Hypoxia-ischemic injury in the neonate represents a major medical problem in the U.S.A. and results in neurological sequelae and death. Current treatment regimens are not optimal and there is a need for new therapeutic approaches. A novel experimental approach first described by us in the brain and cerebral circulation involves the initiation of immediate and delayed preconditioning against anoxic stress by the selective activation of mitochondria! ATP-sensitive potassium (mitoKATP) channels. No previous studies have systematically examined the dynamics and mechanisms of pharmacological preconditioning in brain tissue or the vasculature of neonatal or adult animals. Furthermore, use of several selective mitoKATP channel openers will clarify the mechanisms of preconditioning. We have created two specific aims to test our hypotheses and speculations in piglets:
Specific Aim 1. Examination of the effects of mitoKATP channel activation without ROS production in immediate and delayed protection of brain and vasculature after IR. We will test the hypothesis that immediate and delayed preconditioning have distinct """"""""windows"""""""" and that only mitoKATP channel activation and not linked ROS production is necessaryfor the initiation and expression of immediate and delayed neuro- and vascular-protection. First, we will define temporal windows for the immediate and delayed phases of protection against anoxic stress. Second, we will assess whether preconditioning via mitoKATP channel activation occurs in cerebral blood vessels as well as in neurons. Third, we will document that preconditioning occurs in the absence of ROS generation.
Specific Aim 2. Determination of the mechanisms of mitoKATP channel activation in immediate and delayed protection of brain and vasculature after IR. We will test the hypothesis that initiating events are similar, but subsequent mechanisms underlying immediate and delayed preconditioning are different. First, we will assessthe role of protein kinase C (PKC) activation as a key component of preconditioning. Second, we will investigate the mechanisms by which mitoKATP channel activation limits calcium influx and mitochondrial swelling during immediate preconditioning. Third, we will explore the mechanisms by which mitoKATP channel activation leads to reduced ROS production during delayed preconditioning. We expect that our studies will lead to the development of therapies which will lessen the severity of neurological injury to ischemia in the neonate.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Vascular Cell and Molecular Biology Study Section (VCMB)
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Reid, Diane M
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Wake Forest University Health Sciences
Schools of Medicine
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Dutta, Somhrita; Rutkai, Ibolya; Katakam, Prasad V G et al. (2015) The mechanistic target of rapamycin (mTOR) pathway and S6 Kinase mediate diazoxide preconditioning in primary rat cortical neurons. J Neurochem 134:845-56
Katakam, Prasad V G; Gordon, Angellica O; Sure, Venkata N L R et al. (2014) Diversity of mitochondria-dependent dilator mechanisms in vascular smooth muscle of cerebral arteries from normal and insulin-resistant rats. Am J Physiol Heart Circ Physiol 307:H493-503
Rutkai, Ibolya; Katakam, Prasad V G; Dutta, Somhrita et al. (2014) Sustained mitochondrial functioning in cerebral arteries after transient ischemic stress in the rat: a potential target for therapies. Am J Physiol Heart Circ Physiol 307:H958-66
Carvalho, Cristina; Katz, Paige S; Dutta, Somhrita et al. (2014) Increased susceptibility to amyloid-? toxicity in rat brain microvascular endothelial cells under hyperglycemic conditions. J Alzheimers Dis 38:75-83
Busija, David W; Katakam, Prasad V (2014) Mitochondrial mechanisms in cerebral vascular control: shared signaling pathways with preconditioning. J Vasc Res 51:175-89
Katakam, Prasad V G; Wappler, Edina A; Katz, Paige S et al. (2013) Depolarization of mitochondria in endothelial cells promotes cerebral artery vasodilation by activation of nitric oxide synthase. Arterioscler Thromb Vasc Biol 33:752-9
Wappler, Edina A; Institoris, Adam; Dutta, Somhrita et al. (2013) Mitochondrial dynamics associated with oxygen-glucose deprivation in rat primary neuronal cultures. PLoS One 8:e63206
Nautiyal, Manisha; Katakam, Prasad V G; Busija, David W et al. (2012) Differences in oxidative stress status and expression of MKP-1 in dorsal medulla of transgenic rats with altered brain renin-angiotensin system. Am J Physiol Regul Integr Comp Physiol 303:R799-806
Katakam, Prasad V G; Snipes, James A; Steed, Mesia M et al. (2012) Insulin-induced generation of reactive oxygen species and uncoupling of nitric oxide synthase underlie the cerebrovascular insulin resistance in obese rats. J Cereb Blood Flow Metab 32:792-804
Institoris, Adam; Lenti, Laura; Domoki, Ferenc et al. (2012) Cerebral microcirculatory responses of insulin-resistant rats are preserved to physiological and pharmacological stimuli. Microcirculation 19:749-56

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