An NMDA receptor-dependent hydroxyl radical pathway in the rabbit hypothalamus may mediate lipopolysaccharide fever.

The aim of this study was to investigate the effects of antioxidants (e.g. alpha-lipoic acid and N-acetyl-L-cysteine) as well as N-methyl-D-aspartate (NMDA) receptor antagonists (e.g. MK-801 and LY235959) on the changes of both core temperature and hypothalamic levels of 2,3-dihydroxybenzoic acid (2,3-DHBA) induced by systemic administration of lipopolysaccharide (LPS) in rabbits. The measurements of 2,3-DHBA were used as an index of the intrahypothalamic levels of hydroxyl radicals. Intravenous administration of LPS (2-10 microg/kg) elicited a biphasic febrile response, with the core temperature maxima at 80 and 200 min post-injection. Each core temperature rise was accompanied by a distinct wave of cellular concentrations of 2,3-DHBA in the hypothalamus. The rise in both the core temperature and hypothalamic 2,3-DHBA could be induced by direct injection of glutamate (100-400 microg in 10 microl/rabbit) into the cerebroventricular fluid system. Either the early or the late phase of fever rise and increased hypothalamic levels of 2,3-DHBA following systemic injection of LPS were significantly antagonized by pretreatment with injection of alpha-lipoic acid (5-60 mg/kg, i.v.), N-acetyl-L-cysteine (2-20 mg/kg, i.v.), MK-801 (0.1-1 mg/kg, i.m.), or LY235959 (0.1-1 mg/kg, i.v.) 1 h before LPS injection. The increased levels of prostaglandin E(2) in the hypothalamus induced by LPS could be suppressed by alpha-lipoic acid or N-acetyl-L-cysteine pretreatment. These findings suggest that an NMDA receptor-dependent hydroxyl radical pathway in the hypothalamus of rabbit brain may mediate both the early and late phases of the fever induced by LPS.