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Complement inhibition and statins prevent fetal brain cortical abnormalities in a mouse model of preterm birth

Author(s): S. M. Pedroni, J. M. Gonzalez, J. Wade, M. A. Jansen, A. Serio, I. Marshall, R. J. Lennen, G. Girardi

Premature babies are particularly vulnerable to brain injury. In this study we focus on cortical brain damage associated with long-term cognitive, behavioral, attentional or socialization deficits in children born preterm. Using a mouse model of preterm birth (PTB), we demonstrated that complement component C5a contributes to fetal cortical brain injury. Disruption of cortical dendritic and axonal cytoarchitecture was observed in PTB-mice. Fetuses deficient in C5aR (-/-) did not show cortical brain damage. Treatment with antibody anti-C5, that prevents generation of C5a, also prevented cortical fetal brain injury in PTB-mice. C5a also showed a detrimental effect on fetal cortical neuron development and survival in vitro. Increased glutamate release was observed in cortical neurons in culture exposed to C5a. Blockade of C5aR prevented glutamate increase and restored neurons dendritic and axonal growth and survival. Similarly, increased glutamate levels - measured by (1)HMRS - were observed in vivo in PTB-fetuses compared to age-matched controls. The blockade of glutamate receptors prevented C5a-induced abnormal growth and increased cell death in isolated fetal cortical neurons. Simvastatin and pravastatin prevented cortical fetal brain developmental and metabolic abnormalities -in vivo and in vitro. Neuroprotective effects of statins were mediated by Akt/PKB signaling pathways. This study shows that complement activation plays a crucial role in cortical fetal brain injury in PTL and suggests that complement inhibitors and statins might be good therapeutic options to improve neonatal outcomes in preterm birth.

Full version: Available here

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ISBN: 0006-3002 (Print)0006-3002 (Linking)
Publication Year: 2014
Periodical: Biochim Biophys Acta
Periodical Number: 1
Volume: 1842
Pages: 107-15
Author Address: MRC Centre for Reproductive Health, University of Edinburgh, Queen's Medical Research Institute, Edinburgh EH16 4TJ, UK.