EXAMINING PYRUVATE S ANTI-INFLAMMATORY ACTIONS IN BRAIN FOLLOWING CARDIAC ARREST

Purpose: Approximately 0.5 million Americans suffer cardiac arrest each year. Cardiac arrest is usually lethal, and survivors often face severe neurological disability due to irreversible brain injury inflicted by global ischemia/reperfusion. Brain ischemia and reperfusion activates matrix metalloproteinases (MMPs) that disrupt the blood-brain barrier (BBB), enabling inflammatory cells to invade the brain parenchyma. We have shown that pyruvate, a metabolic intermediate and antioxidant, prevents death of hippocampal and cerebellar neurons and preserves neurobehavioral function in dogs after cardiac arrest. However, pyruvate's neuroprotective mechanism is elusive. We are testing the hypothesis that pyruvate preserves BBB integrity following cardiac arrest by suppressing MMPs and evoking expression of protective proteins hypoxia-inducible factor (HIF)-1ɑ and heat shock protein (Hsp)-70. Methods: Yorkshire swine (30-40 kg) were subjected to cardiac arrest-resuscitation or non-arrest sham protocols. Ventricular fibrillation was induced by a train of electric impulses transmitted to the right ventricle via a pacing wire. Precordial compressions were given at 6-10 min arrest, and then sinus rhythm was restored with defibrillatory transthoracic countershocks. NaCl or Na-pyruvate was infused iv at the rate of 0.1 mmol/kg/min during chest compressions and the first 60 min post-defibrillation. Cerebral cortex was snap-frozen in liquid nitrogen for immunoblot or fixed in 4% paraformaldehyde for immunohistochemistry (IHC) at 4 h after defibrillation. HIF-1ɑ and Hsp-70 contents were assessed by immunoblots and IHC. Four groups were studied: cardiac arrest + NaCl (n = 9) or Na-pyruvate (n = 7), or sham + NaCl (n = 5) or Na-pyruvate (n = 5). Results: Although immunoblots did not reveal appreciable differences in temporal cortex HIF-1ɑ content among the groups, IHC revealed increased HIF-1ɑ content in pyruvate-treated compared to NaCl-treated sham and cardiac arrest groups. Hsp-70 content also was similar among the groups, suggesting that this cytoprotective protein was not augmented within 3 h after 60 min pyruvate treatment. Conclusions: Current studies are examining neurobehavioral function and brain proteins over 7 days post-arrest. MMP activities in brain are being measured by gel zymography. Future experiments will determine plasma concentrations of neurofilament light chain, which, when elevated up to 7 days post-cardiac arrest, is associated with poor neurological outcomes.