

Cytokine and oxylipin profiles in rat brain homogenates were characterized as an inflammatory response 6 h after a single intracerebroventricular injection of LPS (19.3 µg LPS/ventricle), serving as a model of the inflammatory process in trauma, stroke, and similar stroke-like conditions that cause acute reactions. The potential use of 4-methylumbelliferone (4-MU), an inhibitor of hyaluronic acid (HA) synthesis, clinically approved for the treatment of bile spasm, as an anti-inflammatory drug in the early stages of the brain's response to a damaging stimulus was evaluated. i.c.v. injection of LPS induced proinflammatory genes expression (TNFα, IL-6 and IL-1β) and oxylipins synthesis. Simultaneous addition of 4-MU with LPS reduced LPS-induced TNFα, IL-1β, IL-6 release and reduced the increase in COX-derived metabolites-PGF, PGE, 6-keto-PGF, TXB, 12-HHT, and 15-HETE. LPS stimulated only the expression of HAS2, while the addition of 4-MU reduced the expression of LPS-stimulated HAS2, and induced the expression of HYAL1, but not HYAL2. Our results reveal significant changes in cytokines and oxylipins synthesis in the model of acute inflammation, and suggest that 4-MU can be viewed as a promising therapeutic agent in the early stages of neuroinflammation.