U-74006F

Fig. 30. C2 -Heterocychc steroids that are inhibitors of kon-dependentUpid peroxidation U-74006F [110101-67-2] (296) and U-74500A [110101-65-0]...

Subsequently, it was found that the substitution of a complex amine on the non-glucocorticoid steroid nucleus in place of the 21-hydroxyl functionality results in a dramatic enhancement of the lipid antioxidant activity. Many of these 21-aminosteroid compounds effectively inhibit iron-catalyzed lipid peroxidation in rat-brain tissue homogenates under assay conditions where the glucocorticoid steroid methylprednisolone and the non-glucocorticoid analog U-72099E are completely ineffective [20,21]. Of these, U-74006F (tirilazad mesylate Fig. 2) has shown excellent activity in experimental models of spinal-cord and brain injury. 

The mechanism of action of U-74006F in antagonizing the development of post-traumatic ischemia is believed to involve an inhibition of oxygen-radical-mediated microvascular lipid peroxidation. This conclusion is based upon the concomitant action of U-74006F to attenuate an injury-induced decline in spinal-tissue vitamin E at the same doses that reduce post-traumatic ischemia [24],... 

Recent studies suggest that U-74006F retains its efficacy in promoting post-traumatic recovery after experimental spinal-cord injury even when initiation of treatment is delayed to 4 hours post-injury. However, after a treatment delay... 

Fig. 4. Dose-response correlation in cats of the effects of U-74006F on post-traumatic (compression injury) spinal cord lipid peroxidation (i.e., loss of reduced vitamin E) and on progressive white matter ischemia at 4 hours post-injury (data from ref. [24]) versus chronic (4-week) neurological recovery (data from ref. [46]). Doses indicated were administered at 30 minutes post-injury. Doses in parentheses under the chronic recovery dose-response curve indicate the total 48-hour dosing regimen that these cats received. All values are mean standard error. Numbers of animals are given in parentheses in each bar. Asterisks indicate p < 0.05 vs vehicle-injured animals by ANOVA.

Microinjection of ferrous iron (i.e. ferrous chloride) has also been shown to produce focal edema in rat brain, the degree of which is correlated with tissue levels of the lipid-peroxidation product malonyldialdehyde. Pretreatment with vitamin E (600 mg/kg intramuscularly once daily for 5 days) together with selenium (5 ppm in the drinking water) reduced the iron-induced edema and lipid peroxidation [54]. Similarly, the 21-aminosteroid U-74006F can also reduce iron-induced opening of the blood-brain barrier [53],... 

Coincident with the reduction in brain level of hydroxyl radicals, U-74006F administered at 5 minutes post-injury also acts to reduce post-traumatic opening of the blood-brain barrier (i.e. decreased brain uptake of 14C-albumin) [56]. This effect of U-74006F to close the barrier may be related to the attenuation of hydroxyl-radical levels or an antagonism of the effects of free radicals on the barrier endothelium (i.e. decreased membrane-lipid peroxidation). Indeed, free radicals are known to increase barrier permeability [57]. Consistent with this reduction in post-traumatic opening of the blood-brain barrier which would lead to vasogenic brain edema, U-74006F has been shown to attenuate post-traumatic brain edema in a rat model of fluid percussion head injury [58]. 

Additional experiments have been conducted in severely head-injured cats to assess the effects of U-74006F on brain energy metabolites [61]. A 1 mg/kg i.v. dose administered at 30 minutes post-injury, plus a second 0.5 mg/kg dose 2 hours later, resulted in an improved metabolic profile within the injured hemisphere measured at 4 hours. Most notably, U-74006F significantly reduced post-traumatic accumulation of lactic acid in both the cerebral cortex and the sub-cortical white matter. This biochemical effect suggests an improved maintenance of cerebral blood flow in the injured brain. As noted above, U-74006F does very effectively reduce progressive development of post-traumatic ischemia in experimental cat spinal-cord injury [24,27] which may also provide the explanation for the reduction of post-traumatic lactate levels in the injured brain. 

More recently, the cerebral antioxidant activity of the 21-aminosteroid U-74006F has been enhanced by replacing the steroid functionality, which possesses only weak antioxidant activity without the complex amino substitution, with a more potent and effective antioxidant. A series of compounds has been synthesized in which the steroid of U-74006F has been replaced by the antioxidant ring structure (i.e. chromanol) of a-tocopherol (vitamin E). One of these compounds, U-78517F (Fig. 2) has been demonstrated to have predictably more potent effects with regard to inhibition of lipid peroxidation in vitro and enhancement of early neurological recovery of head-injured mice [62]. 

Hall, E.D., Yonkers, P.A., Horan, K.L. and Braughler, J.M. (1989) Correlation between attenuation of post-traumatic spinal cord ischemia and preservation of vitamin E by the 21-aminosteroid U-74006F evidence for an in vivo antioxidant actio, J. Neurotrauma 6, 169-176. 

Anderson, D.K., Braughler, J.M., Hall, E.D., Waters, T.R., McCall, J.M. and Means, E.D. (1988) Effects of treatment with U-74006F on neurological recovery following experimental spinal cord injury, J. Neurosurg. 69, 562-567. 

A pilot study of safety and eflBcacy. Arch Neurol 47 1126-1130 Anderson DK, Braughler JM, HaU ED, Waters TR, McCall JM, Means ED (1988) Effects of treatment with U-74006F on neurologicat outcome following experimental spintil cord injury. J Neurosurg 69 562-567... 

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