Development of a Neuroprotective Agent For Cerebral Palsy Prevention

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DESCRIPTION (provided by applicant): Cerebral palsy (CP), the most common physical disability in childhood, afflicts more than 800,000 Americans and many more worldwide. In addition to motor difficulties, many children with CP also suffer from intellectual disability, epilepsy, nutritional problems, and language dysfunction. Furthermore, almost 90% of CP-associated brain injuries occur in utero or around the time of birth. Therefore, a medication to prevent CP needs to be able to be safely administered either during pregnancy to the mom and/or shortly after birth to the neonate. The goal of this Phase I grant proposal is to demonstrate the feasibility that a naturally-occurring hormone can be developed into a medicament for CP prevention. There is already evidence supporting the role of this hormone as a neuroprotective agent against CP; receptors for this hormone are expressed in the developing brain, and administration of this hormone has been shown to decrease neuronal cell death, promote the proliferation of developing neurons and the outgrowth of neuronal processes in vitro. Furthermore, we have identified epidemiological evidence of an inverse relationship between CP risk and mean maternal levels of this hormone; offspring from nine epidemiologically distinct groups of women who have higher mean levels of this hormone during pregnancy have a lower CP risk. During Phase I, the capability of this hormone to induce neuroprotection will be investigated in a neonatal mouse model that produces neurological deficits similar to those seen in CP (i.e. pups who have been subjected to term-equivalent hypoxic-ischemic brain injury). Utilizing conventional histochemical methods, the amount of brain tissue loss in a hormone-injected group of neonatal mice will be compared to a control group 7 days after both groups have been subjected to the hypoxia-ischemia regimen. In addition, caspase-3 activation, a quantifiable measure of the extent of apoptotic neuronal cell death in response to neonatal hypoxic-ischemic injury, will be compared between groups. Lastly, the neurobehavioral outcome in the experimental and control groups will be examined utilizing established animal behavioral paradigms. In Phase II, we will refine the concentration, timing and frequency of hCG dosage and perform all preclinical hCG safety experiments to prepare for clinical testing.