The neuroprotective effects of virally-derived caspase inhibitors p35 and crmA following a necrotic insult.
Neuronal excitotoxicity causes energetic impairment and the ensuing cell death has historically been regarded as necrotic. Recent findings, however, indicate that apoptosis may participate in excitotoxicity. Here we examined the neuroprotective mechanisms of the well-characterized viral caspase inhibitors, p35 and crmA, following domoic acid-induced excitotoxicity in hippocampal neurons. We show that though p35 and crmA rescued neurons from toxicity, they did so under conditions of negligible caspase activation and morphological apoptosis. Thus, we characterized the novel neuroprotective effects of p35 and crmA and found that they attenuated the drop in the mitochondrial potential and blunted the decline in ATP levels. These data, to our knowledge, are the first detailed descriptions of the cell death mechanisms following domoic acid treatment of neurons. Moreover, in demonstrating the previously unexplored modulation of these processes, these data underline the capacity for classically "anti-apoptotic" proteins to alter other branches of cell death processes.
D000818:Animals; D020170:Caspase 1 / Q000378:metabolism; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D005822:Genetic Vectors / Q000494:pharmacology; D007608:Kainic Acid / Q000031:analogs & derivatives* / Q000633:toxicity; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009336:Necrosis; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015843:Serpins / Q000494:pharmacology*; D018139:Simplexvirus / Q000737:chemistry; D014709:Vero Cells; D014764:Viral Proteins / Q000494:pharmacology*
D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D018696:Neuroprotective Agents; D015843:Serpins; D014764:Viral Proteins; C074641:interleukin-1beta-converting enzyme inhibitor; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D020170:Caspase 1; C012301:domoic acid; D007608:Kainic Acid