Effect of alpha-phenyl-tert-butylnitrone on endotoxin toxemia in horses

Lipopolysaccharide (LPS), or endotoxin, is a component of the cell wall of gram-negative bacteria and is toxic to humans and animals. The GI tract of horses contains large numbers of endotoxins which may cause disease if gut wall integrity is compromised. The objective of this study was to develop a unique therapeutic approach to the treatment of endotoxemia with a sulfonyl analog of the alpha-phenyl-N-tert-butyl-nitrone (PBN) spin-trap molecule which may prevent the LPS-induced cytokine cascade. Following challenge with 55 mg/kg LPS, the survivability of ICR Swiss mice was significantly improved after treatment with 100 and 175 mg/kg PBN, although survivability of mice treated with 175 mg/kg PBN was significantly less than those treated with 100 mg/kg PBN. Challenged mice treated with 300 and 1000 mg/kg PBN survived for a significantly shorter period of time (vs control). Horses treated with a sublethal dose (1 microgram/kg) of endotoxin experienced 2 periods of distress at 1 and 6 h after challenge. Disulfonyl-PBN significantly reduced the increase in heart and respiratory rates 6 h after challenge. Analogs of PBN appeared to be more beneficial following near-lethal challenge with LPS. Dramatic benefits to horses may only be observed in life-threatening situations.