Evidence for Prolonged Suppression of Stress-Induced Release of Adrenocorticotropic Hormone and Corticosterone with a Brain-Enhanced Dexamethasone-Redox Delivery System

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Abstract
We have developed a redox system for brain-enhanced delivery of dexamethasone based on an interconvertible dihydropyridine d= 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-β-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. Both DX-CDS and DEX produced similar profiles of changes in total and differential leukocyte counts. Rats treated with DX-CDS had higher brain levels of total dexamethasone (free dexamethasone plus the quaternary pyridinium ion form of the delivery system) than animals receiving DEX only. Concomitantly, blood and liver levels of dexamethasone were lower in DX-CDS rats through 6 h than rats receiving DEX only. These data suggest DX-CDS is longer acting than DEX in suppressing stress-induced rises of ACTH and concomitant elevations in corticosterone. These observations, together with evidence of lower peripheral distribution of dexamethasone from the DX-CDS, suggest that DX-CDS acts primarily through local brain-release of DEX.