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

Abstract

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.

• Authors: Wu-Tein Huang, Mao-Tsun Lin, Ching-Ping Chang
• Journal: Neuropharmacology (Neuropharmacology) Vol. 50 Issue 4 Pg. 504-11 (Mar 2006) ISSN: 0028-3908 [Print] England
• PMID: 16406085 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Analgesics, Non-Narcotic
• Antioxidants
• Excitatory Amino Acid Antagonists
• Hydroxybenzoates
• Isoquinolines
• Lipopolysaccharides
• Receptors, N-Methyl-D-Aspartate
• Hydroxyl Radical
• Dizocilpine Maleate
• 2,3-dihydroxybenzoic acid
• Thioctic Acid
• LY 235959
• Acetylcysteine

Topics

• Acetylcysteine (pharmacology)
• Analgesics, Non-Narcotic
• Animals
• Antioxidants (pharmacology)
• Body Temperature (drug effects)
• Dizocilpine Maleate (pharmacology)
• Excitatory Amino Acid Antagonists (pharmacology)
• Fever (chemically induced, prevention & control)
• Hydroxybenzoates (pharmacology)
• Hydroxyl Radical (metabolism)
• Isoquinolines (pharmacology)
• Lipopolysaccharides (toxicity)
• Male
• Rabbits
• Receptors, N-Methyl-D-Aspartate (antagonists & inhibitors, physiology)
• Thioctic Acid (pharmacology)