Neuroprotective Strategy: Novel Purine Derivatives for Neonatal Hypoxia-ischemia

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-3β 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-3β and PHB signaling pathways, including NF-kβ, 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-3β 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
GSK3β and PHB could eventually provide an additional treatment strategy to the current standard of
care for both full term and premature infants.

Grant Number: 5R01NS117428-04
NIH Institute/Center: NIH
Principal Investigator: Xiaodi Chen