21-aminosteroid and 2-(aminomethyl)chromans inhibition of arachidonic acid-induced lipid peroxidation and permeability enhancement in bovine brain microvessel endothelial cell monolayers.
Selected 21-aminosteroids (U74500A, U74006F, and U74389G) and a 2-(aminomethyl)chromans (U78517F) were tested for their efficacy in preventing arachidonate-induced lipid peroxidation and permeability alterations in brain microvessel endothelial cells (BMECs). The 21-aminosteroids and 2-(aminomethyl)chromans were effective in varying degrees in inhibiting (U74500A = U78517F > U74006F = U74389G) concentration- and time-dependent arachidonate-induced thiobarbituric acid reactive substances (TBARS) production by BMECs. Arachidonate produced a corresponding concentration-dependent increase in BMEC monolayer permeability to the membrane impermeant marker, sucrose. Pretreatment of BMEC monolayers with either the 21-aminosteroids or the 2-(aminomethyl)chromans completely blocked the arachidonate-induced increase in permeability to sucrose. Our results demonstrated that these membrane-associating antioxidants were particularly effective in preventing both arachidonic acid-induced lipid peroxidation and permeability changes in BMEC monolayers. However, concentrations of some antioxidants that only partially inhibited TBARS production, completely inhibited the arachidonic acid-induced enhancement in BMEC monolayer permeability. Therefore, arachidonic acid-induced effects on BMEC permeability were likely due in part to both lipid peroxidation and direct or indirect effects of the fatty acid on membrane integrity. This study provides further support for the application of primary cultures of BMECs as a useful in vitro system to evaluate mechanisms through which mediators of disease or injury states compromise blood-brain barrier integrity.
Shi
F
F
Department of Pharmaceutical Chemistry, School of Pharmacy, University of Kansas, Lawrence 66045-2504, USA.
Cavitt
J
J
Audus
K L
KL
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D016718:Arachidonic Acid / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D001921:Brain / Q000098:blood supply; D002199:Capillary Permeability / Q000187:drug effects*; D002417:Cattle; D002478:Cells, Cultured; D002560:Cerebrovascular Circulation; D002839:Chromans / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D005454:Fluorescence Polarization; D016166:Free Radical Scavengers / Q000494:pharmacology*; D015227:Lipid Peroxidation / Q000187:drug effects*; D008833:Microcirculation; D010879:Piperazines / Q000494:pharmacology*; D011281:Pregnatrienes / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000975:Antioxidants; D002839:Chromans; D016166:Free Radical Scavengers; D010879:Piperazines; D011281:Pregnatrienes; C074965:U 74389F; C066382:U 78517F; D016718:Arachidonic Acid; C053356:U 74500A; C053355:tirilazad