C3a Receptor Inhibition Protects Brain Endothelial Cells Against Oxygen-glucose Deprivation/Reperfusion

Ahmad, Saif; Kindelin, Adam; Khan, Shah Alam; Ahmed, Maaz; Hoda, Nasrul; Bhatia, Kanchan; Ducruet, A

doi:10.5607/en.2019.28.2.216

Cited by 20 publications

(9 citation statements)

References 57 publications

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“…Treatment shortly after intracerebral hemorrhage accelerated neurological and cognitive recovery in mice [ 236 ]. In cell culture, oxygen-deprived endothelial cells treated with C3aRA have reduced cell death and activation of adhesion molecules (ICAM1), reduced phosphorylated ERK, and increased occludin, all suggesting preservation of BBB integrity [ 237 ]. It is important to note that the aforementioned C3aRA (SB290157) has been reported to have off-target activity, and in high doses may act as an agonist instead of antagonist [ 172 ].…”

Section: Strokementioning

confidence: 99%

The good, the bad, and the opportunities of the complement system in neurodegenerative disease

Schartz

Tenner

2020

J Neuroinflammation

173

183

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The complement cascade is a critical effector mechanism of the innate immune system that contributes to the rapid clearance of pathogens and dead or dying cells, as well as contributing to the extent and limit of the inflammatory immune response. In addition, some of the early components of this cascade have been clearly shown to play a beneficial role in synapse elimination during the development of the nervous system, although excessive complement-mediated synaptic pruning in the adult or injured brain may be detrimental in multiple neurogenerative disorders. While many of these later studies have been in mouse models, observations consistent with this notion have been reported in human postmortem examination of brain tissue. Increasing awareness of distinct roles of C1q, the initial recognition component of the classical complement pathway, that are independent of the rest of the complement cascade, as well as the relationship with other signaling pathways of inflammation (in the periphery as well as the central nervous system), highlights the need for a thorough understanding of these molecular entities and pathways to facilitate successful therapeutic design, including target identification, disease stage for treatment, and delivery in specific neurologic disorders. Here, we review the evidence for both beneficial and detrimental effects of complement components and activation products in multiple neurodegenerative disorders. Evidence for requisite co-factors for the diverse consequences are reviewed, as well as the recent studies that support the possibility of successful pharmacological approaches to suppress excessive and detrimental complement-mediated chronic inflammation, while preserving beneficial effects of complement components, to slow the progression of neurodegenerative disease.

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Section: Strokementioning

confidence: 99%

The good, the bad, and the opportunities of the complement system in neurodegenerative disease

Schartz

Tenner

2020

J Neuroinflammation

173

183

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“…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. )…”

Section: Discussionmentioning

confidence: 99%

The “C3aR Antagonist” SB290157 is a Partial C5aR2 Agonist

Kumar

Clark

et al. 2021

Front. Pharmacol.

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Innate immune complement activation generates the C3 and C5 protein cleavage products C3a and C5a, defined classically as anaphylatoxins. C3a activates C3aR, while C5a activates two receptors (C5aR1 and C5aR2) to exert their immunomodulatory activities. The non-peptide compound, SB290157, was originally reported in 2001 as the first C3aR antagonist. In 2005, the first report on the non-selective nature of SB290157 was published, where the compound exerted clear agonistic, not antagonistic, activity in variety of cells. Other studies also documented the non-selective activities of this drug in vivo. These findings severely hamper data interpretation regarding C3aR when using this compound. Unfortunately, given the dearth of C3aR inhibitors, SB290157 still remains widely used to explore C3aR biology (>70 publications to date). Given these issues, in the present study we aimed to further explore SB290157's pharmacological selectivity by screening the drug against three human anaphylatoxin receptors, C3aR, C5aR1 and C5aR2, using cell models. We identified that SB290157 exerts partial agonist activity at C5aR2 by mediating β-arrestin recruitment at higher compound doses. This translated to a functional outcome in both human and mouse primary macrophages, where SB290157 significantly dampened C5a-induced ERK signaling. We also confirmed that SB290157 acts as a potent agonist at human C3aR in transfected cells, but as an antagonist in primary human macrophages. Our results therefore provide even more caution against using SB290157 as a research tool to explore C3aR function. Given the reported immunomodulatory and anti-inflammatory activities of C5aR2 agonism, any function observed with SB290157 could be due to these off-target activities.

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“…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. )…”

Section: Discussionmentioning

confidence: 99%

The ‘C3aR antagonist’ SB290157 is a partial C5aR2 agonist

Kumar

Lee

et al. 2020

Preprint

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Innate immune complement activation generates the C3 and C5 protein cleavage products C3a and C5a, defined classically as anaphylatoxins. C3a activates C3a receptors (C3aR), while C5a activates two receptors (C5aR1 and C5aR2) to exert their immunomodulatory activities. The non-peptide compound, SB290157, was originally reported in 2001 as the first C3aR antagonist. In 2005, the first report on non-selective nature of SB290157 was published, where the compound exerted clear agonistic, not antagonistic, activity in variety of cells. Other studies also documented non-selective activities of this drug in vivo. These findings severely hamper data interpretation regarding C3aR when using this compound. Unfortunately, given the dearth of C3aR inhibitors, SB290157 still remains widely used to explore C3aR biology (>70 publications to date). Given these issues, in the present study we aimed to further explore SB290157's pharmacological selectivity by screening the drug against three human anaphylatoxin receptors, C3aR, C5aR1 and C5aR2, using transfected cells. We first confirmed that SB290157 acts as a potent agonist at human C3aR. We also identified that SB290157 exerts partial agonist activity at C5aR2 by mediating β-arrestin recruitment at higher compound doses. Notably, SB290157's activity at C5aR2 was more potent and efficacious than the current 'lead' C5aR2 agonist P32. Notwithstanding this, SB290157 showed inhibitory effect on C3a-mediated signalling in primary human macrophages. Our results therefore provide even more caution against using SB290157 as a research tool to explore C3aR function. Given the reported immunomodulatory and anti-inflammatory activities of C3aR and C5aR2 agonism, any function observed with SB290157 could be due to these off target activities.

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C3a Receptor Inhibition Protects Brain Endothelial Cells Against Oxygen-glucose Deprivation/Reperfusion

Cited by 20 publications

References 57 publications

The good, the bad, and the opportunities of the complement system in neurodegenerative disease

The good, the bad, and the opportunities of the complement system in neurodegenerative disease

The “C3aR Antagonist” SB290157 is a Partial C5aR2 Agonist

The ‘C3aR antagonist’ SB290157 is a partial C5aR2 agonist

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