Complement anaphylatoxin C5a neuroprotects through mitogen‐activated protein kinase‐dependent inhibition of caspase 3

We previously reported that pretreatment of murine cortico‐hippocampal neuronal cultures with the complement‐derived anaphylatoxin C5a, protects against glutamate neurotoxicity. In this study we explored the potential mechanisms involved in C5a‐mediated neuroprotection. We found that C5a neuroprotects in vitro through inhibition of apoptotic death because pretreatment with human recombinant (hr)C5a prevented nuclear DNA fragmentation coincidental to inhibition of the pro‐apoptotic caspase 3 activity mediated by glutamate treatment. Also, hrC5a‐mediated responses appeared to be receptor‐mediated because pretreatment of cultures with the specific C5a receptor antagonist C177, prevented hrC5a‐mediated neuroprotection. Based on this evidence, we further explored possible signaling pathways involved in hrC5a inhibition of caspase 3 activation and apoptotic neuronal death. We found that treatment of cultures with the mitogen‐activated protein kinase (MAPK) pathway inhibitor PD98059 prevented hrC5a‐mediated inhibition of caspase 3 and apoptotic neuron death. MAPK pathways, whose activation by hrC5a is inhibited by PD98059 and C177, include the extracellular signal‐regulated kinase (ERK)2 and, to a lesser extent, ERK1. The study suggests that C5a may protect against glutamate‐induced apoptosis in neurons through MAPK‐mediated regulation of caspase cascades.