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 2024-01-20T08:00:24Z 2024-01-20T08:00:24Z 2021-09-05 2015-02 0007-1188 https://pubs.kist.re.kr/handle/201004/125816 Background and PurposeNeuroinflammation through microglial activation is involved in the pathogenesis of neurodegenerative diseases including Parkinson's disease (PD), a major neurodegenerative disorder characterized by dopaminergic neuronal death in the substantia nigra. We examined our novel synthetic compound VSC2 for its anti-inflammatory properties towards development of a PD therapy. Experimental ApproachWe tested the effects of VSC2 on production of various NF-B-dependent proinflammatory molecules and Nrf2-dependent antioxidant enzymes in BV-2 microglia and in vivo. Key ResultsThe vinyl sulfone compound, VSC2, most effectively suppressed the production of NO in LPS-activated microglia. It also down-regulated expression of inducible NOS (iNOS), COX-2, IL-1 and TNF- and inhibited nuclear translocalization and transcriptional activity of NF-B. VSC2 increased total and nuclear Nrf2 levels, induced Nrf2 transcriptional activity and was bound to Keap1 with high affinity. Expression of the Nrf2-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 VSC2. In the MPTP mouse model of PD, oral administration of VSC2 decreased the number of activated microglia in the substantia nigra, lowered the levels of iNOS, COX-2 and IL-1, and protected the dopaminergic neurons. VSC2 also elevated the levels of NQO1, HO-1, GCL and Nrf2 in the nigrostriatal area. Conclusions and ImplicationsVSC2 has both anti-inflammatory and antioxidant properties and prevented neuroinflammation in microglia and in an animal model of PD. This suggests VSC2 as a potential candidate for PD therapy. English WILEY MPTP-MOUSE MODEL HEME OXYGENASE-1 DOPAMINERGIC-NEURONS NRF2 PROTECTS SULFORAPHANE INFLAMMATION ACTIVATION AGENTS TRANSCRIPTION A novel compound VSC2 has anti-inflammatory and antioxidant properties in microglia and in Parkinson's disease animal model Article 10.1111/bph.12973 1 BRITISH JOURNAL OF PHARMACOLOGY, v.172, no.4, pp.1087 - 1100 BRITISH JOURNAL OF PHARMACOLOGY 172 4 1087 1100 scie scopus 000348507700010 2-s2.0-84921717510 Pharmacology & Pharmacy Pharmacology & Pharmacy Article MPTP-MOUSE MODEL HEME OXYGENASE-1 DOPAMINERGIC-NEURONS NRF2 PROTECTS SULFORAPHANE INFLAMMATION ACTIVATION AGENTS TRANSCRIPTION