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

Abstract

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.

The “C3aR Antagonist” SB290157 is a Partial C5aR2 Agonist

“…It is not uncommon for SB290157 to be used at doses higher than needed to block C3aR. For example, doses of 10–30 mg/kg SB290157 are commonly used in vivo ( Hutamekalin et al, 2010 ; Ahmad et al, 2020 ; Shu et al, 2020 ), and doses of 10 µM are used in vitro ( Ahmad et al, 2019 ; Litvinchuk et al, 2018 ). Based on prior pharmacokinetic reports as summarized in Table 1 , intravenous ( i.v. )…”

“…Functioning as a competitive C3aR antagonist ( Ames et al, 2001 ), SB290157 has served as a major pharmacological tool used to explore C3aR biology. For instance, SB290157 treatment was shown to improve survival in experimental lupus nephritis ( Bao et al, 2005 ), ameliorate anti-ovalbumin polyclonal antibody–induced arthritis ( Hutamekalin et al, 2010 ), reduce infarct volume in a model of thromboembolic stroke ( Ahmad et al, 2020 ), and rescue cognitive impairment in a model of Alzheimer's disease ( Lian et al, 2015 ). The promising results shown by administering SB290157 in these experimental models has heightened interest in C3aR blockade as a therapeutic strategy for diverse diseases.…”

The ‘C3aR antagonist’ SB290157 is a partial C5aR2 agonist

“…It is not uncommon for SB290157 to be used at doses higher than needed to block C3aR in in vivo studies. For example, doses of 10-30 mg/kg SB290157 are commonly used in vivo (12, 13, 39), and doses of 10 μM are used in vitro (40, 41). Based on prior pharmacokinetic reports as summarized in Table 1 , intravenous ( i.v. )…”

“…Functioning as a competitive C3aR antagonist (10), SB290157 has served as a major pharmacological tool used to explore C3aR biology. For instance, SB290157 treatment was shown to improve survival in experimental lupus nephritis (11), ameliorate anti-ovalbumin polyclonal antibody–induced arthritis (12), reduce infarct volume in a model of thromboembolic stroke (13), and rescue cognitive impairment in a model of Alzheimer’s disease (14). The promising results shown by administering SB290157 in these experimental models has heightened interest in C3aR blockade as a therapeutic strategy for diverse diseases.…”

Therapeutic Targeting of the Complement System: From Rare Diseases to Pandemics

“…There are several receptors that bind C3 fragments. The C3a molecule and its receptor C3aR are both therapeutic targets ( Ames et al, 2001 ; Lohman et al, 2017 ; Ahmad et al, 2020 ). C3a is generated as a result of activation of any of the three initiation pathways upon cleavage of C3.…”