Inflammation-induced Preterm Birth Alters Neuronal Morphology in the Mouse Fetal Brain

Maternal and Child Health Research Program, Department of Obstetrics and Gynecology, Center for Research on Reproduction and Women's Health, University of Pennsylvania, Philadelphia, PA 19104-6142, USA.
Journal of Neuroscience Research (Impact Factor: 2.73). 07/2010; 88(9):1872-81. DOI: 10.1002/jnr.22368
Source: PubMed

ABSTRACT Adverse neurological outcome is a major cause of long-term morbidity in ex-preterm children. To investigate the effect of parturition and inflammation on the fetal brain, we utilized two in vivo mouse models of preterm birth. To mimic the most common human scenario of preterm birth, we used a mouse model of intrauterine inflammation by intrauterine infusion of lipopolysaccharide (LPS). To investigate the effect of parturition on the immature fetal brain, in the absence of inflammation, we used a non-infectious model of preterm birth by administering RU486. Pro-inflammatory cytokines (IL-10, IL-1beta, IL-6 and TNF-alpha) in amniotic fluid and inflammatory biomarkers in maternal serum and amniotic fluid were compared between the two models using ELISA. Pro-inflammatory cytokine expression was evaluated in the whole fetal brains from the two models. Primary neuronal cultures from the fetal cortex were established from the different models and controls in order to compare the neuronal morphology. Only the intrauterine inflammation model resulted in an elevation of inflammatory biomarkers in the maternal serum and amniotic fluid. Exposure to inflammation-induced preterm birth, but not non-infectious preterm birth, also resulted in an increase in cytokine mRNA in whole fetal brain and in disrupted fetal neuronal morphology. In particular, Microtubule-associated protein 2 (MAP2) staining was decreased and the number of dendrites was reduced (P < 0.001, ANOVA between groups). These results suggest that inflammation-induced preterm birth and not the process of preterm birth may result in neuroinflammation and alter fetal neuronal morphology.

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Available from: Irina Burd, Apr 08, 2014
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    • "However, a role for fetal membrane activation in PTD has also been described as clinical and histological chorioamnionitis (inflammation of the amnion and chorion) can lead to preterm premature rupture of membranes (pPROM) (reviewed by Menon & Fortunato (2007) and Gomez-Lopez et al. (2010)). PTD can be artificially induced by treating pregnant mice with LPS (via the i.p., intrauterine, intra-amniotic or vaginal routes), allowing the effect of preterm labour (and potential therapeutic targets) on neonatal morbidity and mortality to be investigated (Elovitz et al. 2003, Pirianov et al. 2009, Burd et al. 2010, Gonzalez et al. 2011). "
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    • "To study the effects of intra-uterine inflammation on fetal brain injury and development, various experimental animal models have been developed [13,35–37]. Animal models of maternal inflammation and perinatal brain injury through intranasal, intra-venous, intra-peritoneal, and intra-cervical administration or injections in the uterine wall and uterine horns with different agents, such as viruses, bacteria or bacterial components (LPS) have been described in mice [37] [38] [39] [40] [41], rats [42] [43], rabbits [35] [44] [45] and guinea pigs [36] (Table 1). "
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    • "In a rat model, intrauterine administration of LPS at E15 resulted in early cortical cell death and dysmyelination, similar to PVL lesions, at 3 weeks of age in the offspring (Bell and Hallenbeck, 2002). A preterm model of intrauterine LPS administration in mouse caused significant fetal brain injury (Burd et al., 2010; Ernst et al., 2010) as did a similar \to term" model (Elovitz et al., 2011). Diffuse PVL lesions in cerebral palsy brains are initiated by loss of developing oligodendrocytes and subsequent hypomyelination, which is mediated, in part, by free radical-induced oxidative stress, glutamate toxicity, and circulating cytokines (Kinney and Back, 1998). "
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