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Transl Stroke Res. 2019 Dec 6. doi: 10.1007/s12975-019-00757-0. [Epub ahead of print]

Complement C5 Contributes to Brain Injury After Subarachnoid Hemorrhage.

Author information

1
UMC Utrecht Brain Center, Department of Translational Neurosciences, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, Utrecht, The Netherlands.
2
UMC Utrecht Brain Center, Department of Neurology and Neurosurgery, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, Utrecht, The Netherlands.
3
Department of Experimental Vascular Medicine, Academic Medical Center, Meibergdreef 9, Amsterdam, The Netherlands.
4
Department of Plasma Proteins, Sanquin Research, Plesmanlaan 125, Amsterdam, The Netherlands.
5
Department of Neurology, Amsterdam Neuroscience, Academic Medical Center, Meibergdreef 9, Amsterdam, The Netherlands.
6
Systems Immunity Research Institute, Cardiff University, Heath Park, Cardiff, UK.
7
Department of Neurological Surgery, Aichi Medical University, 1-1 Karimatayazako, Aichi, Japan.
8
Department of Neuropathology, Academic Medical Center, Meibergdreef 9, Amsterdam, The Netherlands.
9
Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Medicinaregatan 9A, Gothenburg, Sweden.
10
Netherlands Institute for Neuroscience, Institute of the Royal Netherlands Academy of Arts and Sciences, Meibergdreef 47, Amsterdam, The Netherlands.
11
UMC Utrecht Brain Center, Department of Neurology and Neurosurgery, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, Utrecht, The Netherlands. m.d.i.vergouwen@umcutrecht.nl.

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.

KEYWORDS:

Aneurysmal subarachnoid hemorrhage; Brain injury; Complement system

PMID:
31811640
DOI:
10.1007/s12975-019-00757-0

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