Effects of the 21-aminosteroid U74006F on experimental head injury in mice

Abstract

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.

Effect of methylprednisolone, tirilazad mesylate and vitamin E on lipid peroxidation after experimental spinal cord injury

“…8 In vitro studies suggest that tirilazad exerts its antioxidant activity by multiple mechanisms including; increasing membrane stability, scavenging of lipid peroxyl radicals, reducing LP, induced arachidonic acid release, decreased formation or scavenging of hydroxyl radicals, and maintenance of the level of endogenous vitamin E. 11,21,22 In contrast to MP, it has no steroidal side e ects or peripheral vasodilator activity and is far more potent. 3,29,30 These characteristics make TM an interesting compound for possible treatment of CNS injury. In this study, even short-term therapy with TM at a dose of 10 mg/kg signi®cantly improved the LP after experimental SCI in the rats.…”

“…9,27 Recently, a new class of compounds has been developed, the nonglucocorticoid 21-aminosteroid, TM (U74006F), which has been shown to be e ective in reducing neurologic injury in animal models with head and spinal cord trauma. 23,28,29 TM is a free radical scavenger, antioxidant, and LP inhibitor, and had a lack of side e ects in volunteers. 30 Vitamin E (alpha-tocopherol) also known as an antioxidant has protective e ects on central nervous system (CNS) trauma.…”

Lazaroid U-74389F attenuates phorbol ester-induced lung injury in rabbits

“…In vivo efficacy of lazaroids has been documented in experimental models of traumatic injury of the central nervous system [3], ischaemia-reperfusion injury in a variety of organs [4][5][6], and haemorrhagic shock [7]. Lazaroids were also found to afford protection against E. coli-induced lung injury in guinea-pigs [8], and bleomycin-induced lung fibrosis in rats [9].…”

Pharmacology of Traumatic Brain Injury: Where Is the “Golden Bullet”?

“…Once initiated, peroxidation is considered to be a self-propagating process that leads to cell membrane damage and cell death (14). Oxygen radical formation and lipid peroxidation start early after TBI and lead to ischemia and hypoxia.…”

“…Free radicals in TBI are generated by mitochondrial damage (15)(16)(17)(18)(19)(20). Tirilazad mesylate is a 21-aminosteroid that has been shown to inhibit lipid peroxidation in experimental animals (14). Tirilazad mesylate penetrates the intact bloodbrain-barrier poorly but has a strong affinity for the vascular endothelium (21).…”