Development of a model of recurrent stroke consisting of a mild transient stroke followed by a second moderate stroke in rats.

Recurrent stroke often consists of a transient ischemic attack or mild stroke followed by a moderate stroke. Lacking is knowledge of the mechanisms of interaction of such multiple ischemic insults. Our aim was to develop a rat model of recurrent stroke and to test whether such multiple insults would enhance brain injury. A mild focal ischemic insult was produced by transient (40min) occlusion of the middle cerebral artery (MCAO) and this resulted in scattered necrosis and areas of increased labeling of astrocytes with glial fibrillary acidic protein. Additional animals were subjected to a moderate stroke alone or a recurrent stroke-a mild stroke followed 3 days later by a moderate stroke (60min MCAO). Damage was dependent on the proximal or distal cerebral cortical location from the occlusion (P<0.007) and the type of stroke insult (mild, moderate or recurrent, P<0.002). Following recurrent stroke, the cumulative injury score was similar to a mild stroke in distal parietal cortex but enhanced proximally. Recurrent stroke also resulted in changes in magnetic resonance imaging T(2), in neuronal microtubule associated protein2, in reactive astrocytes and in microglia/macrophages that were enhanced in proximal but not distal parietal cortex. This model demonstrates that when a minor stroke is combined with a second stroke, both distributed within the same middle cerebral artery territory, there are different injury processes regionally. Proximally, damage exceeds that of the first insult whereas distally the response is consistent with a tolerance to the second insult.