Different cytokine levels in thrombolysis patients as predictors for clinical outcome G. Mazzotta a , P. Sarchielli a , V. Caso a , M. Paciaroni a , A. Floridi b , A. Floridi b and V. Gallai a a Stroke Unit, Department of Neuroscience, University of Perugia; and b Department of Internal Medicine, Institute of Clinical and Applied Biochemistry, University of Perugia, Perugia, Italy Keywords: cytokine, inflammation, NINDS, thrombolysis Received 21 July 2003 Accepted 10 November 2003 Thrombolytic therapy not always improves clinical outcome in ischemic stroke patients. This could cause lymphomonocyte accumulation in the infarcted brain area. These produce an excessive amount of proinflammatory cytokines, such as IL-1beta, IL-6 and TNF-alfa. The aim of our study was to determine ILs levels in fibrinolytic therapy treated patients, compared with healthy controls and to evaluate if the varying levels can predictors of neurological outcome. Eighteen patients underwent throm- bolytic treatment with t-PA within 3 h. Plasma levels of IL-1beta, IL-6, TNF-alfa and IL-10 were determined by ELISA method before and within 24 h after t-PA infusion and compared with controls. Significantly higher levels of IL-1beta and Il-6 emerged in stroke patients before treatment compared with the control group (P < 0.05 and 0.04, respectively). Slightly higher plasma levels of TNF-alfa and lower plasma levels of IL-10 were also found at base line in stroke patients. After thrombolytic treatment no significant variations were observed in the levels of TNF-alfa and IL-6, whereas a trend toward lower values for IL-1beta and higher levels for IL-10 was observed. Positive correlations among the values of IL-6, TNF-alfa and National Institute of Health Stroke Scale (NIHSS) at discharges were observed. A similar correlation with modified Rankin scale score at 3 month was found. Pre-treatment cytokine status seems to influence pre-and long-term clinical outcome. Therefore an investigation into the possible predictor of cytokines seem worthy. Introduction Intravenous thrombolysis has been shown to improve stroke patient outcome, despite an increased rate of symptomatic intracerebral hemorrhage (The National Institute of Neurological Disorders and Stroke rtPA Stroke Study group (NINDS), 1995; Grond et al., 1998; Albers et al., 2000; Buchan et al., 2000; Hill et al., 2000; Marler et al., 2000). Often, an abnormal inflammatory response to ischemic brain injury induces a lack of ischemic tissue reperfusion during recanalization or the Ôno-refoldÕ defect (del Zoppo et al., 1991). Lymphomonocytes accumulating in the infarcted brain area produce a great amount of proinflammatory cytokines, such as IL-1b and TNF-a, which can directly or indirectly contribute to ischemic damage (Kim, 1996; Clark, 1997; van Lookeren Campagne et al., 1999; Frijns and Kap- pelle, 2002). Activated microglia seems to be the major source of TNF-a and astrocytes seem to be the major source of IL-1b (Becker, 1998). Stroke progression also seems to depend on IL-6. The result is a proinflam- matory and prothrombotic cerebral endothelium that contributes to secondary damage, involving the pen- umbra area, primarily in the reperfusion phase. Although experimental studies based on the modula- tion of pro-inflammatory cytokines have shown neu- roprotection, there are no current clinical anticytokine treatment studies for stroke. The anti-inflammatory cytokine IL-10 (Strle et al., 2001) plays different role in stroke. This cytokine pre- vents cellular apoptotic events induced by glutamate overload and neural death after excitotoxic insult. Whereas IL-10 knockout mice seem to be more vulnerable to the in vitro damage induced by N-methyl- D-aspartate (NMDA) receptors (Grilli et al., 2000). Lower IL-10 levels emerged in patients with stroke and its down-regulation seems to be accompanied by the up- regulation of TNF-a, with an unfavorable prognostic value (Perini et al., 2001). Subjects with low IL-10 production have an increased risk of stroke (van Exel et al., 2002). It became evident in recent years that stroke patients are heterogeneous not only with respect to etiology but also with regard to their baseline status at the time of stroke. The aim of our study was to determine the effect of peripheral pro-inflammatory cytokines levels (IL-1b, Correspondence: Valeria Caso, Department of Neuroscience, University of Perugia, Via E. dal Pozzo, 06126 Perugia, Italy (fax: 0039/075/5783583870; e-mail: vcaso@hotmail.com). Ó 2004 EFNS 377 European Journal of Neurology 2004, 11: 377–381