A novel compound VSC2 has anti-inflammatory and antioxidant properties in microglia and in Parkinson's disease animal model.

Abstract

BACKGROUND AND PURPOSE: Neuroinflammation through microglial activation is involved in the pathogenesis of neurodegenerative diseases including Parkinson's disease (PD), a major neurodegenerative disorder characterized by dopaminergic neuronal demise in the substantia nigra. We examined our novel synthetic compound VSC2 for its anti-inflammatory properties toward development of a PD therapy. EXPERIMENTAL APPROACH: We tested effects of VSC2 on production of various NFκB -dependent proinflammatory molecules and Nrf2-dependent antioxidant enzymes in BV-2 microglia and in vivo. KEY RESULTS: Among various vinyl sulfone compounds that we have newly synthesized, VSC2 was found to dramatically and most effectively suppress the production of nitric oxide in lipopolysaccharide-activated microglia. It also downregulated expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), IL-1β and TNF-α, and inhibited nuclear translocalization and transcriptional activity of NFκB. VSC2 increased total and nuclear Nrf2 levels, induced Nrf2 transcriptional activity, and bound to Keap1 with high affinity. Expression of the Nrf2-regulated antioxidant enzyme genes NAD(P)H quinone oxidoreducase-1 (NQO-1), heme oxygenase-1 (HO-1), and glutamylcysteine ligase (GCL) were upregulated by VSC2. In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-elicited mouse model of PD, oral administration of VSC2 decreased the number of activated microglia in the substantia nigra and lowered the levels of iNOS, COX-2 and IL-1β, and protected the dopaminergic neurons. VSC2 also elevated the levels of NQO1, HO-1, GCL and Nrf2 in the nigrostriatal area. CONCLUSIONS AND IMPLICATIONS: VSC2 has both anti-inflammatory and anti-oxidant properties and prevented neuroinflammation in microglia as well as in a PD animal model. This suggests utility of VSC2 as a potential candidate for PD therapy.