Complement C5 Contributes to Brain Injury After Subarachnoid Hemorrhage

Bart J Van Dijk,Gabriel J.E Rinkel,Joost C.M Meijers,B Paul Morgan,Marcela Pekna,Diederik Van De Beek,Marije J Van Der Kamp,Matthijs Brouwer,Anne T Kloek,Eleonora Aronica,Veronique L Knaup,Ynte M Ruigrok,Elly M Hol,Koji Osuka,Mervyn D.I Vergouwen

doi:10.1007/s12975-019-00757-0

Abstract

Previous studies showed that complement activation is associated with poor functional outcome after aneurysmal subarachnoid hemorrhage (SAH). We investigated whether complement activation is underlying brain injury after aneurysmal SAH (n = 7) and if it is an appropriate treatment target. We investigated complement expression in brain tissue of aneurysmal SAH patients (n = 930) and studied the role of common genetic variants in C3 and C5 genes in outcome. We analyzed plasma levels (n = 229) to identify the functionality of a single nucleotide polymorphism (SNP) associated with outcome. The time course of C5a levels was measured in plasma (n = 31) and CSF (n = 10). In an SAH mouse model, we studied the extent of microglia activation and cell death in wild-type mice, mice lacking the C5a receptor, and in mice treated with C5-specific antibodies (n = 15 per group). Brain sections from aneurysmal SAH patients showed increased presence of complement components C1q and C3/C3b/iC3B compared to controls. The complement component 5 (C5) SNP correlated with C5a plasma levels and poor disease outcome. Serial measurements in CSF revealed that C5a was > 1400-fold increased 1 day after aneurysmal SAH and then gradually decreased. C5a in plasma was 2-fold increased at days 3–10 after aneurysmal SAH. In the SAH mouse model, we observed a ≈ 40% reduction in both microglia activation and cell death in mice lacking the C5a receptor, and in mice treated with C5-specific antibodies. These data show that C5 contributes to brain injury after experimental SAH, and support further study of C5-specific antibodies as novel treatment option to reduce brain injury and improve prognosis after aneurysmal SAH.

Highlights

Aneurysmal subarachnoid hemorrhage (SAH) is a devastating subtype of stroke, caused by rupture of an aneurysm of an intracranial artery in the subarachnoid space
We evaluated the association between common complement component polymorphisms and functional outcome and delayed cerebral ischemia, and elucidated the time-course of complement activation in CSF and plasma after SAH using serial measurements
The component 5 (C5) rs17611 allele A was associated with poor functional outcome, but not with delayed cerebral ischemia

Summary

Introduction

Aneurysmal SAH is a devastating subtype of stroke, caused by rupture of an aneurysm of an intracranial artery in the subarachnoid space. The prognosis after aneurysmal SAH has improved over the last decades, 90-day case fatality is still around 30% in hospital-based studies [1]. The most important determinant of poor functional outcome after aneurysmal SAH is early brain injury directly related to the initial bleeding [1, 2]. Other major determinants of poor functional outcome are rebleeding of the aneurysm and delayed cerebral ischemia, which may occur 4–14 days after the initial hemorrhage [1, 3]. No treatment exists for early brain injury, while the effect of calcium antagonist nimodipine in preventing delayed cerebral ischemia is only modest [4]. New treatment options are needed to reduce brain injury after SAH

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