Maternal exposure to LPS induces hypomyelination in the internal capsule and programmed cell death in the deep gray matter in newborn rats.
Epidemiologic and experimental findings implicate maternal infection in the etiology of injury to brain white matter, which may lead to cerebral palsy in preterm newborns. In the present study, inflammation and brain damage in 1- and 7-d-old rats were investigated after maternal inflammation. Intraperitoneal injection of 300 microg/kg of Escherichia coli lipopolysaccharide was administered to pregnant Wistar rats at d 19 and 20 of gestation (LPS group). Control females received a saline injection. Proinflammatory cytokines IL-1beta, tumor necrosis factor-alpha, and IL-6 expression in the fetal brain were determined by reverse transcription quantitative polymerase chain reaction. Brain injury was examined in 16-mum coronal brain sections by GFAP, MBP, caspase-3 immunohistochemistry, and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling. Expression of IL-1beta was significantly increased 3 d after maternal administration (P1). A significant increase in cell death occurred at P1 and P7 in specific brain areas, i.e. in the subventricular striatal zone at P1, and in 1) the periventricular striatum, 2) the periventricular white matter, and 3) the germinative ventricular zone at P7. We also observed typical astrogliosis and strong hypomyelination in the external and internal capsule in the LPS group at P7. These results demonstrate that maternal LPS treatment induces persistent fetal inflammatory reactions associated with significant white matter injury in progeny at P1 and P7. This model should be relevant for the study of the pathophysiological mechanisms involved in cerebral white matter damage in preterm human newborns and in the development of therapeutic strategies.
INSERM U619, 37000 Tours, France.
Catherine I
CI
Rousset
Sylvie
S
Chalon
Sylvain
S
Cantagrel
Sylvie
S
Bodard
Christian
C
Andres
Pierre
P
Gressens
Elie
E
Saliba
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000502:physiology*; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002540:Cerebral Cortex / Q000033:anatomy & histology / Q000276:immunology / Q000473:pathology*; D016207:Cytokines / Q000276:immunology; D005260:Female; D006801:Humans; D020287:In Situ Nick-End Labeling; D020772:Internal Capsule / Q000033:anatomy & histology / Q000276:immunology / Q000473:pathology*; D008070:Lipopolysaccharides / Q000276:immunology*; D004676:Myelin Basic Protein / Q000378:metabolism; D009186:Myelin Sheath / Q000378:metabolism*; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar
D016207:Cytokines; D008070:Lipopolysaccharides; D004676:Myelin Basic Protein; C505407:CASP3 protein, human; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases