A model of asphyxic cardiac arrest was developed in one-week old piglets in which the pattern of selective injury involving basal ganglia, sensorimotor cortex and thalamic sensory nuclei resembles that in human neonatal hypoxic-ischemic encephalopathy. The present application is focused on mechanisms of injury in striatum, where injury evolves rapidly, is most severe, and requires early therapeutic intervention. Because the morphology of striatal injury and the markers of cellular oxidative stress evolve over the first 6 hours of recovery in a manner analogous to N-methyl-D-aspartate (NMDA) excitotoxicity, the aims of the present proposal investigate possible strategies to modulate NMDA receptor signal/transduction pathways and their downstream consequences. Dopamine is known to amplify NMDA responses, possibly by receptor phosphorylation.
In Aim 1, dopamine antagonists will be used to determine if increased NMDA receptor phosphorylation and decreased Na,K-ATPase, normally observed after resuscitation, can be prevented and if striatal neurons are protected. Sigma receptor ligands are known to reduce NMDA responses. In Project 1 of this grant, a sigma ligand was found previously to decrease nitric oxide production evoked by NMDA and focal ischemia, and to reduce focal ischemic striatal injury in mature brain.
In Aim 2, this sigma ligand will be tested in immature brain to determine if neuroprotection from global ischemia occurs in striatum in association with decreased protein nitration and decreased NMDA receptor phosphorylation. Oxidative stress was found to progress rapidly after reoxygenation as indicated by decreased glutathione, increased protein carbonyl formation, and hydroxyl radical damage to DNA and RNA.
In Aim 3, the effect of immediate and delayed antioxidant treatment on striatal injury and markers of cellular oxidative stress will be determined. Inducing mild hypothermia immediately after resuscitation for a 24 hour period was found to provide complete, long-term striatal protection in piglets.
In Aim 4, the impact of using a more clinically relevant delay in instituting hypothermia will be evaluated, and the efficacy of early antioxidant treatment in extending the therapeutic window for hypothermia will be assessed. These studies will provide unique mechanistic insights into the cause of rapid neurodegeneration in immature basal ganglia using a large animal model of asphyxia cardiac arrest and resuscitation. These results will permit translation into clinical therapeutic approaches to help prevent the devastating consequences of neonatal hypoxic-ischemic encephalopathy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
2P01NS020020-20
Application #
6825328
Study Section
Special Emphasis Panel (ZNS1-SRB-K (01))
Project Start
2003-09-30
Project End
2008-06-30
Budget Start
2003-09-30
Budget End
2004-06-30
Support Year
20
Fiscal Year
2003
Total Cost
$247,285
Indirect Cost
Name
Oregon Health and Science University
Department
Type
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
Fonken, Laura K; Gaudet, Andrew D; Gaier, Kristopher R et al. (2016) MicroRNA-155 deletion reduces anxiety- and depressive-like behaviors in mice. Psychoneuroendocrinology 63:362-9
Ni, Xinli; Yang, Zeng-Jin; Wang, Bing et al. (2012) Early antioxidant treatment and delayed hypothermia after hypoxia-ischemia have no additive neuroprotection in newborn pigs. Anesth Analg 115:627-37
Ni, Xinli; Yang, Zeng-Jin; Carter, Erin L et al. (2011) Striatal neuroprotection from neonatal hypoxia-ischemia in piglets by antioxidant treatment with EUK-134 or edaravone. Dev Neurosci 33:299-311
Woodworth, K Nina; Palmateer, Julie; Swide, Joseph et al. (2011) Short- and long-term behavioral effects of exposure to 21%, 40% and 100% oxygen after perinatal hypoxia-ischemia in the rat. Int J Dev Neurosci 29:629-38
Yang, Sufang; Abrahams, Matthew S; Hurn, Patricia D et al. (2011) Local anesthetic Schwann cell toxicity is time and concentration dependent. Reg Anesth Pain Med 36:444-51
Nakano, Takaaki; Hurn, Patricia D; Herson, Paco S et al. (2010) Testosterone exacerbates neuronal damage following cardiac arrest and cardiopulmonary resuscitation in mouse. Brain Res 1357:124-30
Yang, Zeng-Jin; Carter, Erin L; Torbey, Michel T et al. (2010) Sigma receptor ligand 4-phenyl-1-(4-phenylbutyl)-piperidine modulates neuronal nitric oxide synthase/postsynaptic density-95 coupling mechanisms and protects against neonatal ischemic degeneration of striatal neurons. Exp Neurol 221:166-74
Ohata, Hiroto; Gebremedhin, Debebe; Narayanan, Jayashree et al. (2010) Onset of pulmonary ventilation in fetal sheep produces pial arteriolar constriction dependent on cytochrome p450 omega-hydroxylase activity. J Appl Physiol 109:412-7
Zhu, W; Wang, L; Zhang, L et al. (2010) Isoflurane preconditioning neuroprotection in experimental focal stroke is androgen-dependent in male mice. Neuroscience 169:758-69
Neigh, Gretchen N; Karelina, Kate; Glasper, Erica R et al. (2009) Anxiety after cardiac arrest/cardiopulmonary resuscitation: exacerbated by stress and prevented by minocycline. Stroke 40:3601-7

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