Article

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). 02/2010; 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.

1 Bookmark
 · 
103 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Preterm birth, a global healthcare problem, is commonly associated with inflammation. As Slit2 plays an emerging role in inflammation, the purpose of this study was to determine the effect of Slit2 on labour mediators in human gestational tissues. Slit2 mRNA and protein expression were assessed using qRT-PCR and immunohistochemistry in fetal membranes and myometrium obtained before and after labour. Slit2 silencing was achieved using siRNA in primary myometrial cells. Pro-inflammatory and pro-labour mediators were evaluated by qRT-PCR, ELISA and gelatin zymography. Slit2 mRNA and protein expression were found to be significantly lower in myometrium after labour onset. There was no effect of term or preterm labour on Slit2 expression in fetal membranes. Slit2 mRNA expression was decreased in myometrium treated with LPS and IL-1β. Slit2 siRNA in myometrial cells increased IL-1β-induced pro-inflammatory cytokine gene expression and release (IL-6 and IL-8), COX-2 expression and prostaglandin PGE2 and PGF2α release, and MMP-9 gene expression and pro MMP-9 release. There was no effect of Slit2 siRNA on IL-1β-induced NF-κB transcriptional activity. Our results demonstrate that Slit2 is decreased in human myometrium after labour and our knock-down studies describe an anti-inflammatory effect of Slit2 in myometrial cells.
    Journal of Reproductive Immunology 12/2014; · 2.37 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: To develop an in vivo diffusion magnetic resonance imaging (dMRI) technique to study embryonic mouse brain structure and injury. Pregnant CD-1 mice were examined on embryonic day 17 on an 11.7T scanner. Spatially selective excitation pulses were used to achieve localized imaging of individual mouse brains, in combination with a 3D fast imaging sequence to acquire dMRI at 0.16-0.2 mm isotropic resolution. Subject motions were corrected by navigator echoes and image registration. Further acceleration was achieved by simultaneous imaging of two embryos in an interleaved fashion. We applied this technique to detect embryonic brain injury in a mouse model of intrauterine inflammation. With the localized imaging technique, we achieved in utero high-resolution T2 -weighted and dMRI of the embryonic mouse brain for the first time. Early embryonic brain structures were delineated from diffusion tensor images, and major white matter tracts were reconstructed in 3D. Comparison with ex vivo data showed significant changes in the apparent diffusion coefficient (ADC), but mostly unchanged fractional anisotropy. In the inflammation-affected embryonic brains, ADC in the cortical regions was reduced at 6 hours after the injury, potentially caused by cellular edema. The feasibility of in utero dMRI of embryonic mouse brains was demonstrated. The technique is important for noninvasive monitoring of embryonic mouse brain microstructure and injury. J. Magn. Reson. Imaging 2014. © 2014 Wiley Periodicals, Inc.
    Journal of Magnetic Resonance Imaging 12/2014; · 2.57 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Interventions to treat cerebral palsy should be initiated as soon as possible in order to restore the nervous system to the correct developmental trajectory. One drawback to this approach is that interventions have to undergo exceptionally rigorous assessment for both safety and efficacy prior to use in infants. Part of this process should involve research using animals but how good are our animal models? Part of the problem is that cerebral palsy is an umbrella term that covers a number of conditions. There are also many causal pathways to cerebral palsy, such as periventricular white matter injury in premature babies, perinatal infarcts of the middle cerebral artery, or generalized anoxia at the time of birth, indeed multiple causes, including intra-uterine infection or a genetic predisposition to infarction, may need to interact to produce a clinically significant injury. In this review, we consider which animal models best reproduce certain aspects of the condition, and the extent to which the multifactorial nature of cerebral palsy has been modeled. The degree to which the corticospinal system of various animal models human corticospinal system function and development is also explored. Where attempts have already been made to test early intervention in animal models, the outcomes are evaluated in light of the suitability of the model.
    Frontiers in Neurology 12/2014; 5:258.

Full-text (2 Sources)

Download
18 Downloads
Available from
May 29, 2014