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.
Huang
Wu-Tein
WT
Department of Health Care Administration, Diwan College of Management, Taiwan. hwt@mail.dwu.edu.tw
Lin
Mao-Tsun
MT
Chang
Ching-Ping
CP
D000111:Acetylcysteine / Q000494:pharmacology; D018712:Analgesics, Non-Narcotic; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001831:Body Temperature / Q000187:drug effects; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005334:Fever / Q000139:chemically induced / Q000517:prevention & control*; D062385:Hydroxybenzoates / Q000494:pharmacology; D017665:Hydroxyl Radical / Q000378:metabolism*; D007546:Isoquinolines / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000633:toxicity*; D008297:Male; D011817:Rabbits; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000502:physiology*; D008063:Thioctic Acid / Q000494:pharmacology
D018712:Analgesics, Non-Narcotic; D000975:Antioxidants; D018691:Excitatory Amino Acid Antagonists; D062385:Hydroxybenzoates; D007546:Isoquinolines; D008070:Lipopolysaccharides; D016194:Receptors, N-Methyl-D-Aspartate; D017665:Hydroxyl Radical; D016291:Dizocilpine Maleate; C009135:2,3-dihydroxybenzoic acid; D008063:Thioctic Acid; C088643:LY 235959; D000111:Acetylcysteine