Linked Life Data

10448911

Source:http://linkedlifedata.com/resource/pubmed/id/10448911

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
1-2
pubmed:dateCreated
1999-9-21
pubmed:abstractText
Immediately after bacterial endotoxin (LPS) enters the circulatory system there is increased production of free oxygen radicals by cells of the reticulo-endothelial system, followed by the release of cytokines considered as putative endogenous pyrogens. Fever originates by central nervous system activities, but neither exogenous nor endogenous pyrogens are able to cross the blood-brain barrier and the true signal which is transmitted to structures inside the blood-brain barrier is still unknown. To study the role of oxygen 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 as an index of lipid peroxidation by oxygen radicals. Methylene blue lowered resting malondialdehyde levels to near detection level and significantly suppressed its rise which was regularly found following LPS in the untreated state. Pretreatment with methylene blue completely blocked the febrile response. Since fever is a central nervous system-mediated response these results indicate that the brain is able to sense oxidative stress and vicinal thiol 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 temperatures. DTT induced, independently of ambient temperature, within minutes and dose-dependently the full pattern of heat loss responses causing a fall of core temperature, indicative of a lowered thermoregulatory setpoint. Pretreatment with a bolus dose of 5 mg/kg DTT, followed by a continuous infusion 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 febrile 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 activation, and, thus, enhanced formation of NO, which, in turn, lowers the thermoregulatory setpoint. Reduction of other disulfide-containing molecules, especially oxidized glutathione and thiol-containing enzymes, by DTT by might additionally contribute to preventing fever.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jun
pubmed:issn
0300-8177
pubmed:author
pubmed:issnType
Print
pubmed:volume
196
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
125-32
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed:year
1999
pubmed:articleTitle
Fever: an integrated response of the central nervous system to oxidative stress.
pubmed:affiliation
Max-Planck-Institut für physiologische und klinische Forschung, Bad Nauheim, Germany.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't