It is well established that a brief period of global brain ischemia causes delayed cell death in vulnerable hippocampal CA1 pyramidal neurons days after reperfusion in animals and humans. Although numerous factors have been suggested to account for this phenomenon, the mechanisms underlying this delayed vulnerability for neuronal death are still poorly understood. Reperfusion after cerebral ischemia is known to produce oxidative stress in mitochondria, which mediate apoptotic cell death. An increase in the cytosolic antioxidant copper/zinc-superoxide dismutase in transgenic mice and transgenic rats significantly ameliorates molecular and cellular signaling events and the subsequent reduction in delayed death of hippocampal CA1 neurons. Also, transcription-independent activity of p53, a tumor suppressor gene and a central player in cell death, translocates to mitochondria and mediates the release of cytochrome c in the vulnerable hippocampal CA1 subregion after transient global cerebral ischemia (tGCI). We hypothesize that p53 and oxidative stress act in concert to mediate apoptotic signaling in vulnerable hippocampal CA1 neurons after global cerebral ischemia. It is our goal to test this hypothesis using various molecular, genetic, and pharmacological strategies in rodent models of global cerebral ischemia.
Our specific aims are: 1) to elucidate the role of p53 signaling in the intrinsic mitochondrial apoptotic pathway in hippocampal CA1 neuronal death/survival after tGCI;2) to elucidate the role of oxidative stress and endogenous superoxide dismutases during reperfusion in p53- mediated hippocampal neuronal death after tGCI;and 3) to elucidate the role of reduced nicotinamide-adenine dinucleotide phosphate oxidase in hippocampal CA1 death and its crosstalk in p53 signaling after tGCI.
Reperfusion after global cerebral ischemia generates oxygen free radicals that kill vulnerable neurons in hippocampi. The mechanism underlying this selective neuronal death is unclear. With this application, we seek to elucidate this cell death mechanism and provide therapeutic strategies to prevent or to ameliorate brain damage in stroke patients.
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