Delayed cortical impairment following lipopolysaccharide exposure in preterm fetal sheep
Article first published online: 14 OCT 2011
Copyright © 2011 American Neurological Association
Annals of Neurology
Volume 70, Issue 5, pages 846–856, November 2011
How to Cite
Dean, J. M., van de Looij, Y., Sizonenko, S. V., Lodygensky, G. A., Lazeyras, F., Bolouri, H., Kjellmer, I., Huppi, P. S., Hagberg, H. and Mallard, C. (2011), Delayed cortical impairment following lipopolysaccharide exposure in preterm fetal sheep. Ann Neurol., 70: 846–856. doi: 10.1002/ana.22480
- Issue published online: 7 DEC 2011
- Article first published online: 14 OCT 2011
- Accepted manuscript online: 11 MAY 2011 01:36PM EST
- Manuscript Accepted: 6 MAY 2011
- Manuscript Revised: 28 APR 2011
- Manuscript Received: 4 NOV 2010
Preterm infants exhibit chronic deficits in white matter (WM) and cortical maturation. Although fetal infection/inflammation may contribute to WM pathology, the factors contributing to cortical changes are largely unknown. We examined the effect of fetal lipopolysaccharide (LPS) exposure on WM and cortical development as assessed by magnetic resonance imaging (MRI), electroencephalography (EEG), and histopathology in fetal sheep at preterm human equivalent age.
LPS was administered to fetal sheep at 102.5 ± 0.5 days of gestation. Continuous biophysical recordings were analyzed for 10 days after LPS. At postmortem, measurement of cerebral WM and cortical tissue volumes was achieved by stereological techniques. Specific effects of LPS on MRI-assessed T1-weighted and T2-weighted images, and immunohistochemical expression of oligodendrocytes, proliferating cells, cortical NeuN-positive and Nurr1-positive neurons (subplate marker), and cell death mechanisms were examined.
We observed reductions in WM (∼21%; LPS, 1.19 ± 0.04 vs control, 1.51 ± 0.07cm3; p < 0.001) and cortical (∼18%; LPS, 2.34 ± 0.10 vs control, 2.85 ± 0.07cm3; p < 0.001) volumes, associated with overt and diffuse WM injury, T1-/T2-weighted signal alterations, and reduced numbers of WM oligodendrocytes (LPS, 485 ± 31 vs control, 699 ± 69 cells/mm2; p = 0.0189) and NeuN-positive (LPS, 421 ± 71 vs control 718 ± 92 cells/mm2; p = 0.04) and Nurr1-positive (control, 2.5 ± 0.6 vs LPS, 0.6 ± 0.1 cells/mm2; p = 0.007) cortical neurons after LPS. Moreover, there was loss of the normal maturational increase in cortical EEG amplitude, which correlated with reduced cortical volumes.
Fetal exposure to LPS prior to myelination onset can impair both white matter and cortical development in a preclinical large animal model, supporting a role for maternal/fetal infection in the pathogenesis of preterm brain injury. ANN NEUROL 2011