The PI proposes technologically intense, NMR/MRI based investigations of cardiac arrest using a new, clinically relevant rat cardiac arrest model. MRI/MRS data will be correlated with histopathologic and neurobehavioral outcomes. State-of-the-art interleaved multi-nuclear magnetic resonance spectroscopy and imaging are conducted in a customized 9.4 Tesla instrument with powerful gradient coils. Diffusion-weighted MR-imaging is used to detect rapid changes in brain edema, and spin-tagging of blood is used for perfusion imaging of the brain. Cardiac arrest will be induced by controlled asphyxiation in anesthetized, normothermic rats. Resuscitation will occur at four predetermined time points (12, 16, 20 and 24 minutes) after cardiac arrest. All events will occur inside a superwide-bore, 9.4 Tesla high-resolution NMR spectrometer, during which time MRI and MRS measurements will be continually made of rCBF, cerebral ion and water homeostasis, and brain metabolism. Measurements will be made before, during, and after cardiac arrest and resuscitation. Pre- and post-arrest pharmacological treatments will combine three classes of novel neuroprotective agents: (i) agents that improve cerebral energy metabolism, (ii) antioxidants that inhibit iron-dependent lipid peroxidation and key enzymes of the arachidonic acid cascade, and (iii) glutamate receptor antagonists that mitigate excitotoxicity injury. Seven series of experiments are proposed. The four specific aims are: (1) to correlate changes caused by global ischemia in cerebral perfusion, water homeostasis, and energy metabolism, with brain damage and neurologic outcome; (2) to correlate energy metabolism and water homeostasis with post-resuscitation hypoperfusion; (3) to study the effects of antioxidants on reperfusion injury; and (4) to study glutamate excitotoxicity in global ischemia.
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