The Novel C5aR Antagonist DF3016A Protects Neurons Against Ischemic Neuroinflammatory Injury

Neurotox Res. 2019 Jul;36(1):163-174. doi: 10.1007/s12640-019-00026-w. Epub 2019 Apr 5.


The central nervous system (CNS) constitutively expresses complement (C) membrane receptors and complement proteins, including the component C5a. This is a crucial terminal effector of the C cascade, mostly involved in pain and neuroinflammatory conditions. Aberrant activation of C5a protein and its receptor C5aR has been reported to play a critical role in neurodegenerative diseases, with important clinical consequences. Here we have investigated the effects of DF3016A, a novel selective C5aR antagonist, able to penetrate the blood-brain barrier (BBB), on cortical neurons exposed to oxygen-glucose deprivation-reoxygenation (OGD/R), a neuroinflammation-related process. We demonstrated that a mild ischemic insult induces an early upregulation of C5aR associated with the over-production of pro-inflammatory cytokines and the over-expression of the transcriptional regulatory factor miR-181. Furthermore, we report the first experimental evidence of the effect of DF3016A, modulating complement component C5a, on neurons in a model of injury. Interestingly, DF3016A protects neuronal viability by restoring intracellular calcium levels, thus opposing the increase in pro-inflammatory cytokine levels and miR-181 expression. Based on our results, we suggest that DF3016A is a novel C5aR antagonist promoting protective effects against OGD/R-induced damage that could be a new therapeutic approach to controlling CNS neuroinflammatory conditions.

Keywords: C5a; Complement; Cortical neurons; Cytokines; Neuroinflammation; Pain.

MeSH terms

  • Animals
  • Brain Ischemia / complications*
  • Cell Survival / drug effects
  • Cells, Cultured
  • Complement C5a / metabolism
  • Encephalitis / etiology
  • Encephalitis / prevention & control*
  • Humans
  • Inflammation Mediators / metabolism
  • Male
  • Mice, Inbred BALB C
  • MicroRNAs / metabolism
  • Neurons / drug effects*
  • Neuroprotective Agents / pharmacology*
  • Receptor, Anaphylatoxin C5a / antagonists & inhibitors*
  • Receptor, Anaphylatoxin C5a / metabolism


  • C5AR1 protein, human
  • Inflammation Mediators
  • MIRN-181 microRNA, human
  • MicroRNAs
  • Neuroprotective Agents
  • Receptor, Anaphylatoxin C5a
  • Complement C5a