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Principal Investigator: Elizabeth A Nance
Organization: UNIVERSITY OF WASHINGTON
Fiscal Year: 2020
Award: $183,558
Funding agency: Eunice Kennedy Shriver National Institute of Child Health and Human Development
PROJECT SUMMARY/ABSTRACT
Perinatal asphyxia (PA), where newborn infants suffer from a lack of oxygen and blood flow to
the brain, is a leading cause of morbidity and mortality around the time of birth. PA in term infants,
and the resulting neurodevelopmental sequelae such as intellectual disability, cerebral palsy,
epilepsy, and hearing or vision impairment, result in a huge burden to society. Current therapies
such as therapeutic hypothermia have a limited effect (15% reduction ins death or disability), and
are not curative. We propose to develop an effective neuroprotective treatment using enzyme-
loaded nanoparticles in a neonatal model of hypoxia-ischemic (HI) brain injury. Cellular oxidative
stress often begins with the production of superoxide, for example, within the electron transport
chain of dysfunctional mitochondria after HI brain injury. Superoxide is primarily scavenged by
superoxide dismutase (SOD), catalyzing its dismutation anion to hydrogen peroxide,43 which is
then converted to water and oxygen by catalase. The cooperative action of these multiple
enzymes is crucial to the successful clearance of reactive oxygen species. For instance, while
SOD overexpression is neuroprotective in a rodent model of adult stroke, it may exacerbate injury
in the neonatal brain due to a relative under-expression of catalase, resulting in accumulation of
hydrogen peroxide. Therefore, precisely-targeted and controlled co-delivery of cooperative
antioxidant enzymes has significant potential for ameliorating oxidative stress in the setting of
neonatal HI brain injury. Therefore, we will investigate the neuroprotective capability of combined
catalase-loaded and SOD-loaded nanoparticles in a neonatal rodent model of term HI brain injury.
The first aim focuses on determining the biodistribution and effective dose of SOD-loaded and
catalase-loaded poly(lactic-co-glycolic)-poly(ethylene glycol) (PLGA-PEG) nanoparticles. The
second aim will evaluate the efficacy of a combined delivery of SOD-loaded and catalase-loaded
PLGA-PEG nanoparticles to determine the neuroprotective effects in newborn rats with HI in
comparison to free drug and saline treated controls. This study is significant because it explores
the potential of nanomedicine-based therapy for neuroprotection in a clinically-relevant model of
neonatal HI, with implications for other perinatal brain injuries that share pathological hallmarks.
Terms: <0-11 years old><0-4 weeks old><1,2-Ethanediol><2-Hydroxyethanol><21+ years old><Acquired brain injury><Active Oxygen><Address><Adult><Adult Human><Affect><Anions><Antioxidants><Apoplexy><Apoptotic><Asphyxia Neonatorum><Behavior><Biodistribution><Birth><Blood - brain barrier anatomy><Blood Circulation><Blood flow><Blood-Brain Barrier><Bloodstream><Brain><Brain Injuries><Brain Nervous System><Brain Vascular Accident><Calcium><Calcium Channel><Calcium Channel Antagonist Receptor><Calcium Channel Blocker Receptors><Calcium Ion Channels><Cell Death><Cell membrane><Cerebral Palsy><Cerebral Stroke><Cerebrovascular Apoplexy><Cerebrovascular Stroke><Cessation of life><Child><Child Youth><Childhood><Children (0-21)><Circulation><Common Rat Strains><Complex I Dehydrogenase><Curcumin><Cytoplasmic Membrane><Data><Death><Developed Countries><Diferuloylmethane><Dihydroxyethanes><Diminished Vision><Dose><Drugs><Electron Transport><Electron Transport Complex I><Encephalon><Endotoxins><Enzyme Gene><Enzymes><Epilepsy><Epileptic Seizures><Epileptics><Erythrocuprein><Ethanediols><Ethylene Glycols><Exposure to><Failure><Fullterm