The Novel C5aR Antagonist DF3016A Protects Neurons Against Ischemic Neuroinflammatory Injury

• DOI: 10.1007/s12640-019-00026-w
• Publication Date: 2019-04-05T16:04:30Z
• Authors: Laura Brandolini; Marta Grannonico; Gianluca Bianchini; Alessia Colanardi; Pierluigi Sebastiani; Antonella Paladini; Alba Piroli; Marcello Allegretti; Giustino Varrassi; Silvia Di Loreto
• Keywords: Male; Neurons; 0301 basic medicine; Mice, Inbred BALB C; 0303 health sciences; Cell Survival; Complement C5a; Brain Ischemia; 3. Good health; MicroRNAs; 03 medical and health sciences; Neuroprotective Agents; Neuroinflammation . Complement . C5a . Cortical neurons . Cytokines . Pain; Animals; Encephalitis; Humans; Original Article; Inflammation Mediators; Receptor, Anaphylatoxin C5a; Cells, Cultured

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.