Coronary artery bypass graft (CABG) surgery is a procedure after which patients manifest significant neurological dysfunction, including stroke and cognitive impairment. In fact, patients in high-risk groups have an incidence of adverse cerebral outcome greater than 16%. The studies of this proposal are directed toward a model that utilizes a technique that may reduce perisurgical neurological problem by preconditioning the brain to be more resistant to ischemic insults. We will try to accomplish this goal using a rat model of middle cerebral artery occlusion (MCAO), and we will attempt to precondition using a unique drug delivery system-intranasal. The drug we have chosen to use-deferoxamine (DFO)-has been demonstrated to precondition in a number of experimental systems, from cell culture to neonatal animals to adult animals. The administration of DFO in these studies provided protection from ischemia; however, the parenteral administration of DFO is problematic because of its short half-life and side-effects. The experiments of this proposal will utilize intranasal deli very of DFO in rats. First, intranasal deli very will documented using DFO radio labeled with a small quantity of ferric 59Fe, and the amount of DFO in brain will be determined qualitatively and quantitatively. Second, a dose-response relationship for the induction of HIF1alpha and its endurance over time will be determined. Third, at the time point of maximal HIF-1 alpha induction, a MCAO will be performed and neurological outcome and infarct size will be assessed. Our preliminary studies indicate that three doses of intranasal DFO, three hours apart, significantly up-regulate the concentration of HIF-1alpha in brain 48 hours later. When a MCAO is performed at this time point, a 65% reduction in infarct size was observed. These studies may yield data that could be translated into the clinic and eventually provide neuroprotection to patients undergoing procedures that put them at risk for neurological injury, such as CABG surgery.
