PPARγ-induced upregulation of CD36 enhances hematoma resolution and attenuates long-term neurological deficits after germinal matrix hemorrhage in neonatal rats

Germing matrix hemorrhage remains the leading cause of morbidity and mortality in preterm infants in the United States with little progress made in its clinical management. Survivors are often afflicted with long-term neurological sequelae, including cerebral palsy, mental retardation, hydrocephalus, and psychiatric disorders. Blood clots disrupting normal cerebrospinal fluid circulation and absorption after germinal matrix hemorrhage are thought to be important contributors towards post-hemorrhagic hydrocephalus development We evaluated if upregulating CD36 scavenger receptor expression in microglia and macrophages through PPAR gamma stimulation, which was effective in experimental adult cerebral hemorrhage models and is being evaluated clinically, will enhance hematoma resolution and ameliorate long-term brain sequelae using a neonatal rat germinal matrix hemorrhage model. PPAR gamma stimulation (15d-PGJ(2)) increased short-term PPAR gamma and CD36 expression levels as well as enhanced hematoma resolution, which was reversed by a PPAR gamma antagonist (GW9662) and CD36 siRNA. PPAR gamma stimulation (15d-PGJ(2)) also reduced long-term white matter loss and post-hemorrhagic ventricular dilation as well as improved neurofunctional outcomes, which were reversed by a PPAR-gamma antagonist (GW9662). PPAR gamma-induced upregulation of CD36 in macrophages and microglia is, therefore, critical for enhancing hematoma resolution and ameliorating long-term brain sequelae. (C) 2015 Elsevier Inc All rights reserved.