Effects of antioxidants on post-traumatic neurological recovery and survival

Effects of antioxidants on post-traumatic neurological recovery and survival 

There is also evidence that the neuroprotective properties of lipid-peroxidation-inhibiting doses of methylprednisolone, extensively studied in spinal-cord injury, are applicable to brain injury. The steroid has been shown to enhance the early recovery of mice subjected to a moderately severe concussive head injury when administered at 5 minutes post-injury [59], The dose-response curve for this effect is remarkably similar to that discussed above for spinal-cord injury. A 30mg/kg i.v. dose was observed to be optimal, while lower (15 mg/kg) and higher (60 and 120 mg/kg) doses were ineffective. 

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 A series of compounds has been synthesized in which the steroid of U-74006F has been replaced by the antioxidant ring structure (i.e. chromanol) of a-tocopherol (vitamin E).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]. 

Still further evidence of the pathophysiological significance of iron-catalyzed lipid peroxidation in acute head injury comes from the demonstration that a dextran-coupled form of the iron chelator deferoxamine can also improve the early neurological outcome of severely head-injured mice [63]. 

---