Fever: An integrated response of the central nervous system to oxidative stress

Immediately after bacterial endotoxin (LPS) enters the circulatory system t here is increased production of free oxygen radicals by cells of the reticu lo-endothelial system, followed by the release of cytokines considered as p utative endogenous pyrogens. Fever originates by central nervous system act ivities, but neither exogenous nor endogenous pyrogens are able to cross th e blood-brain barrier and the true signal which is transmitted to structure s inside the blood-brain barrier is still unknown. To study the role of oxy gen radicals in fever, we pretreated rats with methylene blue, an inhibitor of superoxide and hydroxyl radical production and investigated the febrile response to LPS in conscious rats by measuring malondialdehyde formation a s an index of lipid peroxidation by oxygen radicals. Methylene blue lowered resting malondialdehyde levels to near detection level and significantly s uppressed its rise which was regularly found following LPS in the untreated state. Pretreatment with methylene blue completely blocked the febrile res ponse. Since fever is a central nervous system-mediated response these resu lts indicate that the brain is able to sense oxidative stress and vicinal t hiol groups of the redox-modulatory site of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor-channel complex could function as a possible receptive structure. To test this hypothesis we injected rabbits with the disulfide reducing agent dithiothreitol (DTT), known to penetrate the blood -brain barrier, and monitored its effect on normal and febrile body tempera tures. DTT induced, independently of ambient temperature, within minutes an d dose-dependently the full pattern of heat loss responses causing a fall o f core temperature, indicative of a lowered thermoregulatory setpoint. Pret reatment with a bolus dose of 5 mg/kg DTT, followed by a continuous infusio n of 5 mg/kg/h for 3 h completely prevented LPS-induced fever. A bolus dose of 20 mg/kg DTT, starting 30 min after LPS, immediately reversed the febri le cold defense pattern and lowered body temperature. We conclude that DTT reduces in the central nervous system oxidized vicinal thiol groups of NMDA receptors, thereby augmenting glutamate-induced nitric oxide synthase acti vation, and, thus, enhanced formation of NO, which, in turn, lowers the the rmoregulatory setpoint. Reduction of other disulfide-containing molecules, especially oxidized glutathione and thiol-containing enzymes, by DTT by mig ht additionally contribute to preventing fever.