title: PPARγ-induced upregulation of CD36 enhances hematoma resolution and attenuates long-term neurological deficits after germinal matrix hemorrhage in neonatal rats.
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.
authors.affiliation: Department of Physiology & Pharmacology, Loma Linda University School of Medicine, Loma Linda, CA, USA.
authors.forename: Jerry J
authors.initials: JJ
authors.lastname: Flores
authors.affiliation: Department of Physiology & Pharmacology, Loma Linda University School of Medicine, Loma Linda, CA, USA.
authors.forename: Damon
authors.initials: D
authors.lastname: Klebe
authors.affiliation: Department of Physiology & Pharmacology, Loma Linda University School of Medicine, Loma Linda, CA, USA.
authors.forename: William B
authors.initials: WB
authors.lastname: Rolland
authors.affiliation: Department of Physiology & Pharmacology, Loma Linda University School of Medicine, Loma Linda, CA, USA.
authors.forename: Tim
authors.initials: T
authors.lastname: Lekic
authors.affiliation: Department of Physiology & Pharmacology, Loma Linda University School of Medicine, Loma Linda, CA, USA.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Krafft
authors.affiliation: Department of Physiology & Pharmacology, Loma Linda University School of Medicine, Loma Linda, CA, USA; Departments of Anesthesiology and Neurosurgery, Loma Linda University School of Medicine, Loma Linda, CA, USA. Electronic address: johnzhang3910@yahoo.com.
authors.forename: John H
authors.initials: JH
authors.lastname: Zhang
mesh_terms: D000813:Anilides / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism*; D002491:Central Nervous System Agents / Q000494:pharmacology; D004195:Disease Models, Animal; D055785:Gene Knockdown Techniques; D006406:Hematoma / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*; D020300:Intracranial Hemorrhages / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*; D008262:Macrophage Activation / Q000187:drug effects / Q000502:physiology; D017628:Microglia / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000008:administration & dosage; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation
chemical_list: C477819:15-deoxyprostaglandin J2; C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D018955:CD36 Antigens; C008132:Cd36 protein, rat; D002491:Central Nervous System Agents; D018696:Neuroprotective Agents; D047495:PPAR gamma; D034741:RNA, Small Interfering; D015230:Prostaglandin D2
keywords: CD36; Germinal matrix hemorrhage; Hematoma resolution; PPARγ; Post-hemorrhagic ventricular dilation