Ibuprofen inhibits neuroinflammation and attenuates white matter damage following hypoxia–ischemia in the immature rodent brain

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% O2). An initial dose of ibuprofen (100 mg/kg, s.c.) was administered 2 h after HI followed by a maintenance dose (50 mg/kg, s.c.) every 24 h 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.

► Ibuprofen for one week attenuates white matter injury after HI. ► Post-insult ibuprofen administration is effective. ► Ibuprofen effects could be mediated by inhibition of brain COX-2. ► Ibuprofen effects could be mediated by inhibition of cytokines in the brain. ► Ibuprofen could be a new intervention to stem brain injury in HI-affected neonates.