Birth><Glutamates><Glycolates><H2O2><Half-Life><Hearing Loss><Hemato-Encephalic Barrier><Hemocuprein><Hydrogen Oxide><Hydrogen Peroxide><Hydroperoxide><Hypoacuses><Hypoacusis><Hypothermia><Hypoxia><Hypoxic><Hypoxic-Ischemic Brain Injury><Industrialized Countries><Industrialized Nations><Infant><Inflammation><Inflammatory><Injury><Intellectual disability><Intellectual functioning disability><Intellectual limitation><Kinetics><L-Glutamate><Lipid Peroxidation><Lipopolysaccharides><Low Vision><Medication><Membrane><Mitochondria><Modeling><Monoethylene Glycol><Morbidity><Morbidity - disease rate><N-Methyl-D-Aspartate Receptors><N-Methylaspartate Receptors><NADH DH I><NADH Dehydrogenase Complex 1><NADH Dehydrogenase I><NADH Q1 Oxidoreductase><NADH dehydrogenase (ubiquinone)><NADH-CoQ Reductase><NADH-Coenzyme Q Reductase><NADH-Ubiquinone Oxidoreductase><NADH-Ubiquinone Reductase><NMDA Receptor-Ionophore Complex><NMDA Receptors><Nanotechnology><Neonatal><Neonatal Brain Injury><Neurodevelopmental Disability><Neurodevelopmental Impairment><Neurologic outcome><Neurological outcome><Neuronal Injury><Newborn Infant><Newborns><O element><O2 element><Outcome><Oxidative Stress><Oxygen><Oxygen Deficiency><Oxygen Radicals><Partial Sight><Parturition><Pathologic><Peptides><Perinatal Brain Injury><Perinatal brain damage><Permeability><Peroxonitrite><Pharmaceutic Preparations><Pharmaceutical Preparations><Plasma Membrane><Polymers><Pro-Oxidants><Process><Production><Public Health><Rat><Rats Mammals><Rattus><Reactive Oxygen Species><Reduced Vision><Research><Respiratory Complex I><Rodent Model><Rotenone-Sensitive Mitochondrial NADH-Ubiquinone Oxidoreductase><Saline><Saline Solution><Seizure Disorder><Slice><Societies><Stroke><Subnormal Vision><Superoxide Anion><Superoxide Dismutase><Superoxide Radical><Superoxides><Term Birth><Testing><Therapeutic><Time><Toxic effect><Toxicities><Turmeric Yellow><Ubiquinone Reductase><VDCC><Visual impairment><Voltage-Dependent Calcium Channels><Water><Work><adulthood><anti-oxidant><anti-oxidant enzyme><antioxidant enzyme><base><birth asphyxia><bloodbrain barrier><brain attack><brain damage><brain-injured><catalase><cerebral vascular accident><cerebrovascular accident><children><childrens'><clinical relevance><clinically relevant><complex 1 dehydrogenase><controlled release><cytocuprein><cytokine><death risk><developed country><developed nation><developed nations><disability><drug/agent><dysfunctional hearing><electron transfer><enzyme activity><epilepsia><epileptiform><epileptogenic><ethylene glycol><excitotoxicity><full-term birth><fullterm newborn><glutamatergic><glutathione peroxidase><glycolic acid><hearing defect><hearing deficit><hearing difficulty><hearing disability><hearing dysfunction><hearing impairment><hypoxia neonatorum><hypoxic ischemic encephalopathy><improved><injured><injuries><intellectual and developmental disability><membrane structure><mitochondrial><mitochondrial dysfunction><mortality><mortality risk><nano medicinal><nano medicine><nano particle><nano tech><nano technology><nano-sized particle><nano-technological><nanomedicinal><nanomedicine><nanoparticle><nanosized particle><nanotech><nanotechnological><natural hypothermia><necrocytosis><neonatal HIE><neonatal brain><neonatal hypoxia><neonatal hypoxia-ischemia><neonatal hypoxic-ischemic brain injury><neonate><neurobehavioral><neuron injury><neuropathology><neuroprotection><new approaches><newborn brain injury><newborn child><newborn children><novel approaches><novel strategies><novel strategy><overexpress><overexpression><pediatric><perinatal asphyxia><perinatal period><perinatal phase><peroxiredoxin><peroxynitrite><plasmalemma><post-natal asphyxia><postnatal><postnatal asphyxia><stroke model><term newborn><therapeutic nanoparticles><type 1 dehydrogenase><uptake><vision impairment><visually impaired><youngster>