The Novel C5aR Antagonist DF3016A Protects Neurons Against Ischemic Neuroinflammatory Injury
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
DOI:
10.1007/s12640-019-00026-w
Publication Date:
2019-04-05T16:04:30Z
AUTHORS (10)
ABSTRACT
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.
SUPPLEMENTAL MATERIAL
Coming soon ....
REFERENCES (60)
CITATIONS (24)
EXTERNAL LINKS
PlumX Metrics
RECOMMENDATIONS
FAIR ASSESSMENT
Coming soon ....
JUPYTER LAB
Coming soon ....