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Published on: November 20, 2015
Complement inhibition and statins prevent fetal brain cortical abnormalities in a mouse model of preterm birth
Silvia M A Pedroni1, Juan M Gonzalez, Jean Wade
1MRC Centre for Reproductive Health, University of Edinburgh, Queen's Medical Research Institute, Edinburgh EH16 4TJ, UK.
Insights
Complement activation via C5a contributes to preterm brain injury by disrupting neuronal development. Inhibiting C5a or using statins may offer neuroprotection for preterm infants.
Area of Science:
- Neuroscience
- Immunology
- Developmental Biology
Background:
- Preterm birth (PTB) poses significant risks for neonatal brain injury, leading to long-term neurodevelopmental deficits.
- Cortical brain damage in preterm infants can manifest as cognitive, behavioral, attentional, and socialization impairments.
Purpose of the Study:
- To investigate the role of complement component C5a in fetal cortical brain injury associated with preterm birth.
- To explore potential therapeutic strategies, including complement inhibitors and statins, for preventing or mitigating this injury.
Main Methods:
- Utilized a mouse model of preterm birth (PTB).
- Assessed cortical brain damage, dendritic and axonal cytoarchitecture, and neuronal survival.
- Investigated the effects of C5a, C5a receptor (C5aR) blockade, glutamate levels, and statin treatment in vivo and in vitro.
- Employed (1)HMRS for in vivo glutamate level measurements.
Main Results:
- Preterm birth induced cortical brain damage, characterized by disrupted cytoarchitecture and reduced neuronal survival.
- C5a was identified as a key mediator of this injury, with C5aR deficiency or anti-C5 antibody treatment preventing damage.
- C5a exposure increased glutamate release and impaired neuronal development and survival, effects reversed by C5aR blockade.
- Statins (simvastatin and pravastatin) demonstrated neuroprotective effects, mediated by Akt/PKB signaling.
Conclusions:
- Complement activation, specifically via C5a, plays a critical role in fetal cortical brain injury following preterm birth.
- Targeting C5a (complement inhibitors) and utilizing statins show promise as therapeutic interventions to improve outcomes for preterm infants.
Abstract:
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.
