Elucidation of molecular mechanisms underlying ischemic brain damage is crucial for developing novel strategy of brain protection against stroke. Glutamate toxicity, free radical and apoptosis have been believed important for ischemic neuronal vulnerability. Although morphological studies have not demonstrated the characteristics of apoptosis in vulnerable neurons, growing evidence show the involvement of apoptotic mechanism such as caspase activation and gene expression of Bcl-2 family protein in ischemic neuronal damage. Overexpression of BCL-2 by gene transfer and transgenic mice attenuates ischemic brain damage, suggesting the potential strategy to inhibit apoptotic mechanism. Several neuroprotective genes such as BCL-2 includes cAMP-response element in their 5'-promoter region. Phosphorylation of cyclic AMP-response element binding protein (CREB) and activation of CRE-mediated gene expression have been shown in surviving neurons after ischemia and believed important in acquisition of ischemic tolerance. Moreover, apoptosis may be involved in survival of newborn neurons. Recent evidences show activation of neural stem cells and neurogenesis in the hippocampus after ischemia. It is likely that enhancement of survival of newborn cells would lead to functional recovery after stroke. CREB phosphorylation is transiently unregulated in immature neurons after bromodeoxyuridine labeling, suggesting the role of CRE-mediated gene expression in survival of newborn cells.
