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Description

A cell-permeable vinylsulfone that acts as a more potent Nrf-2 activator than the chalcones (e.g. Cat. No. 492040) in stimulating HO-1 expression in murine microglial BV-2 cultures (3.82-fold of control in 24 h, 20 µ,M). Shown to induce overall Nrf2 cellular accumulation & nuclear translocation (1 to10 µ,M) in murine dopaminergic CATH.a cultures, presumably by freeing Nrf2 from its negative regulator keap1, with concomitant upregulation of Nrf2-regulated antioxidant enzymes expression, effectively protecting CATH.a against BH4 toxicity (effective conc. 0.1 to 1.0 µ,M against 200 µ,M BH4, 24 h) in vitro and preventing MPTP- (Cat. No. 506382) induced motor dysfunctions and neurodegeneration in a murine PD model in vivo (3X 10 mg drug/kg/d p.o., 4X 20 mg MPTP/kg/2 h i.p.)., A cell-permeable vinylsulfone compound that acts as a more potent Nrf-2 activator than the analogous alpha,beta-unsaturated ketone-based chalcones (e.g. Cat. No. 492040) in stimulating HO-1 expression in murine microglial BV-2 cultures (382% of control protein level in 24 h, 20 µ,M). Drug treatment in murine dopaminergic (DAergic) CATH.a cultures likewise effectively induces Nrf2 nuclear translocation (Fold of control in 3 h/dose = 1.4/1 µ,M, 2.3/5 µ,M, 3.4/10 µ,M) and overall Nrf2 cellular accumulation (Fold of control in 24 h/dose = 1.5/0.5 µ,M, 2.0/1 µ,M, 2.8/2 µ,M, 4.3/5 µ,M), presumably by freeing Nrf2 from its negative regulator keap1, with concomitant upregulation of Nrf2-regulated antioxidant enzymes expression, including heme oxygenase-1/OH-1, NAD(P)H quinone oxidoreductase 1/NQO1, glutamate-cysteine ligase modifier & catalytic subunits, QCLM & GCLC. Shown to protect CATH.a against BH4 toxicity (effective conc. 0.1 to 1.0 µ,M against 200 µ,M BH4 for 24 h) in vitro and prevent MPTP- (Cat. No. 506382) induced motor deficits/dysfunctions (by vertical grid test 6 d post MPTP injection) and neurodegeneration (by TH staining 7 d post MPTP injection) in a murine PD model in vivo (3 X 10 mg drug/kg/d oral dosages, 4X 20 mg MPTP/kg/2 h i.p. dosages starting 24 h post the 1st drug dosage).