Motor deficits are triggered by reperfusion-reoxygenation injury as diagnosed by MRI and by a mechanism involving oxidants. J Neurosci 2012 Apr 18;32(16):5500-9
Date
04/20/2012Pubmed ID
22514312Pubmed Central ID
PMC3332550DOI
10.1523/JNEUROSCI.5986-11.2012Scopus ID
2-s2.0-84859768476 (requires institutional sign-in at Scopus site) 28 CitationsAbstract
The early antecedents of cerebral palsy (CP) are unknown but are suspected to be due to hypoxia-ischemia (H-I). In our rabbit model of CP, the MRI biomarker, apparent diffusion coefficient (ADC) on diffusion-weighted imaging, predicted which fetuses will develop postnatal hypertonia. Surviving H-I fetuses experience reperfusion-reoxygenation but a subpopulation manifested a continued decline of ADC during early reperfusion-reoxygenation, which possibly represented greater brain injury (RepReOx). We hypothesized that oxidative stress in reperfusion-reoxygenation is a critical trigger for postnatal hypertonia. We investigated whether RepReOx predicted postnatal neurobehavior, indicated oxidative stress, and whether targeting antioxidants at RepReOx ameliorated motor deficits, which included testing of a new superoxide dismutase mimic (MnTnHex-2-PyP). Rabbit dams, 79% gestation (E25), were subjected to 40 min uterine ischemia. Fetal brain ADC was followed during H-I, immediate reperfusion-reoxygenation, and 4-72 h after H-I. Endpoints were postnatal neurological outcome at E32, ADC at end of H-I, ADC nadir during H-I and reperfusion-reoxygenation, and area under ADC curve during the first 20 min of reperfusion-reoxygenation. Antioxidants targeting RepReOx were administered before and/or after uterine ischemia. The new MRI-ADC biomarker for RepReOx improved prediction of postnatal hypertonia. Greater superoxide production, mitochondrial injury, and oligodendroglial loss occurred in fetal brains exhibiting RepReOx than in those without. The antioxidants, MnTnHex-2-PyP and Ascorbate and Trolox combination, significantly decreased postnatal motor deficits and extent of RepReOx. The etiological link between early injury and later motor deficits can thus be investigated by MRI, and allows us to distinguish between critical oxidative stress that causes motor deficits and noncritical oxidative stress that does not.
Author List
Drobyshevsky A, Luo K, Derrick M, Yu L, Du H, Prasad PV, Vasquez-Vivar J, Batinic-Haberle I, Tan SAuthor
Jeannette M. Vasquez-Vivar PhD Professor in the Biophysics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Age FactorsAnimals
Animals, Newborn
Antioxidants
Ascorbic Acid
Benzimidazoles
Blood Flow Velocity
Brain
Brain Mapping
Carbocyanines
Chromans
Diffusion Magnetic Resonance Imaging
Disease Models, Animal
Embryo, Mammalian
Female
Flow Cytometry
Hypoxia-Ischemia, Brain
Ionophores
Laser-Doppler Flowmetry
Membrane Potential, Mitochondrial
Metalloporphyrins
Microvessels
Mitochondria
Movement Disorders
Muscle Hypertonia
O Antigens
Pregnancy
Rabbits
Reperfusion Injury
Superoxides
Time Factors
Valinomycin
