title: Ibuprofen inhibits neuroinflammation and attenuates white matter damage following hypoxia-ischemia in the immature rodent brain.
abstract: Damage to major white matter tracts is a hallmark mark feature of hypoxic-ischemic (HI) brain injury in the preterm neonate. There is, however, no therapeutic intervention to treat this injury. Neuroinflammation is thought to play a prominent role in the pathogenesis of the HI-induced white matter damage but identification of the key mediators that constitute the inflammatory response remain to be fully elucidated. Cyclooxygenase enzymes (COX-1 and COX-2) are candidate neuroinflammatory mediators that may contribute to the HI-induced demise of early oligodendrocyte progenitors and myelination. We investigated whether ibuprofen, a non-steroidal anti-inflammatory drug that inhibits COX enzymes, can attenuate neuroinflammation and associated white matter damage incurred in a rodent model of preterm HI. On postnatal day 3 (P3), HI was produced (right carotid artery ligation and 30 min 6% O(2)). An initial dose of ibuprofen (100mg/kg, s.c.) was administered 2h after HI followed by a maintenance dose (50mg/kg, s.c.) every 24h for 6 days. Post-HI ibuprofen treatment significantly attenuated the P3 HI-induced increases in COX-2 protein expression as well as interleukin-1beta (IL-1β) and tumour necrosis factor-alpha (TNF-α) levels in the brain. Ibuprofen treatment also prevented the HI-induced loss O4- and O1-positive oligodendrocyte progenitor cells and myelin basic protein (MBP)-positive myelin content one week after P3 HI. These findings suggest that a repeated, daily, ibuprofen treatment regimen administered after an HI insult may be a potential therapeutic intervention to prevent HI-induced damage to white matter progenitors and early myelination in the preterm neonate.
authors.affiliation: The University of Queensland, Perinatal Research Centre, The University of Queensland Centre for Clinical Research, Royal Brisbane and Women's Hospital, Herston, Queensland 4029, Australia.
authors.forename: M L
authors.initials: ML
authors.lastname: Carty
authors.forename: J A
authors.initials: JA
authors.lastname: Wixey
authors.forename: H E
authors.initials: HE
authors.lastname: Reinebrant
authors.forename: G
authors.initials: G
authors.lastname: Gobe
authors.forename: P B
authors.initials: PB
authors.lastname: Colditz
authors.forename: K M
authors.initials: KM
authors.lastname: Buller
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D004195:Disease Models, Animal; D004660:Encephalitis / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D006801:Humans; D020925:Hypoxia-Ischemia, Brain / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D007052:Ibuprofen / Q000494:pharmacology*; D007231:Infant, Newborn; D007969:Leukomalacia, Periventricular / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D009413:Nerve Fibers, Myelinated / Q000187:drug effects* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D007052:Ibuprofen