A significant number of individuals die soon after a successful cardiopulmonary resuscitation form cardiac arrest, and of those that survive a significant fraction have residual neurological deficit. Most of the morbidity and mortality after initially successful resuscitation from cardiac arrest can be assigned to the immediate and delayed effects of reperfusion injury in the central nervous system. With aging, there is an increased incidence of cardiac arrest and subsequent death or residual neurological deficit secondary to reperfusion injury. This outcome is probably due to an increase in free radical production and decrease in defense mechanisms that exacerbates reperfusion injury in the aging. Nevertheless, the poor ability of the brain to recover from such reversible ischemic events remains, in all ages, unpromising and is most likely due to free radical damage and unstabilized energy metabolism. This project represents a new collaboration between investigators specializing in the area of reperfusion injury. We propose to investigate new treatment strategies aimed at using alternate energy substrates such as, pyruvate and ketones in combination with antioxidant type drugs, such as, melatonin, N-t-Butyl-a-Phenyl-nitrone, adenosine and methylisobutyl amiloride, as therapies for improving recovery from cardiac arrest. Novel esters will also be tested for their neuroprotective properties in brain against reperfusion injury. These compounds are unique in that they are metabolized to physiological substrates, such as, pyruvate, glycerol and N-acetylcyteine, and have shown to decrease the effects of reperfusion injury in other organ systems. An animal model of cardiac arrest and resuscitation, adult (3 mos) and aged (18 mos) rats will be used to test the efficacy of these new treatment strategies. One set of experimental protocols measures delayed loss of hippocampal CA1 neurons 4 and 30 days after cardiac arrest and resuscitation and survival rates. Another set of experimental protocols will elucidate specific mechanism(s) by which the selected energy substrates and agents and are effective.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS046074-03
Application #
6766713
Study Section
Special Emphasis Panel (ZHL1-CSR-M (S1))
Program Officer
Pancrazio, Joseph J
Project Start
2002-09-30
Project End
2006-06-30
Budget Start
2004-07-01
Budget End
2005-06-30
Support Year
3
Fiscal Year
2004
Total Cost
$363,375
Indirect Cost
Name
Case Western Reserve University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Xu, Kui; Puchowicz, Michelle A; LaManna, Joseph C (2018) Post-resuscitation Arterial Blood Pressure on Survival and Change of Capillary Density Following Cardiac Arrest and Resuscitation in Rats. Adv Exp Med Biol 1072:77-82
Xu, Kui; Puchowicz, Michelle A; LaManna, Joseph C (2016) Aging Effect on Post-recovery Hypofusion and Mortality Following Cardiac Arrest and Resuscitation in Rats. Adv Exp Med Biol 876:265-270
Zhang, Le; Puchowicz, Michelle A; LaManna, Joseph C et al. (2016) Protective Effect of Dl-3-n-Butylphthalide on Recovery from Cardiac Arrest and Resuscitation in Rats. Adv Exp Med Biol 923:31-36
Xu, K; Radhakrishnan, K; Serhal, A et al. (2011) Regional brain blood flow in mouse: quantitative measurement using a single-pass radio-tracer method and a mathematical algorithm. Adv Exp Med Biol 701:255-60
Xu, Kui; Puchowicz, Michelle A; Sun, Xiaoyan et al. (2010) Decreased brainstem function following cardiac arrest and resuscitation in aged rat. Brain Res 1328:181-9
Xu, Kui; LaManna, Joseph C (2009) The loss of hypoxic ventilatory responses following resuscitation after cardiac arrest in rats is associated with failure of long-term survival. Brain Res 1258:59-64
Puchowicz, Michelle A; Zechel, Jennifer L; Valerio, Jose et al. (2008) Neuroprotection in diet-induced ketotic rat brain after focal ischemia. J Cereb Blood Flow Metab 28:1907-16
Xu, Kui; Sun, Xiaoyan; Puchowicz, Michelle A et al. (2007) Increased sensitivity to transient global ischemia in aging rat brain. Adv Exp Med Biol 599:199-206
Puchowicz, Michelle A; Xu, Kui; Sun, Xiaoyan et al. (2007) Diet-induced ketosis increases capillary density without altered blood flow in rat brain. Am J Physiol Endocrinol Metab 292:E1607-15
Xu, Kui; Puchowicz, Michelle A; Lust, W David et al. (2006) Adenosine treatment delays postischemic hippocampal CA1 loss after cardiac arrest and resuscitation in rats. Brain Res 1071:208-17

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