Attenuated c-fos mRNA induction after middle cerebral artery occlusion in CREB knockout mice does not modulate focal ischemic injury

To elucidate the mechanism of ischemia-induced signal transduction in vivo, we investigated the effect of the targeted disruption of the alpha and Del ta isoforms of the cAMP-responsive element-binding protein (CREB) on c-fos and heat-shock protein (hsp) 72 gene induction. Permanent focal ischemia wa s induced by occlusion of the middle cerebral artery of the CREB mutant mic e (CREB(-/-), n = 5) and the wild-type mice (n = 6). Three hours after onse t of ischemia, the neurologic score was assessed and pictorial measurements of ATP and cerebral protein synthesis (CPS) were carried out to differenti ate between the ischemic core (where ATP is depleted), the ischemic penumbr a (where ATP is preserved but CPS is inhibited), and the intact tissue (whe re both ATP and CPS are preserved). There were no significant differences i n neurologic score or in ATP, pH, and CPS between the two groups, suggestin g that the sensitivity of both strains to ischemia is the same. Targeted di sruption of the CREB gene significantly attenuated c-fos gene induction in the periischemic ipsilateral hemisphere but had no effect on either c-fos o r hsp72 mRNA expression in the penumbra. The observations demonstrate that CREB expression, despite its differential effect on c-fos, does not modulat e acute focal ischemic injury.