GLUTATHIONE TRANSFERASE PROTECTS NEURONAL CULTURES AGAINST 4-HYDROXYNONENAL TOXICITY

Peroxidation of polyunsaturated fatty acids (PUFA), particularly arach idonic acid, leads to the generation of reactive aldehydes, including 4-hydroxynonenal (HNE). Recent studies have demonstrated an increase i n lipid peroxidation, a decline in PUFA, as well as an increase in HNE , and a decrease in glutathione transferase (GST) in the brain in Alzh eimer's disease. Four-hydroxynonenal is toxic to cultured neurons and to the brain of experimental animals. Although glutathione (GSH) has b een shown to offer protection against HNE, no enzymatic system has bee n described which serves to detoxify these reactive species in neurona l cultures. Here, we describe the use of GST in the protection of neur onal cultures against HNE toxicity. Glutathione transferases are a sup erfamily of enzymes functioning to catalyze the nucleophilic attack of GSH on electrophilic groups on a second substrate. These enzymes func tion efficiently with 4-hydroxyalkenals, particularly HNE, as substrat es. To investigate the protective effects of GST against HNE, primary hippocampal cultures were pretreated with GST before exposure to toxic doses of HNE which led to a statistically significant enhancement in cell survival. Pretreatment of cultures with equivalent levels of heat inactivated GST or antibody against GST did not offer protection agai nst HNE. Control cultures pretreated with GST also demonstrated enhanc ed survival compared with control cells receiving no pretreatment. The se data suggest that GST may be an important source of protection agai nst the toxic effects of HNE. (C) 1998 Elsevier Science Inc.