Neuroprotection by the inhibition of apoptosis

Accumulating evidence strongly suggests that apoptosis contributes to neuro nal cell death in a variety of neurodegenerative contexts. Activation of th e cysteine protease caspase-3 appears to be a key event in the execution of apoptosis in the central nervous system (CNS). As a result, mice null for caspase-3 display considerable neuronal expansion usually resulting in deat h by the second week of life. At present, 14 caspase family members have be en identified and subdivided into three subgroups on the basis of preferenc e for specific tetrapeptide motifs using a positional scanning combinatoria l substrate library. Caspase-3 is a group II member (2, 3, 7) categorized b y an absolute substrate requirement for aspartic acid in the P-4 position o f the scissile bond. The preferred cleavage motif (DExD) far group II caspa ses is found in many structural, metabolic and repair proteins essential fo r cellular homeostasis. Consistent with the proposal that apoptosis plays a central in role human neurodegenerative disease, caspase-3 activation has recently been observed in stroke, spinal cord trauma, head injury and Alzhe imer's disease. Indeed, peptide-based caspase inhibitors prevent neuronal l oss in animal models of head injury and stroke suggesting that these compou nds may be the forerunners of nonpeptide small molecules that halt apoptosi s processes implicated in these neurodegenerative disorders. A clear link b etween an hereditary neurodegenerative disorder and failed caspase inhibiti on has recently been proposed for spinal muscular atrophy (SMA). In severe SMA, the neuronal specific inhibitor of apoptosis (IAP) family member known as NAIP is often dysfunctional due to missense and truncation mutations. I APs such as NAIP potently block the enzymatic activity of group II caspases (3 and 7) suggesting that NAIP mutations may permit unopposed developmenta l apoptosis to occur in sensory and motor systems resulting in lethal muscu lar atrophy. Conversely, adenovirally-mediated overexpression of NAIP or th e X-linked IAP called XIAP reduces the loss of CA1 hippocampal neurons foll owing transient forebrain ischemia. Taken together, these findings suggest that anti-apoptotic strategies may some day have utility in the treatment o f neurodegenerative disease. The present review will summarize some of the recent evidence suggesting that apoptosis inhibitors may become a practical therapeutic approach for both acute and chronic neurodegenerative conditio ns.