Pathogenesis and pharmacological strategies for mitigating secondary damage in acute spinal cord injury

OBJECTIVE: Experimental models and clinical observations of acute spinal co rd injury (SCI) support the concepts of primary and secondary injury, in wh ich the initial mechanical insult is succeeded by a series of deleterious e vents that promote progressive tissue damage and ischemia. Whereas the prim ary injury is fated by the circumstances of the trauma, the outcome of the secondary injury may be amenable to therapeutic modulation. This article re views the pathogenetic determinants of these two phases of injury and summa rizes the pharmacological manipulations that may restore neurological funct ion after SCI. METHODS: Experimental models of SCI and their inherent limitations in simul ating human SCI are surveyed. The pathogenesis of primary and secondary inj ury, as well as the theoretical bases of neurological recovery, are examine d in detail. The effects of glucocorticoids, lazeroids, gangliosides, opiat e antagonists, calcium channel blockers, glutamate receptor antagonists, an tioxidants, free radical scavengers, and other pharmacological agents in bo th animal models and human trials ave summarized. Practical limitations to inducing neural regeneration are also addressed. RESULTS: The molecular events that mediate the pathogenesis of SCI are logi cal targets for pharmacological manipulation and include glutamate accumula tion, aberrant calcium fluxes, free radical formation, lipid peroxidation, and generation of arachidonic acid metabolites. Enhancement of neural regen eration and plasticity comprise other possible strategies. CONCLUSION: Pharmacological agents must be given within a narrow window of opportunity to be effective. Although many therapeutic agents show potentia l promise in animal models, only methylprednisolone has been shown in large , randomized, double-blinded human studies to enhance the functional recove ry of neural elements after acute SCI. Future therapy is likely to involve various combinations of these agents.