Minocycline Prevents IL-6 Increase after Acute Ischemic Stroke
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Minocycline Prevents IL-6 Increase after Acute Ischemic Stroke Jeffrey A. Switzer & Andrea Sikora & Adviye Ergul & Jennifer L. Waller & David C. Hess & Susan C. Fagan
Received: 5 January 2012 / Revised: 23 February 2012 / Accepted: 29 February 2012 / Published online: 15 March 2012 # Springer Science+Business Media, LLC 2012
Abstract Higher levels of the inflammatory biomarker interleukin-6 (IL-6) correlate with poor clinical outcome in acute ischemic stroke (AIS). Minocycline (MC) is a known anti-inflammatory agent; thus, the effect of MC on IL-6 in the first 24 h of AIS was investigated to determine potential anti-inflammatory activity. The Minocycline to Improve Neurologic Outcome in Stroke (MINOS) study was a non-randomized dose-escalation (3.0–10.0 mg/kg) trial of IV MC for AIS within 6 h of onset. Plasma IL-6 samples were collected prior to MC treatment at 1, 24, and 72 h and compared to those collected in a separate observational study of blood biomarkers in AIS. IL-6 levels were measured by commercially available ELISA kits. The lower limit of detection for IL-6 was 1 pg/ml. Sixty MINOS subjects J. A. Switzer (*) : D. C. Hess : S. C. Fagan Department of Neurology, Georgia Health Sciences University, 1120 15th St, Augusta, GA 30912, USA e-mail: [email protected] A. Ergul Department of Physiology, Georgia Health Sciences University, Augusta, GA 30912, USA A. Ergul : J. L. Waller Department of Biostatistics, Georgia Health Sciences University, Augusta, GA 30912, USA A. Sikora : A. Ergul : D. C. Hess : S. C. Fagan Program in Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia, Augusta, GA 30912, USA A. Ergul : S. C. Fagan Charlie Norwood VA Medical Center, Augusta, GA 30912, USA
and 29 non-MINOS subjects were enrolled, and there was no difference in baseline stroke severity. There was no significant difference in IL-6 level pre-MC treatment at 1, 24, or 72 h. However, the odds of a non-detectable IL-6 at 24 h in MINOS were 8.94 (95% CI 2.62–30.46) compared with non-MINOS subjects. It is likely that even low doses of MC have a potent systemic anti-inflammatory effect in AIS. Whether this results in improved outcome will be tested in a randomized clinical trial. Keywords Acute cerebral infarction . Emergency treatment of stroke . Inflammation . Interleukin-6 . Biomarkers
Introduction Post-stroke inflammation as characterized by elevated levels of inflammatory mediators, including interleukin-6 (IL-6), is correlated with both stroke severity and poor clinical outcome, prompting an interest in using agents with known anti-inflammatory activity in the acute phase of ischemic stroke (AIS) [1]. Minocycline (MC) is a potent antiinflammatory agent with multiple mechanisms of action, a well-elucidated pharmacokinetic and safety profile, and compatibility with the only approved pharmacologic treatment for ischemic stroke (t-PA) [2, 3]. In this analysis, the relationship of intravenous MC administered to plasma IL-6 levels in AIS was investigated.
Methods Subjects Intrav
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