bcl-2 antisense treatment prevents induction of tolerance to focal ischemia in the rat brain

In the rat, 60 minutes of transient ischemia to the middle cerebral artery results in infarction of the caudate putamen. Ischemic preconditioning with 20 minutes of transient focal ischemia produced tolerance (attenuated infa rction volume) to 60 minutes of subsequent focal ischemia administered thre e days, five days, or seven days later. Western blots from tolerant caudate putamen demonstrated increased bcl-2 expression, maximum at 3 days and per sisting through 7 days. Immunocytochemical examination found that bcl-2 was expressed in cells with both neuronal and nonneuronal morphology in striat um after preconditioning ischemia. bcl-2 antisense oligodeoxynucleotides (O DNs), bcl-2 sense ODNs, or artificial cerebrospinal fluid (CSF, vehicle) wa s infused into the lateral ventricle for the 72 hours between the 20-minute ischemic preconditioning and the 60-minute period of ischemia. Antisense O DN treatment reduced expression of bcl-2 in the striatum and blocked the in duction of tolerance by preconditioning ischemia. Sense and CSF treatments had no effect on either bcl-2 expression or tolerance. In this model of ind uced tolerance to focal ischemia, bcl-2 appears to be a major determinant.