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

Autor:	Adam Kindelin, Andrew F. Ducruet, Kanchan Bhatia, Nasrul Hoda, Jennifer M. Eschbacher, Saif Ahmad, Chirayu D. Pandya, Rafay Chaudhary, Michael F. Waters, Alok Dwivedi, Qiang Liu
Rok vydání:	2020
Předmět:	0301 basic medicine medicine.medical_specialty medicine.medical_treatment Infarction Thromboembolic stroke Arginine Neuroprotection Mice 03 medical and health sciences 0302 clinical medicine Internal medicine Animals Medicine Thrombolytic Therapy Benzhydryl Compounds Stroke Pharmacology biology business.industry Antagonist Thrombolysis medicine.disease Research Papers 030104 developmental biology biology.protein Cardiology C3a receptor business Adjuvant 030217 neurology & neurosurgery
Zdroj:	Br J Pharmacol
ISSN:	1476-5381 0007-1188
Popis:	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.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::2b253af5cb5ecb3ead145346160d7862 https://doi.org/10.1111/bph.14989 Zobrazit plný text záznamu Plný text ve formátu PDF Plný text ve formátu HTML
Nepřihlášeným uživatelům se plný text nezobrazuje	K zobrazení výsledku je třeba se přihlásit.