Minocycline reduces lipopolysaccharide-induced neurological dysfunction and brain injury in the neonatal rat.
Preferential brain white matter injury and hypomyelination induced by intracerebral administration of the endotoxin lipopolysaccharide (LPS) in the neonatal rat brain has been characterized as associated with the activation of microglia. To examine whether inhibition of microglial activation might provide protection against LPS-induced brain injury and behavioral deficits, minocycline (45 mg/kg) was administered intraperitoneally 12 hr before and immediately after an LPS (1 mg/kg) intracerebral injection in postnatal day 5 (P5) Sprague-Dawley rats and then every 24 hr for 3 days. Brain injury and myelination were examined on postnatal day 21 and the tests for neurobehavioral toxicity were carried out from P3 to P21. LPS administration resulted in severe white matter injury, enlarged ventricles, deficits in the hippocampus, loss of oligodendrocytes and tyrosine hydroxylase neurons, damage to axons and dendrites, and impaired myelination as indicated by the decrease in myelin basic protein immunostaining in the P21 rat brain. LPS administration also significantly affected physical development (body weight) and neurobehavioral performance, such as righting reflex, wire hanging maneuver, cliff avoidance, locomotor activity, gait analysis, and responses in the elevated plus-maze and passive avoidance task. Treatment with minocycline significantly attenuated the LPS-induced brain injury and improved neurobehavioral performance. The protective effect of minocycline was associated with its ability to attenuate LPS-induced microglial activation. These results suggest that inhibition of microglial activation by minocycline may have long-term protective effects in the neonatal brain on infection-induced brain injury and associated neurologic dysfunction in the rat.
Fan
Lir-Wan
LW
Department of Pediatrics, Division of Newborn Medicine, University of Mississippi Medical Center, Jackson, Mississippi 39216-4504, USA.
Pang
Yi
Y
Lin
Shuying
S
Tien
Lu-Tai
LT
Ma
Tangeng
T
Rhodes
Philip G
PG
Cai
Zhengwei
Z
D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D001362:Avoidance Learning / Q000187:drug effects; D001522:Behavior, Animal; D001921:Brain / Q000187:drug effects / Q000254:growth & development / Q000473:pathology / Q000503:physiopathology; D001930:Brain Injuries / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D039481:CD11b Antigen / Q000378:metabolism; D002452:Cell Count / Q000379:methods; D005684:Gait / Q000187:drug effects; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000502:physiology; D007150:Immunohistochemistry / Q000379:methods; D020547:Lateral Ventricles / Q000187:drug effects / Q000473:pathology; D037102:Lectins / Q000378:metabolism; D008070:Lipopolysaccharides; D018782:Maze Learning / Q000187:drug effects; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008911:Minocycline / Q000627:therapeutic use*; D009043:Motor Activity / Q000187:drug effects; D004676:Myelin Basic Protein / Q000378:metabolism; D009422:Nervous System Diseases / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D011597:Psychomotor Performance / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012018:Reflex / Q000187:drug effects; D013194:Staining and Labeling / Q000379:methods; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D039481:CD11b Antigen; D037102:Lectins; D008070:Lipopolysaccharides; D008869:Microtubule-Associated Proteins; D004676:Myelin Basic Protein; D014446:Tyrosine 3-Monooxygenase; D008911:Minocycline