Do caspase and proteasome inhibitors influence the delayed maturation of cortical infarction by preventing apoptosis or neuroinflammation?

Transient cortical ischemia ultimately results in cerebral infarction which is an energetically active process characterized in death by morphological pan-necrosis. The many biochemical features, however, suggest at least a component of the apoptotic pathway. With brief ischemia there is a slow maturation of injury, endonuclease dependant DNA laddering, end labelling or tunel staining of the dying neurones, mitochondrial release of cytochrome c, and activation of a series of caspases and proteins influenced by the activation of NF-KB. Spontaneously hypertensive rats were subjected to 30, 45, 60, 90, or 120 minutes of middle cerebral artery occlusion followed by reperfusion. Volumes of cerebral infarction were calculated with an image analyzing system. Animals were treated with a variety of caspase inhibitors including ICV-Z.VAD.FMK, ICV-Z.DEVD.FMK and an IV caspase inhibitor, the Cytovia compound, CV1013. Animals were also treated with two proteasome inhibitors IV-CVT-634 and IV-PS-519 to inhibit the activation of the transcription factor NF-kappaB. No infarction was detected following 30 minutes of ischemia although selective neuronal injury was observed after seven days. With 45 and 60 minutes of ischemia, less than 50% of the maturing infarct was seen at 24 hours, but this then evolved, in a delayed fashion over a period of 7-14 days, to the full infarct (20% of hemisphere). With 90 minutes of ischemia, 85% of the infarct was apparent at 24 hours with further maturation to a complete infarct at 7 days. Durations of ischemia of 120 minutes or 3 or 4 hours demonstrate a complete infarct within 24 hours of the onset of reperfusion. Both ICV and IV caspase inhibition achieved a 30% infarct volume reduction following 90 minutes of ischemia. Both novel proteasome inhibitors which prevent the activation of NF-kappaB, PS-519 and CVT-634, achieved approximately 40% infarct volume reductions at 24 hours. These drugs reduce a number of inflammatory events including the migration of polymorphs. In a comparative study, neither caspase nor NF-kappaB inhibition prevented CA(1) injury following global ischemia using the 4-vessel occlusion model, which induces little in the way of inflammation. Brief periods of ischemia give rise to a slowly maturing infarct which can be inhibited by either caspase or NF-kappaB inhibitors. These disease modifiers protect through anti-inflammatory, rather than anti-apoptotic mechanisms.