Neuroprotection and traumatic brain injury: theoretical option or realistic proposition.

Abstract

Preclinical studies have shown that treatment to limit secondary cell damage can significantly improve outcome after traumatic brain injury. In contrast, neuroprotection trials in human traumatic brain injury have failed to convincingly demonstrate therapeutic benefit. Recent literature has begun to address this discrepancy between preclinical and clinical trials. Perhaps the most important recent observations relate to the potential role of apoptosis in secondary brain injury. Because apoptosis peaks more than 24 h after injury, concepts about the therapeutic window for traumatic brain injury treatment have changed. Apoptosis and necrosis are in delicate balance and inhibition of one cell death pathway may enhance the other. This raises questions about the ultimate effectiveness of treatment strategies directed toward a single injury mechanism. In contrast to clinical head injury, which reflects a complex multi-factorial disorder, animal models are generally designed to address only a single injury component and are performed in genetically inbred animals of a single sex. Moreover, animal studies usually employ pretreatment or early posttreatment administration, examine moderate rather than severe injury, fail to examine brain drug levels or treatment optimization, and do not use an intent-to-treat methodology. Recognition of these methodological differences between animal and human studies has led to new trial design proposals. For clinical studies, there should be better stratification of patients, a focus on moderate injury and earlier treatment, and larger sample sizes. Animal experiments should better parallel clinical studies and address therapeutic window and treatment optimization. Recognition of multiple cell death pathways should lead to new treatment strategies--including both combination drug treatment and drugs that affect multiple components of the secondary injury cascade.