Atherosclerosis 204 (2009) 315–320 Contents lists available at ScienceDirect Atherosclerosis journal homepage: www.elsevier.com/locate/atherosclerosis Strong complement activation after acute ischemic stroke is associated with unfavorable outcomes Gábor Széplaki a , Róbert Szegedi b , Kristóf Hirschberg c , Tímea Gombos a , Lilian Varga a , István Karádi a,c , László Entz b , Zoltán Széplaki b , Peter Garred d , Zoltán Prohászka a,e , George Füst a,d,∗ a 3rd Department of Internal Medicine, Semmelweis University, Budapest, Hungary b Department of Neurology, Kútvölgyi Clinical Centre, Semmelweis University, Budapest, Hungary c Department of Cardiovascular Surgery, Faculty of Medicine, Semmelweis University, Budapest, Hungary d Department of Clinical Immunology, Rigshospitalet, Sect. 7631, Copenhagen, Denmark e Research Group of Inflammation Biology and Immunogenomics, Hungarian Academy of Sciences, Budapest, Hungary article info Article history: Received 9 June 2008 Received in revised form 3 July 2008 Accepted 20 July 2008 Available online 14 August 2008 Keywords: Stroke Ischemic stroke Complement Complement activation C5b-5 C3a MBL C4d abstract Objective: According to data from animal models, complement activation plays a major role in the brain injury after acute ischemic stroke. Scarce findings are, however, available on the detection of complement activation products in stroke patients. Methods: We have measured plasma levels of the five complement activation products (C1rC1sC1inh, C4d, C3a, C5a and SC5b-9) in samples of 26 patients with ischemic stroke upon admission. Twenty-six patients with severe carotid atherosclerosis served as patient controls. Results: Levels of two activation products (SC5b-9 and C4d)) were significantly elevated in the plasma of stroke patients, SC5b-9 levels, exhibited significant positive correlation with the clinical severity of stroke, the severity of neurological deficit, as well as with the level of functional disability. Conclusion: These findings suggest that complement activation plays an active role in the development of brain infarct. The measurement of complement activation products might help to determine the clin- ical prognosis after acute ischemic stroke. Furthermore, there is potential usefulness of complement modulating therapy in ischemic stroke. © 2008 Elsevier Ireland Ltd. All rights reserved. 1. Introduction Increasing evidence shows that ischemic stroke is followed by a systemic acute inflammatory response of the host [1–3]. The complement system plays an essential and specific role in most pathological inflammatory events (up-regulation of adhe- sion molecules, PMN activation, chemotaxis, expression of IL-8 and MCP-1 by endothelial cells), which occur shortly after the ischemic insult [4]. The essential role of complement activation in microvascular failure and neuronal cell death in experimental models of perma- nent or transient middle cerebral artery occlusion (MCAO) was demonstrated as an increase in the expression of C3a and C5a recep- tors and presence of C1q and C3 in the core area [5,6]. ∗ Corresponding author at: 3rd Department of Internal Medicine, Faculty of Medicine, Semmelweis University, Kútvölgyi út 4, Budapest H-1125, Hungary. Tel.: +36 1 212 9351; fax: +36 1 225 3899. E-mail address: fustge@kut.sote.hu (G. Füst). Recent studies found milder pathological events to occur after the onset of cerebral ischemia, in complement-deficient than in- sufficient animals. After transient MCAO, C3 knock-out mice were partially protected as demonstrated by the significant reduction of both infarct volume and reduced oxidative stress [7]. Atkinson et al. [8] reported that compared to wild-type mice, C3-deficent animals exhibited significant improvement in survival, neurological deficit and infarct size 24h after MCAO and reperfusion. Most recently, Arumugam et al. [9] found that C5-deficient mice were significantly protected from I/R injury, compared to wild-type littermates. In rodent experimental models, complement inhibitors were proven to have beneficial, neuroprotective effects. Several stud- ies have evaluated the protective effect of specific complement inhibitors such as cobra venom factor (CVF) [10,11], C1-inhibitor [12,13] and CR2-Crry [8] in stroke models in rodents with positive effect. Recently, Arumugam et al. [9] demonstrated in mice that intravenous immunoglobulin (IVIG) protected the brain against experimental stroke, by preventing complement- mediated neuronal cell death. In contrast to the results obtained in rodents, administration of the complement inhibitor CR1 did 0021-9150/$ – see front matter © 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.atherosclerosis.2008.07.044