It is estimated that 1.2 million infants die annually from birth asphyxia and its complication, hypoxic- ischemic (HI) brain injury. In U.S. neonatal HI-brain injury remains one of the major causes for a life-long neurological disability in children. This indicates an urgent need to develop therapeutic strategies based on a better understanding the mechanisms of HI injury in the developing brain. Mitochondrial dysfunction is the most fundamental biological event leading to neuronal injury in this disease. Although, mitochondrial complex-I (C-I) is severely inhibited by a HI insult, upon re-oxygenation/reperfusion the energy-generating function of C-I rapidly recovers. This reperfusion-driven re-activation of C-I is tightly linked to the generation of reactive oxygen species (ROS). We hypothesize that the inhibition of mitochondrial C-I recovery upon reperfusion represents a therapeutic strategy against an oxidative burst during early reperfusion. We show that compared to controls, mice exposed to C-I inhibitor, pyridaben exhibited significant attenuation of cerebral injury, despite a sluggish recovery of the C-I linked mitochondrial respiration. Mitochondria isolated from these pyridaben-exposed HI-mice demonstrated a limited acceleration in ROS production during reperfusion. This suggests that during reperfusion post-HI restoration of electron transport flow in the C-I contributes not only to cellular recovery, but also to cellular injury.
Specific aims are designed to determine;
Aim 1, whether an inhibition of the C-I recovery during reperfusion attenuates oxidative damage to mitochondrial matrix and as a result, increases mitochondrial tolerance to Ca++ induced opening of permeability transition pore (PTP).
and Aim 2, whether hypoxemia during reperfusion slow down reactivation of mitochondrial C-I and whether this protects brain against reperfusion-driven oxidative stress Thus, the project is designed to establish both, mechanistic rationale and a clinical translation for an innovative therapeutic concept of a gradual metabolic recovery of the C-I directed against reperfusion-driven oxidative stress.

Public Health Relevance

This proposal is focused to develop a novel therapeutic concept for protection of the ischemic brain against reperfusion-driven oxidative stress. Potential implication of this research is very broad, because an ischemic brain injury (stroke, hypoxic-ischemic encephalopathy) is a leading cause for neurological handicap in adults and children.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21NS071121-01A1
Application #
8111590
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Bosetti, Francesca
Project Start
2011-04-01
Project End
2013-03-31
Budget Start
2011-04-01
Budget End
2012-03-31
Support Year
1
Fiscal Year
2011
Total Cost
$200,313
Indirect Cost
Name
Columbia University (N.Y.)
Department
Pediatrics
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Sosunov, Sergey A; Ameer, Xavier; Niatsetskaya, Zoya V et al. (2015) Isoflurane anesthesia initiated at the onset of reperfusion attenuates oxidative and hypoxic-ischemic brain injury. PLoS One 10:e0120456
Utkina-Sosunova, Irina V; Niatsetskaya, Zoya V; Sosunov, Sergey A et al. (2013) Nelfinavir inhibits intra-mitochondrial calcium influx and protects brain against hypoxic-ischemic injury in neonatal mice. PLoS One 8:e62448
Niatsetskaya, Zoya V; Charlagorla, Pradeep; Matsukevich, Dzmitry A et al. (2012) Mild hypoxemia during initial reperfusion alleviates the severity of secondary energy failure and protects brain in neonatal mice with hypoxic-ischemic injury. J Cereb Blood Flow Metab 32:232-41
Niatsetskaya, Zoya V; Sosunov, Sergei A; Matsiukevich, Dzmitry et al. (2012) The oxygen free radicals originating from mitochondrial complex I contribute to oxidative brain injury following hypoxia-ischemia in neonatal mice. J Neurosci 32:3235-44
Wang, Xiaoyang; Leverin, Anna-Lena; Han, Wei et al. (2011) Isolation of brain mitochondria from neonatal mice. J Neurochem 119:1253-61