Free radicals in CNS injury

This chapter has reviewed the current state of knowledge regarding the occurrence and possible role of oxygen radical generation and lipid peroxidation in experimental models of acute CNS injury. Although much work remains, four criteria that are logically required to establish the pathophysiological importance of oxygen radical reactions have been met, at least in part. First of all, oxygen radical generation and lipid peroxidation appear to be early biochemical events subsequent to CNS trauma. Second, a growing body of direct or circumstantial evidence suggests that oxygen radical formation and lipid peroxidation are linked to pathophysiological processes such as hypoperfusion, edema, axonal conduction failure, failure of energy metabolism, and anterograde (wallerian) degeneration. Third, there is a striking similarity between the pathology of blunt mechanical injury to CNS tissue and that produced by chemical induction of peroxidative injury. Fourth, and most convincing, is the repeated observation that compounds that inhibit lipid peroxidation or scavenge oxygen radicals can block posttraumatic pathophysiology and promote functional recovery and survival in experimental studies. Nevertheless, the significance of oxygen radicals and lipid peroxidation ultimately depends on whether it can be demonstrated that early application of effective antifree radical or antiperoxidative agents can promote survival and neurological recovery after CNS injury and stroke in humans. The results of the NASCIS II clinical trial, which have shown that an antioxidant dosing regimen with methylprednisolone begun within 8 hr after spinal cord injury can significantly enhance chronic neurological recovery, strongly supports the significance of lipid peroxidation as a posttraumatic degenerative mechanism. However, ongoing Phase III trials with the more selective and effective antioxidant U74006F (tirilazad mesylate) will give a more clear-cut answer as to the therapeutic importance of inhibition of posttraumatic free radical reactions in the injured CNS.