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Statins Prevent Fetal Cortical Brain Abnormalities in Preterm Fetuses in Mice

Presented at the Neonatal Society 2013 Summer Meeting (programme).

Pedroni S1, Jansen M2, Lenner R2, Wade J1, Girardi G1,2

1 MRC Centre for Reproductive Health, University of Edinburgh, UK
2 BHF/University Centre for Cardiovascular Science, University of Edinburgh, UK
3 MRC Centre for Inflammation Research, University of Edinburgh, UK

Background: Premature babies are particularly vulnerable to brain injury. In this study we focus on cortical brain damage that can result in the long-term cognitive, behavioural, attentional or socialization deficits. We tested the hypothesis that complement activation plays a role in the cortical brain abnormalities in foetuses born preterm in a mouse model of inflammation-induced preterm labour. We also investigate potential treatments to prevent foetal cortical brain abnormalities and preterm birth.

Methods: We used a mouse model of inflammation-induced preterm birth (PTB) that resembles the spontaneous PTB clinical scenario. We also studied isolated foetal cortical neurons in culture. Non-invasive proton magnetic resonance spectroscopy (1HMRS) was used to study in vivo foetal brain metabolism in uterus. BOLD imaging was used to measure brain oxygenation. We detected complement C3 deposition by MRI in the foetal brains with anti-C3 antibodies conjugated with superparamagnetic iron oxide (SPIO) particles. All mouse studies were conducted in accordance with Home Office welfare and ethical regulations

Results: Increased C3 deposition and increased C5a levels were observed in foetal brains in PTB compared to age-matched control. Disruption of cortical dendritic and axonal cytoarchitecture was observed in PTB-mice. Genetically deletion of C5aR and treatment with anti-C5 antibody prevented cortical foetal brain injury in PTB-mice. Fetal cortical neurons exposed to C5a showed increased glutamate (Glu) release ((nmol/ml) (5.94±0.7 vs 2.93±0.6 in untreated cells) and abnormal development and survival in vitro. Blockade of C5aR and Glu receptor restored neurons growth and survival in these cells. MRI studies showed decreased oxygenation and increased Glu levels in PTB-foetuses compared to age-matched controls (1HMRS :Glu/tCR (ppm): 1.49±0.32 vs 1.00±0.16 ppm). Simvastatin and pravastatin prevented cortical foetal brain developmental and metabolic abnormalities -in vivo and in vitro. Statins also prevented myometrial contractions that contribute to brain damage by reperfusion–ischaemic episodes. Akt/PKB signaling pathways played a role in the neuroprotective effects of statins.

Conclusion: This study shows that complement activation plays a crucial role in cortical foetal brain injury in PTL and suggests that complement inhibitors and statins might be good therapeutic options to improve neonatal outcomes in preterm birth. Clinical trials should be organized to confirm these studies in humans.

Corresponding author:

This work was supported by the Jennifer Brown Research Fund.

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