Evidence for prolonged suppression of stress-induced release of adrenocorticotropic hormone and corticosterone with a brain-enhanced dexamethasone-redox delivery system.
We have developed a redox system for brain-enhanced delivery of dexamethasone based on an interconvertible dihydropyridine in equilibrium pyridinium salt carrier. Dexamethasone, when combined with the lipoidal carrier, readily crosses the blood-brain barrier. The carrier, when oxidized, reduces its rate of exit from the brain. The aim of the study was to evaluate the capacity of a dexamethasone-chemical delivery system (DX-CDS) and dexamethasone (DEX) to suppress stress-induced elevations of plasma adrenocorticotropic hormone (ACTH) and corticosterone (CORT). Adult male Sprague-Dawley (CD) rats were administered either DX-CDS (10 mg/kg), an equimolar dose of DEX or the drug vehicle (2-hydroxypropyl-beta-cyclodextrin) by a single tail vein injection. Rats then received either no stress or a restraint stress for a 5- or 15-min duration on days 1, 3, 5 or 7 after drug administration and trunk blood was rapidly collected. To assess peripheral effects of DX-CDS and DEX, 1 ml of blood was removed via orbital puncture and evaluated for total and differential leukocyte counts in a separate group of animals. Both DX-CDS and DEX were effective on day 1 in suppressing, by greater than 95%, ACTH secretion induced by a 5-min stress. However, DX-CDS was effective through day 5 (44% suppression) while DEX was not effective after 24 h. When 15 min of stress was applied, DX-CDS effected a significant ACTH suppression through 7 days while DEX was effective for only 3 days. DX-CDS was effective through day 7 (55%) in suppressing CORT after a 15-min stress while DEX was effective for 3 days only.(ABSTRACT TRUNCATED AT 250 WORDS)
Anderson
W R
WR
College of Pharmacy, University of Florida, Gainesville.
Simpkins
J W
JW
Brewster
M E
ME
Bodor
N S
NS
D000324:Adrenocorticotropic Hormone / Q000378:metabolism*; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects*; D003345:Corticosterone / Q000097:blood / Q000378:metabolism*; D003907:Dexamethasone / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D006207:Half-Life; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D013315:Stress, Psychological / Q000378:metabolism*
D003907:Dexamethasone; D000324:Adrenocorticotropic Hormone; D003345:Corticosterone