There is growing evidence that estrogen (E2) and SERMs may have beneficial effects upon the CNS in neurodegenerative diseases. This application would study the potential mechanisms of E2/SERM neuroprotection in cerebral ischemia, and would follow up on exciting preliminary work by our lab which suggests that E2/SERMs enhance neurogenesis following cerebral ischemia. With regards to neuroprotection, our preliminary studies suggest that E2 and the SERM, tamoxifen (TMX) inhibit activation of putative prodeath factors (ROS, ERKs, INK, c-Jun), with an increase in activation of the prosurvival factor, Akt. To confirm these preliminary findings and clarify the underlying mechanisms, Aim 1 would determine the temporal pattern and cell type of ERK/JNK/Akt activation following cerebral ischemia in female animals (which is currently lacking), establish the onset and duration of E2/SERM regulatory effects upon these key kinases, and determine the role of estrogen receptors in the regulatory effects. Aim 2 would determine whether reactive oxygen species (ROS) function as the major upstream activator of ERKs/JNK following cerebral ischemia, and establish whether E2 and TMX can suppress ROS production as a mechanism for suppression of ERK/JNK activation. Causation between ROS and ERK/JNK activation would be determined through the use of the antioxidant SOD mimetic compound, tempol (which scavenges/reduces ROS production). Aim 3 would determine whether AP-1 transcription complex and proapoptotic BH-3 proteins act downstream of ERKs/JNK to induce apoptosis in the penumbra region, and establish whether E2 and TMX suppress AP-1 activation and induction of BH-3 proteins as a means of neuroprotection. Aim 4 would characterize the temporal pattern of E2/SERM effects on neurogenesis, and characterize the migration, differentiation and long-term survival of newly generated cells into the injured regions of the brain following cerebral ischemia. Correlation to functional neurological outcomes will also be determined. As a whole, the proposed studies would significantly advance our understanding of the neuroprotective and neurogenic actions of E2 and SERMs in the injured brain.