title: Celecoxib attenuates systemic lipopolysaccharide-induced brain inflammation and white matter injury in the neonatal rats.
abstract: Lipopolysaccharide (LPS)-induced white matter injury in the neonatal rat brain is associated with inflammatory processes. Cyclooxygenase-2 (COX-2) can be induced by inflammatory stimuli, such as cytokines and pro-inflammatory molecules, suggesting that COX-2 may be considered as the target for anti-inflammation. The objective of the present study was to examine whether celecoxib, a selective COX-2 inhibitor, can reduce systemic LPS-induced brain inflammation and brain damage. Intraperitoneal (i.p.) injection of LPS (2mg/kg) was performed in postnatal day 5 (P5) of Sprague-Dawley rat pups and celecoxib (20mg/kg) or vehicle was administered i.p. 5 min after LPS injection. The body weight and wire-hanging maneuver test was performed 24h after the LPS exposure, and brain injury was examined after these tests. Systemic LPS exposure resulted in an impairment of behavioral performance and acute brain injury, as indicated by apoptotic death of oligodendrocytes (OLs) and loss of OL immunoreactivity in the neonatal rat brain. Treatments with celecoxib significantly reduced systemic LPS-induced neurobehavioral disturbance and brain damage. Celecoxib administration significantly attenuated systemic LPS-induced increments in the number of activated microglia and astrocytes, concentrations of IL-1β and TNFα, and protein levels of phosphorylated-p38 MAPK in the neonatal rat brain. The protection of celecoxib was also associated with a reduction of systemic LPS-induced COX-2+ cells which were double labeled with GFAP+ (astrocyte) cells. The overall results suggest that celecoxib was capable of attenuating the brain injury and neurobehavioral disturbance induced by systemic LPS exposure, and the protective effects are associated with its anti-inflammatory properties.
authors.affiliation: Department of Pediatrics, Division of Newborn Medicine, University of Mississippi Medical Center, Jackson, MS 39216-4505, USA. lwfan@umc.edu
authors.forename: L-W
authors.initials: LW
authors.lastname: Fan
authors.forename: A
authors.initials: A
authors.lastname: Kaizaki
authors.forename: L-T
authors.initials: LT
authors.lastname: Tien
authors.forename: Y
authors.initials: Y
authors.lastname: Pang
authors.forename: S
authors.initials: S
authors.lastname: Tanaka
authors.forename: S
authors.initials: S
authors.lastname: Numazawa
authors.forename: A J
authors.initials: AJ
authors.lastname: Bhatt
authors.forename: Z
authors.initials: Z
authors.lastname: Cai
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002135:Calcium-Binding Proteins / Q000378:metabolism; D000068579:Celecoxib; D016923:Cell Death / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004660:Encephalitis / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy*; D005260:Female; D005552:Forelimb / Q000503:physiopathology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D020287:In Situ Nick-End Labeling; D053583:Interleukin-1beta; D056784:Leukoencephalopathies / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy*; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D008840:Microfilament Proteins / Q000378:metabolism; D053580:Muscle Strength / Q000187:drug effects; D019081:O Antigens / Q000378:metabolism; D011247:Pregnancy; D011720:Pyrazoles / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C491049:Aif1 protein, mouse; D002135:Calcium-Binding Proteins; D052246:Cyclooxygenase 2 Inhibitors; D005904:Glial Fibrillary Acidic Protein; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D008840:Microfilament Proteins; D019081:O Antigens; D011720:Pyrazoles; D013449:Sulfonamides; D014409:Tumor Necrosis Factor-alpha; D051546:Cyclooxygenase 2; D048051:p38 Mitogen-Activated Protein Kinases; D000068579:Celecoxib