title: Role of glucocorticoids in the regulation of brain prostaglandin biosynthesis under basal conditions and in response to endotoxin.
abstract: Glucocorticoids (GC) are known to inhibit eicosanoid production in various peripheral tissues; however, their role in the regulation of basal and induced prostaglandin (PG) biosynthesis in the brain is still not clear. In the present study we examined the effect of exogenous dexamethasone (dex) or endogenous GC on basal and on bacterial endotoxin (lipopolysaccharide, LPS) induced ex vivo production of PGE2 by the frontal cortex of rat brain. The experimental groups were: 1) intact rats; 2) rats in whom endogenous GC were removed either by surgical or by chemical (metopirone) adrenalectomy (adex); and 3) rats exposed to specific corticosteroid receptor antagonists. In intact rats, the basal rate of PGE2 ex vivo synthesis was about 120 pg/mg protein.hr; dex (0.05-0.5 mg/100 g body wt ip) did not affect this level. Exposure to LPS (50 micrograms, intracerebroventricular) induced a 2-fold increase in PGE2, whereas pretreatment with dex abolished this increase. Bilateral adex or metopirone alone did not change PGE2 synthesis, whereas LPS administration to surgical or chemical adex rats resulted in a 4-fold increase in PGE2 production. Administration (intracerebroventricular) of either one or both of the specific corticosteroid receptor antagonists, RU-28318 (type I) and RU-38486 (type II) did not affect basal PGE2 production. When LPS was given after either one of these antagonists, a slight but significant elevation of PGE2 occurred, as compared to LPS-treated controls. When both antagonists were coadministered, the LPS-induced production of PGE2 was much more pronounced, similar to levels of LPS-treated, adex rats. These results suggest that LPS-induced production of PGE2, but not the basal production, is regulated by either endogenous or exogenous GC, and the inhibitory effect of GC on brain PG synthesis is mediated via both type I and II corticosteroid receptors.
authors.affiliation: Department of Neurology, Hadassah University Hospital, Jerusalem, Israel.
authors.forename: J
authors.initials: J
authors.lastname: Weidenfeld
authors.forename: I
authors.initials: I
authors.lastname: Amir
authors.forename: E
authors.initials: E
authors.lastname: Shohami
mesh_terms: D000315:Adrenalectomy; D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D002552:Cerebral Ventricles / Q000187:drug effects / Q000502:physiology*; D003907:Dexamethasone / Q000494:pharmacology*; D015232:Dinoprostone / Q000096:biosynthesis*; D066298:In Vitro Techniques; D007276:Injections, Intraventricular; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D015735:Mifepristone / Q000494:pharmacology; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D012016:Reference Values; D013148:Spironolactone / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D008070:Lipopolysaccharides; D000451:Mineralocorticoid Receptor Antagonists; D013148:Spironolactone; D015735:Mifepristone; C041006:RU 28318; D003907:Dexamethasone; D015232:Dinoprostone