Method of preventing necrosis and apoptosis

Details Method of preventing necrosis and apoptosis Method of preventing necrosis and apoptosis

A - Human Necessities

61

K

A61K 31/22 (2006.01) A61K 31/00 (2006.01) A61K 31/121 (2006.01) A61K 31/198 (2006.01)

Patent

CA 2268462

Manipulation of the intracellular redox state has been shown to alter cell activation pathways with resultant changes in cellular function. Previous studies have suggested that thiol oxidation, using the glutathione-depleting agent diethyl maleate, was able to inhibit endothelial cell activation. We hypothesized that this agent might exert beneficial effects following endotoxemia in the rat, a model where transendothelial migration of neutrophils is central to the development of hepatocellular injury. Sprague Dawley rats treated intraperitoneally with LPS (200 µg/kg) plus D- galactosamine (600 mg/kg) developed hepatocellular necrosis, as evidenced by liver enzyme release and morphological changes. Pretreatment with diethyl maleate abrogated this injury in a dose dependent fashion. Histology revealed reduced neutrophil accumulation in both the parenchyma and sinusoids, consistent with reduced neutrophil sequestration and transendothelial migration. This effect appeared to be related to the ability of diethyl maleate to prevent LPS-induced upregulation of both VCAM-1 mRNA and ICAM-1 mRNA in the liver as well as reducing TNF mRNA expression. In addition, diethyl maleate prevented hepatocyte apoptosis followings LPS treatment. The effect was reproduced when TNF was used as an inflammatory stimulus, suggesting a direct protective effect on the hepatocyte. Taken together, these studies show that redox manipulation through thiol oxidation may represent a novel approach to preventing liver necrosis and apoptosis in inflammatory conditions.

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