Geldanamycin, an inhibitor of heat shock protein 90 (Hsp90) mediated signal transduction has anti-inflammatory effects and interacts with glucocorticoid receptor in vivo.

摘要: Histamine, vascular endothelial growth factor, acetylcholine, oestrogen as well fluid shear stress activates a mechanism that recruits heat shock protein 90 to the nitric oxide synthase. The interaction between Hsp90 and eNOS enhances activation of enzyme in cells intact blood vessels leading NO production. Intraplantar administration carrageenan (50 μl paw−1) mice causes an oedema lasting 72 h. Geldanamycin (0.1, 0.3, 1 mg kg−1), specific inhibitor Hsp-90, inhibits endothelium-dependent relaxations rat aorta, mesentery middle artery carrageenan-induced mouse paw dose dependent manner. Co-administration dexamethasone (1 mg kg−1) with geldanamycin (0.3 mg kg−1) at anti-inflammatory loss total effect each agent alone. RU 486 (10 mg kg−1), known glucocorticoid receptorial antagonist, does not inhibit formation but prevents action (1 mg kg−1). Similarly, RU 486 (0.3 mg kg−1). In conclusion we have described for first time geldanamycin, signal transduction, is vivo implying critical pathways involved oedema. In addition ability GA block release reduce suggests therapeutic rationale inhibitors potential drugs. Keywords: Geldanamycin, Hsp90, inflammation, receptor, dexamethasone, RU 486 Introduction Recently, it has been shown agonists stimulates production such histamine, factor (VEGF), activate (Hsp90) synthase (eNOS). Interaction (Garcia-Cardena et al., 1998; Shah 1999; Viswanathan Russell 2000). member family proteins restoring cellular homeostasis, subcellular trafficking folding several signalling (for review see Pearl & Prodromou, Recent studies also (GA), 1999). cultured cells, reduces VEGF oestrogen-stimulated cyclic GMP related analogue herbamycin A are members benzoquinone ansamicyn antibiotic specifically bind unique ATP binding pocket stable pharmacologically fashion (Whitesell Cook, 1994). Steroid hormone receptors growing nuclear (Mangelsdorf 1995; Gronemeyer Laudet, 1995) assembled into multiprotein complex containing p23, immunophillin, proteins, mostly some Hsp70. Genetic analysis yeast (Picard 1990; Kimura biochemical evidence mammalian (Bresnick 1989; Dalman 1989) indicates necessary maintain receptor (GR) conformation able hormone. When occurs, GR disrupted then translocates nucleus transcription target genes. widely used study its function 1996; Segnitz Gehring, 1990). Thus, plays important role regulating signalling. Since NO, histamine all mediators inflammation sought investigate if effects addition, evaluated possible context.