title: Motor deficits are triggered by reperfusion-reoxygenation injury as diagnosed by MRI and by a mechanism involving oxidants.
abstract: 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.
authors.affiliation: Department of Pediatrics, NorthShore University Healthcare Research Institute, Evanston, Illinois 60201, USA. oldrobys@gmail.com
authors.forename: Alexander
authors.initials: A
authors.lastname: Drobyshevsky
authors.forename: Kehuan
authors.initials: K
authors.lastname: Luo
authors.forename: Matthew
authors.initials: M
authors.lastname: Derrick
authors.forename: Lei
authors.initials: L
authors.lastname: Yu
authors.forename: Hongyan
authors.initials: H
authors.lastname: Du
authors.forename: P V
authors.initials: PV
authors.lastname: Prasad
authors.forename: Jeannette
authors.initials: J
authors.lastname: Vasquez-Vivar
authors.forename: Ines
authors.initials: I
authors.lastname: Batinic-Haberle
authors.forename: Sidhartha
authors.initials: S
authors.lastname: Tan
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D000975:Antioxidants / Q000627:therapeutic use; D001205:Ascorbic Acid / Q000378:metabolism; D001562:Benzimidazoles; D001783:Blood Flow Velocity; D001921:Brain / Q000196:embryology / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D001931:Brain Mapping; D002232:Carbocyanines; D002839:Chromans / Q000378:metabolism; D038524:Diffusion Magnetic Resonance Imaging / Q000379:methods*; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D005260:Female; D005434:Flow Cytometry; D020925:Hypoxia-Ischemia, Brain; D007476:Ionophores / Q000494:pharmacology; D017078:Laser-Doppler Flowmetry; D053078:Membrane Potential, Mitochondrial / Q000502:physiology; D008665:Metalloporphyrins / Q000627:therapeutic use; D055806:Microvessels / Q000503:physiopathology; D008928:Mitochondria / Q000187:drug effects / Q000473:pathology; D009069:Movement Disorders / Q000175:diagnosis* / Q000188:drug therapy / Q000209:etiology*; D009122:Muscle Hypertonia / Q000209:etiology; D019081:O Antigens / Q000378:metabolism; D011247:Pregnancy; D011817:Rabbits; D015427:Reperfusion Injury / Q000150:complications* / Q000517:prevention & control; D013481:Superoxides / Q000378:metabolism; D013997:Time Factors; D014634:Valinomycin / Q000494:pharmacology
chemical_list: D000975:Antioxidants; D001562:Benzimidazoles; D002232:Carbocyanines; D002839:Chromans; D007476:Ionophores; D008665:Metalloporphyrins; C502230:Mn(III) 5,10,15,20-tetrakis(N-methylpyridinium-2-yl)porphyrin; D019081:O Antigens; D013481:Superoxides; D014634:Valinomycin; C068624:5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolocarbocyanine; D001205:Ascorbic Acid; C010643:6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid