C3a receptor antagonist therapy is protective with or without thrombolysis in murine thromboembolic stroke

Saif Ahmad, Chirayu Pandya, Adam Kindelin, Kanchan Bhatia, Rafay Chaudhary, Alok Kumar Dwivedi, Jennifer M. Eschbacher, Qiang Liu, Michael F. Waters, Md Nasrul Hoda, Andrew F. Ducruet

Research output: Contribution to journalArticlepeer-review

11 Scopus citations


Background and Purpose: Intravenous thrombolysis (IVT) after stroke enhances C3a generation, which may abrogate the benefits of reperfusion. The C3aR antagonist SB290157 is neuroprotective following transient but not permanent middle cerebral artery occlusion (MCAo). SB290157 remains untested in thromboembolic (TE) models, which better approximate human stroke and also facilitate testing in combination with IVT. We hypothesized SB290157 would confer neuroprotection in TE stroke with and without “late” IVT. Experimental Approach: We used two different models of TE stroke to examine the efficacy of SB290157 alone and in combination with late IVT. We evaluated the benefit of SB290157 in attenuating post-ischaemic behavioural deficits, infarction, brain oedema and haemorrhage. Key Results: Plasma C3a was elevated 6 hr after TE stroke alongside increased cerebrovascular C3aR expression, which was sustained to 4 weeks. Increased C3aR expression also was visualized in human ischaemic brain. In a photothrombotic (PT) stroke model, which exhibits rapid spontaneous reperfusion, SB290157 given at 1 hr post-PT significantly improved neurofunction and reduced infarction at 48 hr. In an embolic (eMCAo) model, SB290157 administered at 2 hr improved histological and functional outcomes. Conversely, late IVT administered 4.5 hr post-eMCAo was ineffective likely due to increased haemorrhage and brain oedema. However, SB290157 administered prior to late IVT ameliorated haemorrhage and oedema and improved outcomes. Conclusions and Implications: We conclude that SB290157 is safe and effective with and without late IVT following TE stroke. Therefore, C3a receptor antagonist therapy represents a promising candidate for clinical translation in stroke, particularly as an adjuvant to IVT.

Original languageEnglish
Pages (from-to)2466-2477
Number of pages12
JournalBritish Journal of Pharmacology
Issue number11
StatePublished - Jun 1 2020

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© 2020 The British Pharmacological Society

ASJC Scopus subject areas

  • Pharmacology


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