Grants and Contracts Details
Children with intraventricular hemorrhage and post-hemorrhagic hydrocephalus (IVH/PHH) suffer white matter injury, which is associated with persistent cognitive and psychomotor deficits. Oligodendrocyte progenitor cells (OPCs) have the ability to self-renew and give rise to mature oligodendrocytes. OPCs are exquisitely sensitive to many insults that occur across multiple neurological diseases such as excitotoxicity, inflammation, and oxidative stress. Different injurious stimuli may simultaneously increase oxidative stress within OPCs to synergistically cause cell death. Supporting this, data show that OPCs can be protected from injury by a variety of antioxidant compounds. Phenelzine is an FDA-approved antidepressant that has antioxidant and neuroprotective properties related to its ability to scavenge neurotoxic lipid peroxidation damage products. OPC depletion may be an especially devastating consequence of IVH/PHH as OPC proliferation peaks during infancy. Additionally, a small increase in OPC survival could confer a large functional benefit as OPCs persist and maintain their proliferative capacity into adulthood. We have preliminary data demonstrating that hemoglobin alone induces oxidative stress in OPCs in vitro and that IVH induces oxidative stress in developing white matter in vivo as PHH develops. Study Design The overarching goal of this study is to achieve OPC protection after IVH/PHH via antioxidant therapy. Specific Aim 1 will test the antioxidant phenelzine in vitro to reduce OPC oxidative stress and increase survival and maturation into myelinating oligodendrocytes. Specific Aim 2 will test the ability of phenelzine to reduce oxidative stress and improve neurological outcome in an in vivo model of IVH/PHH. This project is a collaboration between Dr. Brandon A. Miller and Dr. Edward D. Hall who are both members of the Spinal Cord and Brain Injury Research Center at University of Kentucky. Dr. Miller is a pediatric neurosurgeon who directs a laboratory studying IVH/PHH. His laboratory utilizes a rat model of IVH/PHH and generates histological, biochemical and behavioral outcomes. Dr. Hall is an expert in antioxidant therapies for traumatic brain injury and is developing phenelzine as a therapy in preclinical models. Dr. Hall played a leading role in the development of methylprednisolone therapy for acute spinal cord injury and other neuroprotective drugs that advanced to clinical trials. Expected Outcomes We expect the phenelzine will reduce oxidative stress in OPCs exposed to hemoglobin, and improve OPC survival and maturation. We expect that in vivo phenelzine treatment will reduce oxidative stress within white matter, reduce ventriculomegaly and improve neurobehavioral outcomes. We plan to collaborate with our neonatology colleagues who have experience in clinical trials assessing neurocognitive outcomes in children in order to move positive results from the lab to the clinic.
|Effective start/end date||7/1/20 → 6/30/21|
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