Intraventricular hemorrhage (IVH) remains the most common neurologic complication of prematurity. IVH leads to hypomyelination and post-hemorrhagic hydrocephalus. Myelination failure in infants with IVH is ascribed to inflammation and oxidative stress, which induces maturational arrest of oligodendrocyte progenitor cells (OPCs). Hydrocephalus in these infants is attributed to obstruction in the CSF flow by blood clots and diminished CSF absorption owing to obliterative arachnoidits of the posterior fossa and subependymal gliosis. Here, we ask whether modulation of microglial phagocytic receptor and their function will enhance hematoma removal, reduce oxidative stress, and minimize inflammation, thereby restoring myelination and ventricle size in premature newborns with IVH. Peroxisome proliferator-activated receptor-? (PPAR?) is a ligand activated receptor, which alleviates inflammation and reprograms microglial cells into neuroprotective phenotype to clear cellular debris and orchestrate neurorestorative processes in the injured brain. Importantly, PPAR-? activation transcriptionally up-regulates expression of CD36 (class II scavenger receptor), which mediates phagocytosis of erythrocytes and damaged cells via the Src family of phosphotyrosine kinases. Rosiglitazone--a PPAR? agonist--differentiates microglia into cytoprotective phenotype, augments phagocytosis, reduces inflammatory mediators, elevates antioxidant enzymes, and enhances OPC maturation. PPAR? overexpression, even in absence of exogenous ligand, inhibits inflammation and is neuroprotective. Accordingly, our preliminary data show that rosiglitazone treatment enhances hematoma removal and reduces ventricle size in rabbit pups with IVH. Therefore, we hypothesize: a) activation of PPAR? will enhance hematoma removal, promote functional changes in microglia, inhibit oxidative injury and inflammation, thereby minimizing hydrocephalus and restoring myelination in premature rabbits with IVH, and b) PPAR?-induced phagocytosis is mediated by CD36-Src kinase signaling. Our approach is to employ rabbit model of IVH, in which preterm pups with IVH exhibit hypomyelination, and hydrocephalus.
In Aim #1, we will determine the effect of Ad-PPAR? gene transfer or rosiglitazone treatment on a) microglial phagocytosis and ventricular hematoma resolution, b) CSF absorption and occurrence of hydrocephalus, c) OPC maturation and myelination, and d) neurobehavioral function in treated pups vs. vehicle controls with IVH.
In Aim #2, we will determine a) the effects of Ad-PPAR? gene transfer or rosiglitazone treatment on microglial transcriptome, pro-inflammatory cytokines, and reactive oxygen species levels in preterm rabbits with IVH, and b) whether PPAR? induced phagocytosis will be mediated by CD36-Src kinase-MAPK signaling. The proposed study might accelerate development of new therapies to prevent or minimize hydrocephalus and white matter injury in premature infants with IVH.
In the United States, about 12,000 premature infants develop bleeding in and around the ventricle (cavity) of the brain each year, which results in cerebral palsy and hydrocephalus (dilated brain cavity with large head) in the survivors. These disorders are attributed to death and arrested maturation of brain cells, which insulate the brain wiring. Hydrocephalus is ascribed to blockage of CSF flow by blood clots. In this proposal, we will determine whether activating scavenger cells (microglia) to remove the blood clot restores ventricle size and insulation of neural wiring in the survivors of IVH.
