Abstract TP320: The Novel Potent Complement C3a Receptor (C3aR) Antagonist JR14a Confers Robust Neuroprotection in Stroke

Abstract

Background: The complement C3a receptor (C3aR) plays a prominent role in deleterious post-stroke neuroinflammation. We and others have shown that either genetic deficiency of C3aR or its pharmacological inhibition in rodents protects against ischemic brain injury. Several limitations of the existing C3aR antagonist (SB290157) limit its translational potential. We therefore sought to evaluate a novel C3aR inhibitor in experimental stroke. Hypothesis: The novel C3aR inhibitor JR14a will confer more robust neuroprotection than SB290157 in experimental models of stroke. Methods: Mouse primary cortical neurons and primary endothelial cells were seeded at a density of 5000 cells/well in 96-well plates. Oxygen-glucose deprivation (OGD) followed by reperfusion was used to compare JR14a and SB290157 in terms of neuronal/endothelial cytotoxicity evaluated using MTT assay. We also compared JR14a and SB290157 by evaluating infarct volume using MRI/TTC in both photothrombotic (PT) and embolic stroke models in C57Bl6 mice. Results: JR14a-treated cortical neurons/endothelial cells demonstrated reduced cell death following OGD. JR14a treatment reduced phosphorylation of ERK/STAT3 in cortical neurons following OGD/R relative to SB290157. JR14a also significantly reduced brain infarction relative to SB290157 following PT and embolic stroke. Conclusion: Here, we conclude that JR14a attenuates neuroinflammation in stroke and may be more potent than existing C3aR antagonists. Additional work is warranted to investigate the neuroprotective properties of JR14a in stroke.