Abstract 15: The Novel Complement C3ar Antagonist Jr14a Is Neuroprotective In Stroke

• Published in: Stroke (1970) Vol. 53; no. Suppl_1
• Main Authors: Ahmad, Saif, Kindelin, Adam, Wang, Kendra, Lambay, Ateeq, Karra, Sakshi, Miller, Karis, Bhatia, Kanchan, Fairlie, David P, Ahmad, Abdullah S, Waters, Michael F, Ducruet, Andrew F
• Format: Journal Article
• Language: English
• Published: 01.02.2022
• ISSN: 0039-2499; 1524-4628
• DOI: 10.1161/str.53.suppl_1.15

Abstract only Background: Stroke is the third leading cause of disability and mortality in the world. The c omplement C3a receptor plays a prominent role in post stroke brain inflammation. We and others have reported that either genetic deficiency of complement C3a receptor (C3aR) or its pharmacological inhibition in rodents protect against cerebral ischemia. The existing C3aR antagonist (SB290157) is limited by its reported agonist effect in different model systems. Hypothesis: The novel highly-selective C3aR antagonist JR14a confers robust neuroprotection in stroke Methods: Mouse primary brain endothelial cells (cell biologics Inc. IL, USA) were seeded at a density of 5000 cells/well in 96-well plates and cultured until 80-90% confluency. Endothelial cytotoxicity was tested using an LDH assay following 24 hours of exposure to JR14a. Oxygen-glucose deprivation (OGD) was followed by reperfusion to compare the in-vitro effects of JR14a and SB290157, using ELISA performed for TNF-α and IL-6 and immunofluorescence for ICAM-1 expression. We also compared JR14a and SB290157 in the middle cerebral artery occlusion (MCAO, C57BL/6) stroke model, evaluating infarct volume. Results: JR14a treated endothelial cells exhibited reduced LDH release (Fig.1) and more potent anti-inflammatory response following OGD/R compared to SB290157. We found that JR14a treatment significantly reduced endothelial TNF-α, IL-6 and ICAM-1 expression. JR14a also significantly reduced brain infarction and microglial activation relative to SB290157 following MCAO in C57BL/6 mice (Fig 2). Conclusion: We conclude that the novel C3aR inhibitor JR14a attenuates inflammation and endothelial dysfunction in stroke and may confer a more potent neuroprotective effect than SB290157. Further work is warranted to explore the mechanisms underlying JR14a-mediated neuroprotection