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Description

A phenylhydrazonodihydropyrazolone compound that inhibits TNF&,amp,amp,amp,amp,amp,alpha,/&,amp,amp,amp,amp,amp,beta,-stimulated biological activity by modulating, but not abolishing, TNF-TNFR interaction via direct TNF affinity interaction (KD = 110 nM in binding study using hTNF&,amp,amp,amp,amp,amp,alpha,). Shown to prevent murine L929 cell death following hTNF&,amp,amp,amp,amp,amp,alpha,/&,amp,amp,amp,amp,amp,beta, (1 ng/mL, Cat. Nos. 654205 &,amp,amp,amp,amp,amp, 654215) and actinomycin D (1 g/mL, Cat. Nos. 114666 &,amp,amp,amp,amp,amp, 2472-OP) treatment (EC50 = 8.73 M by MTT assay, 20 h TNF/ActD treatment) by blocking TNF/ActD-induced caspase-3/8 cleavages &,amp,amp,amp,amp,amp, I&,amp,amp,kappa,B&,amp,amp,alpha, degradation without affecting Fas- (CD95) mediated Jurkat cell death or VP-16 (Etoposide, Cat. No. 341205) and ADR (Adriamycin/Doxorubicin, Cat. No. 324380) cytotoxicity in L292 cultures. When applied prior to D-galactosamine (1.2 g D-GalN/kg, Cat. No. 34539) &,amp,amp,amp,amp,amp, Lipopolysaccharide (LPS, 50 g/kg) injection, C87 effectively prevents D-GalN/LPS-induced upregulation of plasma alanine transaminase &,amp,amp,amp,amp,amp, aspartate transaminase (ALT &,amp,amp,amp,amp,amp, AST) activity, resulting in significantly reduced liver damage and much improved survival rate (58.5% vs. 20.8% with or without 3X 12.5 mg C87/kg i.p. dosings 16, 8, &,amp,amp,amp,amp,amp, 1 h prior to D-GalN/LPS injection) in a murine hepatitis model in vivo. A slow and long-lasting (>12 h) JNK T183/Y185 phosphorylation is induced upon TNF&alpha, stimulation in L929 cultures, while a much faster and more transient, albeit robust, TNF&alpha,-induced JNK pT183/Y185 is seen in the presence of C87 or a TNF&alpha, neutralizing antibody.