Despite recent clinical efforts, there is currently no effective treatment for brain damage due to stroke. As a new pharmacological approach, we propose to test the potential of Ampakines, which are novel allosteric positive modulators of AMPA receptors, as possible therapeutics against neurodegeneration. It has been established that Ampakines are capable of improving learning and memory in both rats and humans. More recently, we have demonstrated that Ampakines can enhance neuronal viability following an excitotoxic insult in an in vitro hippocampal organotypic slice model (HOSM), and may also reduce infarct size following MCAO ischemia in the rat. The present proposal would further advance our understanding by expanding from in vitro to in vivo models, examining Ampakine effects on neuronal injury induced by both global and focal cerebral ischemia. Notably, global forebrain ischemia in the gerbil results in selective damage to the CAl subfield of hippocampus - a region highly implicated in learning and memory. As such, we can address three separate but related issues that could advance Ampakines into clinical trials for stroke therapy. We will determine whether prior administration of a variety of Ampakines can reduce neuronal cell injury to hippocampal CAl in an animal model of cerebral ischemla, and concomitantly examine cognitive improvement resulting from an increase in cellular viability. In a separate approach, we will assess whether Arnpakine administration after an ischemic stroke and resulting CA I injury can improve cognitive functioning. The results of these experiments will determine the neurological and behavioral benefits of Ampakine administration following cerebral ischemic brain damage. In conjunction with in vivo experiments, in vitro methodology utilizing primary cortical cell cultures and organotypic hippocaropal slice cultures will be used to rapidly screen new Ampakines for their neuroprotective potential. Importantly, we will exploit this in vitro technology to address the effects of Ampakine administration on neuroprotective signaling cascades in neuronal cells. These studies will help elucidate and define the critical pathway(s) involved in Ampakine-mediated neuroprotection. This information will help guide drug development to formulate selective and specific modulators of protective signaling cascades linked to AMPA receptors. PROPOSED COMMERCIAL APPLICATION: Drug to benefit recovery from stroke.