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

Jerry J. Flores, Damon Klebe, William B. Rolland, Tim Lekic, Paul R. Krafft, John H. Zhang

Research output: Contribution to journalArticlepeer-review

Abstract

Germinal 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 PPARγ 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. PPARγ stimulation (15d-PGJ2) increased short-term PPARγ and CD36 expression levels as well as enhanced hematoma resolution, which was reversed by a PPARγ antagonist (GW9662) and CD36 siRNA. PPARγ stimulation (15d-PGJ2) also reduced long-term white matter loss and post-hemorrhagic ventricular dilation as well as improved neurofunctional outcomes, which were reversed by a PPARγ antagonist (GW9662). PPARγ-induced upregulation of CD36 in macrophages and microglia is, therefore, critical for enhancing hematoma resolution and ameliorating long-term brain sequelae.

Original languageEnglish
Pages (from-to)124-133
Number of pages10
JournalNeurobiology of Disease
Volume87
DOIs
StatePublished - Mar 1 2016

ASJC Scopus Subject Areas

  • Neurology

Keywords

  • CD36
  • Germinal matrix hemorrhage
  • Hematoma resolution
  • PPARγ
  • Post-hemorrhagic ventricular dilation
  • Animals, Newborn
  • CD36 Antigens/genetics
  • Microglia/drug effects
  • Prostaglandin D2/analogs & derivatives
  • RNA, Small Interfering/administration & dosage
  • Up-Regulation
  • Anilides/pharmacology
  • Random Allocation
  • Neuroprotective Agents/pharmacology
  • Rats, Sprague-Dawley
  • Gene Knockdown Techniques
  • Hematoma/drug therapy
  • Brain/drug effects
  • Intracranial Hemorrhages/drug therapy
  • PPAR gamma/antagonists & inhibitors
  • Animals
  • Central Nervous System Agents/pharmacology
  • Macrophage Activation/drug effects
  • Disease Models, Animal

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