White matter disease, periventricular leukomalacia (PVL) in particular, is a common form of brain injury in very preterm infants, and is frequently associated with severe neurological disorders such as cerebral palsy and cognitive impairment. PVL remains a major problem in preterm infants. Although it has been proposed that maternal or placental infection may contribute to PVL and that inflammatory cytokines are mediators between maternal infection and offspring brain white matter injury, the details of how maternal infection can cause white matter lesions in the infant brain are still poorly understood. The long-term objective of this study is to enhance our understanding of mechanisms involved in PVL and provide necessary information leading to protection of the preterm infant brain from white matter damage. Our preliminary data indicates that intracerebral administration of lipopolysaccharide (LPS), an endotoxin responsible for most of the inflammatory effects of infection from Gram-negative bacteria, increases inflammatory cytokine expression in the neonatal rat brain, causes brain injury resembling that seen in preterm infants with PVL, and results in neurological and learning behavioral alterations. Using this rat model, 4 hypotheses will be examined in the proposed studies: 1). Direct exposure of the neonatal rat brain to inflammatory cytokines or their combinations (IL1b, TNFa and IL-6), via intracerebral injection, may cause brain white matter injury, especially to developing oligodendrocytes; 2). Inhibition of microglial activation by minocycline, a tetracycline derivative, may reduce LPS induced oxidative and nitrosative stress in the neonatal rat brain and attenuate LPS-induced brain injury; 3). Application of alpha-pheny-N-tert-butyl-nitrorie (PBN), a free radical scavenger, may protect the immature brain from LPS-induced injury; and 4). Exogenous insulin-like growth factor-1 may protect oligodendrocytes from LPS-induced injury in vivo and in vitro. The results should further reveal the role of microglial activation and inflammatory cytokines in mediating LPS-induced brain injury and will also reveal the possibility of using microglial activation inhibitors or antioxidants as a potential therapeutic treatment for neonatal white matter lesions such as PVL.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS054278-01A1
Application #
6964892
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Leblanc, Gabrielle G
Project Start
2005-07-01
Project End
2009-06-30
Budget Start
2005-07-01
Budget End
2006-06-30
Support Year
1
Fiscal Year
2005
Total Cost
$171,125
Indirect Cost
Name
University of Mississippi Medical Center
Department
Pediatrics
Type
Schools of Medicine
DUNS #
928824473
City
Jackson
State
MS
Country
United States
Zip Code
39216
Fan, Lir-Wan; Bhatt, Abhay; Tien, Lu-Tai et al. (2015) Exposure to serotonin adversely affects oligodendrocyte development and myelination in vitro. J Neurochem 133:532-43
Wang, K-C; Fan, L-W; Kaizaki, A et al. (2013) Neonatal lipopolysaccharide exposure induces long-lasting learning impairment, less anxiety-like response and hippocampal injury in adult rats. Neuroscience 234:146-57
Fan, L-W; Kaizaki, A; Tien, L-T et al. (2013) Celecoxib attenuates systemic lipopolysaccharide-induced brain inflammation and white matter injury in the neonatal rats. Neuroscience 240:27-38
Kaizaki, Asuka; Tien, Lu-Tai; Pang, Yi et al. (2013) Celecoxib reduces brain dopaminergic neuronaldysfunction, and improves sensorimotor behavioral performance in neonatal rats exposed to systemic lipopolysaccharide. J Neuroinflammation 10:45
Tien, Lu-Tai; Kaizaki, Asuka; Pang, Yi et al. (2013) Neonatal exposure to lipopolysaccharide enhances accumulation of ?-synuclein aggregation and dopamine transporter protein expression in the substantia nigra in responses to rotenone challenge in later life. Toxicology 308:96-103
Cai, Zhengwei; Fan, Lir-Wan; Kaizaki, Asuka et al. (2013) Neonatal systemic exposure to lipopolysaccharide enhances susceptibility of nigrostriatal dopaminergic neurons to rotenone neurotoxicity in later life. Dev Neurosci 35:155-71
Pang, Yi; Fan, Lir-Wan; Zheng, Baoying et al. (2012) Dexamethasone and betamethasone protect against lipopolysaccharide-induced brain damage in neonatal rats. Pediatr Res 71:552-8
Fan, Lir-Wan; Tien, Lu-Tai; Zheng, Baoying et al. (2011) Dopaminergic neuronal injury in the adult rat brain following neonatal exposure to lipopolysaccharide and the silent neurotoxicity. Brain Behav Immun 25:286-97
Wang, Kuo-Ching; Wang, Su-Jane; Fan, Lir-Wan et al. (2011) Interleukin-1 receptor antagonist ameliorates neonatal lipopolysaccharide-induced long-lasting hyperalgesia in the adult rats. Toxicology 279:123-9
Fan, Lir-Wan; Tien, Lu-Tai; Lin, Rick C S et al. (2011) Neonatal exposure to lipopolysaccharide enhances vulnerability of nigrostriatal dopaminergic neurons to rotenone neurotoxicity in later life. Neurobiol Dis 44:304-16

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