Effects of intrauterine inflammation on developing rat brain

Abstract

Damage to the white matter in the brain during development can lead to cerebral palsy (CP), a heterogeneous group of clinical syndromes that results in life-long disorders of movement and posture. Periventricular leukomalacia (PVL) is a pathological process within the white matter characterized by oligodendrocyte loss and is associated with the development of CP. Clinically, CP and PVL are associated with intrauterine infection and inflammation, but mechanisms involved are not well understood. We developed a model of intrauterine inflammation in Lewis and Fischer 344 rats to study the effects of intrauterine inflammation on developing glia. Pregnant rats were intracervically injected with lipopolysaccharide (LPS) at 15 days of gestation (E15) and a dose of LPS that caused low fetal mortality was determined. At E20, treated fetuses had increased TUNEL(+) nuclei and tumor necrosis factor (TNF)-alpha-immunoreactive areas within the brains. In a second series of animals allowed to survive until postnatal day 21 (PND 21), immunostaining was performed against several glial markers. Staining for the oligodendrocyte-specific proteins 2', 3'-cyclic nucleotide phosphodiesterase (CNP) and myelin proteolipid protein (PLP) was decreased in treated pups compared to shams within the corpus callosum, a white matter structure used as a representative area of developing white matter. Treated pups had activated astrocytes lining cerebral blood vessels, as observed by glial fibrillary acidic protein (GFAP) staining, while sham pups did not. Activated microglia were not detected using OX42 as a cell marker. Our model of intrauterine inflammation causes increased TUNEL and TNF-alpha staining early after injury, suggesting increased apoptotic cell death, possibly by cytokine-related mechanisms.