Research Project
10219376
PROJECT SUMMARY/ABSTRACT Hypoxia-ischemia (HI) is the one of leading causes of neurodevelopmental morbidities in preterm and full-term infants. The only therapeutic strategy to treat HI encephalopathy (HIE) in full term infants is hypothermia, which is only partially protective. The only therapy for HI in preterm infants is supportive care. HI brain injury is characterized by a pronounced inflammatory response along with early structural alterations in the blood-brain barrier (BBB)/neurovasculature unit (NVU). Both inflammation and BBB abnormalities predispose to neuronal damage. In the current proposal, we investigate a novel family of molecules, which are purine derivatives (PDD), acting through GSK-3? and prohibitin (PHB) pathways. PHB protects the integrity of OPA1 in brain mitochondria, which is a particularly important protective protein in the immature brain. Previous studies have shown that OPA1 prevents mitochondrial permeabilization, respiratory deterioration and apoptosis in neurons and vascular beds. Our published data show that PDD i) rescue cognitive deficits associated with aging in mice, ii) prevent impairment of neurogenesis, iii) enhance synaptic function and iv) reduce neuroinflammatory brain injury in adult mice. GSK-3? and PHB signaling pathways, including NF-k?, are involved in the neuroprotective mechanisms of PDD. Our preliminary results in the well-characterized Rice-Vannucci model of neonatal HI showed that PDD given after HI i) decreased in the HI related infarct volumes by 40%. Our preliminary data suggests PDDs exert i) important and consistent neuroprotective effects in neonatal and adult models of brain injury, ii) increased OPA-1 expression and iii) increased the transcriptional expression of neurotrophic factors in treated female, but not male, neonatal rats after HI. These results suggest induction of neuronal plasticity and OPA-1 expression in this model that could be beneficial after neonatal HI. The overall hypothesis of our proposal is that PDD targets GSK-3? and PHB to attenuate both the BBB abnormalities and inflammation after neonatal HI. We will test this major hypothesis in two specific aims: Aim 1: PDD303 attenuates brain injury in neonatal rats after exposure to moderate and severe HI. Aim 2: Treatment with PDD303 improves behavioral outcomes and demonstrates durable long-term neuroprotective efficacy after HI in neonatal subjects. We anticipate that this innovative therapeutic strategy targeting the BBB and neuroinflammation through GSK3? and PHB could eventually provide an additional treatment strategy to the current standard of care for both full term and premature infants.
