Effects of the 21-aminosteroid U74006F on experimental head injury in mice.
The ability of a novel non-glucocorticoid 21-aminosteroid U74006F to inhibit lipid peroxidation of central nervous system tissue in vitro and to enhance the early neurological recovery and survival of mice after a severe concussive head injury is described. In the in vitro studies, U74006F was found to be an extremely potent inhibitor of lipid peroxidation in an assay system where the glucocorticoid steroid methylprednisolone and the non-glucocortoid steroids U72099E and U75718A were almost completely ineffective. In the head-injury studies, unanesthetized male CF-1 mice were subjected to a 900 gm-cm closed head injury produced by a 50-gm weight being dropped 18 cm. This concussive injury resulted in immediate unconsciousness (loss of righting reflex) in all animals and death in approximately 30%. Survivors received a tail vein injection of either vehicle or U74006F (0.001 to 30 mg/kg) within 5 minutes postinjury. Their neurological status was evaluated 1 hour later using a grip test. The grip-test score indicated that intravenous administration of a single dose of U74006F resulted in a significant improvement by as much as 168.6% in the neurological status 1 hour postinjury over a broad dose range (0.003 to 30 mg/kg). A 1-mg/kg dose given intravenously within 5 minutes and again at 1 1/2 hours after a severe injury, in addition to improving early recovery, also increased the 1-week survival rate to 78.6% compared to 27.3% in vehicle-treated mice (p less than 0.02). The compound was also effective in enhancing early recovery after a more moderate injury. This study demonstrates that early treatment after severe concussive head injury with a potent inhibitor of iron-dependent lipid peroxidation can significantly benefit the injured brain in mice and promote both early neurological recovery and long-term survival.
Hall
E D
ED
CNS Diseases Research, Upjohn Company, Kalamazoo, Michigan.
Yonkers
P A
PA
McCall
J M
JM
Braughler
J M
JM
D000818:Animals; D001921:Brain / Q000378:metabolism; D001924:Brain Concussion / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D008054:Lipid Peroxides / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D011281:Pregnatrienes / Q000627:therapeutic use*
D008054:Lipid Peroxides; D011281:Pregnatrienes; C053355:tirilazad