The Novel C5aR Antagonist DF3016A Protects Neurons Against Ischemic Neuroinflammatory Injury

• Published in: Neurotoxicity research Vol. 36; no. 1; pp. 163 - 174
• Main Authors: Brandolini, Laura, Grannonico, Marta, Bianchini, Gianluca, Colanardi, Alessia, Sebastiani, Pierluigi, Paladini, Antonella, Piroli, Alba, Allegretti, Marcello, Varrassi, Giustino, Di Loreto, Silvia
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.07.2019
• Subjects: Animals; Biomedical and Life Sciences; Biomedicine; Brain Ischemia - complications; Cell Biology; 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; Neurobiology; Neurochemistry; Neurology; Neurons - drug effects; Neuroprotective Agents - pharmacology; Neurosciences; Original; Original Article; Pharmacology/Toxicology; Receptor, Anaphylatoxin C5a - antagonists & inhibitors; Receptor, Anaphylatoxin C5a - metabolism; Neuroinflammation; Complement; Pain; Cytokines; Cortical neurons; C5a
• DOI: 10.1007/s12640-019-00026-w
• ISSN: 1029-8428

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.