α-Phenyl-n-tert-butyl-nitrone attenuates lipopolysaccharide-induced brain injury and improves neurological reflexes and early sensorimotor behavioral performance in juvenile rats

• Published in: Journal of neuroscience research 2008-12, Vol.86 (16), p.3536-3547
• Main Authors: Fan, Lir-Wan, Chen, Ruei-Feng, Mitchell, Helen J., Lin, Rick C. S., Simpson, Kimberly L., Rhodes, Philip G., Cai, Zhengwei
• Format: Article
• Language: English
• Subjects: Animals; Animals, Newborn; antioxidant; Brain - drug effects; Brain - pathology; Brain - physiopathology; Brain Damage, Chronic - chemically induced; Brain Damage, Chronic - drug therapy; Brain Damage, Chronic - microbiology; Central Nervous System Bacterial Infections - microbiology; Central Nervous System Bacterial Infections - physiopathology; Central Nervous System Bacterial Infections - transmission; Cyclic N-Oxides - therapeutic use; Disease Models, Animal; Female; Gait Disorders, Neurologic - chemically induced; Gait Disorders, Neurologic - drug therapy; Gait Disorders, Neurologic - microbiology; Humans; impaired myelination; Infant, Newborn; Infectious Disease Transmission, Vertical; Leukomalacia, Periventricular - drug therapy; Leukomalacia, Periventricular - microbiology; lipopolysaccharide; Lipopolysaccharides - toxicity; Male; Movement Disorders - drug therapy; Movement Disorders - microbiology; Movement Disorders - physiopathology; Myelin Basic Protein - drug effects; Myelin Basic Protein - metabolism; Nerve Fibers, Myelinated - drug effects; Nerve Fibers, Myelinated - metabolism; Nerve Fibers, Myelinated - pathology; neurobehavioral performance; Neuroprotective Agents - therapeutic use; Oligodendroglia - drug effects; Oligodendroglia - metabolism; Oligodendroglia - pathology; Pregnancy; Rats; Rats, Sprague-Dawley; Recovery of Function - drug effects; Recovery of Function - physiology; Reflex - drug effects; Reflex - physiology; white matter injury
• ISSN: 0360-4012; 1097-4547; 1097-4547
• DOI: 10.1002/jnr.21812

Our previous study showed that treatment with α‐phenyl‐n‐tert‐butyl‐nitrone (PBN) after exposure to lipopolysaccharide (LPS) reduced LPS‐induced white matter injury in the neonatal rat brain. The object of the current study was to further examine whether PBN has long‐lasting protective effects and ameliorates LPS‐induced neurological dysfunction. Intracerebral (i.c.) injection of LPS (1 mg/kg) was performed in postnatal day (P) 5 Sprague Dawley rat pups and PBN (100 mg/kg) or saline was administered intraperitoneally 5 min after LPS injection. The control rats were injected (i.c.) with sterile saline. Neurobehavioral tests were carried out from P3 to P21, and brain injury was examined after these tests. LPS exposure resulted in severe brain damage, including enlargement of ventricles bilaterally, loss of mature oligodendrocytes, impaired myelination as indicated by the decrease in myelin basic protein immunostaining, and alterations in dendritic processes in the cortical gray matter of the parietal cortex. Electron microscopic examination showed that LPS exposure caused impaired myelination as indicated by the disintegrated myelin sheaths in the juvenile rat brain. LPS administration also significantly affected neurobehavioral functions such as performance in righting reflex, wire hanging maneuver, cliff avoidance, negative geotaxis, vibrissa‐elicited forelimb‐placing test, beam walking, and gait test. Treatment with PBN, a free radical scavenger and antioxidant, provided protection against LPS‐induced brain injury and associated neurological dysfunction in juvenile rats, suggesting that antioxidation might be an effective approach for therapeutic treatment of neonatal brain injury induced by infection/inflammation. © 2008 Wiley‐Liss, Inc.