Background: Early inflammation has been suggested as an important factor contributing to unfavorable prognosis after acute ischemic stroke. The present study aimed to clarify the temporal dynamics of discrete inflammatory markers/mediators for future mechanism-targeting anti-inflammatory strategies in ischemic brain damage. Methods: Blood samples of 69 patients with transient ischemic attack or ischemic stroke were taken upon admission and at time points 6, 12 and 24 h, as well as 3 and 7 days after symptom onset for analysis of monocyte chemotactic protein-1 (MCP-1), matrix metalloproteinase-9 (MMP-9), tissue inhibitor of matrix metalloproteinase-1 (TIMP-1), interleukin-6 (IL-6), C-reactive protein (CRP) and the brain damage marker S100B. Clinical scores (modified Rankin Scale, National Institute of Health Stroke Scale) were assessed on day 90. Results: MCP-1, MMP-9, TIMP-1, IL-6, CRP and S100B showed significantly different time courses depending on stroke outcome. While the levels of IL-6, MCP-1 and MMP-9 increased already a few hours after symptom onset, CRP and S100B gradually rose commencing at 12–24 h. TIMP-1 demonstrated an extended plateau. By multiple linear regression analysis IL-6, MCP-1, TIMP-1 and S100B were determined to be independently related to clinical outcome scores at specific time points. Conclusions: Our data show important differences in the early time course of several potential markers for the complex network of inflammation and brain damage after ischemic stroke depending on stroke outcome. This must be considered for any therapeutical approach using anti-inflammatory treatment.

Asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase (NOS) inhibitor, is known as mediator of endothelial cell dysfunction and atherosclerosis. Circulating ADMA levels are correlated with cardiovascular risk factors such as hypercholesterolemia, arterial hypertension, diabetes mellitus, hyperhomocysteinemia, age and smoking. Accordingly, clinical studies found evidence that increased ADMA levels are associated with a higher risk of cerebrovascular events. After the acute event of ischemic stroke, levels of ADMA and its analog symmetric dimethylarginine (SDMA) are elevated through augmentation of protein methylation and oxidative stress. Furthermore, cleavage of ADMA through dimethylarginine dimethylaminohydrolases (DDAHs) is reduced. This increase of dimethylarginines might be predictive for adverse clinical outcome. However, the definite role of ADMA after acute ischemic stroke still needs to be clarified. On the one hand, ADMA might contribute to brain injury by reduction of cerebral blood flow. On the other hand, ADMA might be involved in NOS-induced oxidative stress and excitotoxic neuronal death. In the present review, we highlight the current knowledge from clinical and experimental studies on ADMA and its role for stroke risk and ischemic brain injury in the hyperacute stage after stroke. Finally, further studies are warranted to unravel the relevance of the close association of dimethylarginines with stroke.

Ischemic stroke patients are prone to infection by stroke-induced immunodepression. We hypothesized that levels of lipopolysaccharide binding protein (LBP), interleukin-10 (IL-10), IL-6 and C-reactive protein (CRP) are early predictors for the development of stroke-associated infection. Fifty-six patients with ischemic stroke (n = 51) and transient ischemic attack (TIA) (n = 5) who presented within 6 hours after symptom onset and who were free of detectable infection on admission were included in the study. Of these, 20 developed early infections during the first week. Blood samples were taken at 6, 12, and 24 hours and at 3 and 7 days after stroke onset. Levels of LBP, Il-10, IL-6 and CRP, as well as S100B, were measured as markers of inflammation and brain damage by commercially available immunometric tests. In the univariate analysis, levels of LBP, IL-10, IL-6 and CRP significantly differed between patients who developed an infection and those who did not. In the binary logistic regression analysis, which was adjusted for National Institutes of Health Stroke Scale (NIHSS) on admission, stroke subtype and S100B peak levels, as indicator of the extent of brain damage, IL-10 at 6 hours, CRP at 6 hours and NIHSS on admission were identified as independent predictors of infection (IL-10: P = 0.009; CRP: P = 0.018; NIHSS: P = 0.041). The area under the curve (AUC) of the receiver operating characteristic (ROC) curves in relation to the dichotomized status of the infection (infection versus no infection) was 0.74 (95% confidence interval: 0.59 to 0.88) for CRP at 6 hours, 0.76 (0.61 to 0.9) for IL-10 at 6 hours, 0.83 (0.71 to 0.94) for NIHSS on admission and 0.94 (0.88 to 1) for the combination of CRP, IL-10 and NIHSS. In a subanalysis, 16 patients with early infections were matched with 16 patients without infection according to S100B peak levels. Here, the temporal pattern of LBP, IL-10, IL-6 and CRP significantly differed between the patient groups. Our data show that blood levels of inflammation markers may be used as early predictors of stroke-associated infection. We propose prospective studies to investigate if the calculated cut-offs of CRP, IL-10 and NIHSS might help to identify patients who should receive early preventive antibiotic treatment.

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The amino acid L-arginine serves as substrate for the nitric oxide synthase which is crucial in vascular function and disease. Derivatives of arginine, such as asymmetric (ADMA) and symmetric dimethylarginine (SDMA), are regarded as markers of endothelial dysfunction and have been implicated in vascular disorders. While there is a variety of studies consolidating ADMA as biomarker of cerebrovascular risk, morbidity and mortality, SDMA is currently emerging as an interesting metabolite with distinct characteristics in ischemic stroke. In contrast to dimethylarginines, homoarginine is inversely associated with adverse events and mortality in cerebrovascular diseases and might constitute a modifiable protective risk factor. This review aims to provide an overview of the current evidence for the pathophysiological role of arginine derivatives in cerebrovascular ischemic diseases. We discuss the complex mechanisms of arginine metabolism in health and disease and its potential clinical implications in diverse aspects of ischemic stroke.