alpha-Phenyl-n-tert-butyl-nitrone reduces lipopolysaccharide-induced white matter injury in the neonatal rat brain.
Lipopolysaccharide (LPS)-induced white matter injury in the neonatal rat brain is at least partially associated with oxidative stress. alpha-Phenyl-n-tert-butyl-nitrone (PBN) (100 mg/kg) significantly attenuated LPS (1 mg/kg)-induced brain injury, as indicated by the reduction in bilateral ventricular enlargement, apoptotic cell death of oligodendrocytes (OLs), and the loss of OL immunoreactivity in the neonatal rat brain. Protection of PBN was linked with the attenuated oxidative stress induced by LPS, as indicated by the decreased elevation of 8-isoprostane content and by the reduced number of 4-hydroxynonenal or malondialdehyde positive OLs following LPS exposure. Interestingly, while LPS exposure elevated, rather than depleted, levels of the reduced glutathione (GSH) and the GSH/GSSG (oxidized form) ratio, LPS exposure significantly suppressed glutathione peroxidase activity in the rat brain. PBN attenuated LPS-induced alterations in glutathione homeostasis in the rat brain. Additionally, the inflammatory responses were also reduced in the PBN-treated brain, as indicated by the decreased number of activated microglia following LPS exposure and by the consequently decreased elevation of interleukin1-beta and tumor necrosis factor-alpha contents in the rat brain. The overall results suggest that antioxidant PBN, more than a straightforward free radical scavenger, may also involve anti-inflammatory and anti-apoptotic properties in protection of the neonatal rat brain from LPS-induced injury.
Fan
Lir-Wan
LW
Department of Pediatrics, University of Mississippi Medical Center, Jackson, Mississippi 39216, USA.
Mitchell
Helen J
HJ
Tien
Lu-Tai
LT
Zheng
Baoying
B
Pang
Yi
Y
Rhodes
Philip G
PG
Cai
Zhengwei
Z
D000818:Animals; D000831:Animals, Newborn; D001930:Brain Injuries / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D003497:Cyclic N-Oxides / Q000627:therapeutic use*; D016207:Cytokines / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D005978:Glutathione / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity*; D008297:Male; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009457:Neuroglia / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D010544:Peroxidases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D003497:Cyclic N-Oxides; D016207:Cytokines; D008070:Lipopolysaccharides; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; C029217:phenyl-N-tert-butylnitrone; D010544:Peroxidases; D005978:Glutathione