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A novel compound VSC 2 has anti‐inflammatory and antioxidant properties in microglia and in P arkinson's disease animal model
Author(s) -
Lee Ji Ae,
Kim Ji Hyun,
Woo Seo Yeon,
Son Hyo Jin,
Han Se Hee,
Jang Bo Ko,
Choi Ji Won,
Kim Dong Jin,
Park Ki Duk,
Hwang Onyou
Publication year - 2015
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.12973
Subject(s) - microglia , substantia nigra , neuroinflammation , proinflammatory cytokine , chemistry , mptp , dopaminergic , neurodegeneration , neuroprotection , pharmacology , dopamine , biology , immunology , medicine , endocrinology , inflammation , disease
Background and Purpose Neuroinflammation through microglial activation is involved in the pathogenesis of neurodegenerative diseases including P arkinson's disease ( PD ), a major neurodegenerative disorder characterized by dopaminergic neuronal death in the substantia nigra. We examined our novel synthetic compound VSC 2 for its anti‐inflammatory properties towards development of a PD therapy. Experimental Approach We tested the effects of VSC 2 on production of various NF‐κB ‐dependent proinflammatory molecules and N rf2‐dependent antioxidant enzymes in BV ‐2 microglia and in vivo . Key Results The vinyl sulfone compound, VSC 2, most effectively suppressed the production of NO in LPS ‐activated microglia. It also down‐regulated expression of inducible NOS (i NOS ), COX ‐2, IL ‐1β and TNF ‐α and inhibited nuclear translocalization and transcriptional activity of NF‐κB . VSC 2 increased total and nuclear N rf2 levels, induced N rf2 transcriptional activity and was bound to K eap1 with high affinity. Expression of the N rf2‐regulated antioxidant enzyme genes NAD(P)H quinone oxidoreducase‐1 ( NQO ‐1), haem oxygenase‐1 ( HO ‐1) and glutamylcysteine ligase ( GCL ) were up‐regulated by VSC 2. In the MPTP mouse model of PD , oral administration of VSC 2 decreased the number of activated microglia in the substantia nigra, lowered the levels of iNOS, COX‐2 and IL‐1β, and protected the dopaminergic neurons. VSC 2 also elevated the levels of NQO 1, HO ‐1, GCL and N rf2 in the nigrostriatal area. Conclusions and Implications VSC 2 has both anti‐inflammatory and antioxidant properties and prevented neuroinflammation in microglia and in an animal model of PD . This suggests VSC 2 as a potential candidate for PD therapy.