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Translational Stroke Research

, Volume 3, Issue 3, pp 364–368 | Cite as

Minocycline Prevents IL-6 Increase after Acute Ischemic Stroke

  • Jeffrey A. SwitzerEmail author
  • Andrea Sikora
  • Adviye Ergul
  • Jennifer L. Waller
  • David C. Hess
  • Susan C. Fagan
Brief Communication

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 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 

Notes

Acknowledgments

This study was supported by the NIH/NINDS grants (DCH, R01 NS055728; SCF, RO1 NS063965; and AE, R21 NS070239), AHA EIA (AE, 0740002N), and the MCG Intramural Grants Program Scientist Training Program to JAS.

References

  1. 1.
    Whiteley W, Jackson C, Lewis S, Lowe G, Rumley A, Sandercock P, Wardlaw J, Dennis M, Sudlow C. Inflammatory markers and poor outcome after stroke: a prospective cohort study and systematic review of interleukin-6. PLoS Med. 2009;6:e1000145.PubMedCrossRefGoogle Scholar
  2. 2.
    Fagan SC, Waller JL, Nichols FT, Edwards DJ, Pettigrew LC, Clark WM, Hall CE, Switzer JA, Ergul A, Hess DC. Minocycline to improve neurologic outcome in stroke (minos): a dose-finding study. Stroke. 2010;41:2283–7.PubMedCrossRefGoogle Scholar
  3. 3.
    Switzer JA, Hess DC, Ergul A, Waller JL, Machado LS, Portik-Dobos V, Pettigrew LC, Clark WM, Fagan SC. Matrix metalloproteinase-9 in an exploratory trial of intravenous minocycline for acute ischemic stroke. Stroke. 2011;42:2633–5.PubMedCrossRefGoogle Scholar
  4. 4.
    Welsh P, Barber M, Langhorne P, Rumley A, Lowe GD, Stott DJ. Associations of inflammatory and haemostatic biomarkers with poor outcome in acute ischaemic stroke. Cerebrovasc Dis. 2009;27:247–53.PubMedCrossRefGoogle Scholar
  5. 5.
    Waje-Andreassen U, Krakenes J, Ulvestad E, Thomassen L, Myhr KM, Aarseth J, Vedeler CA. Il-6: an early marker for outcome in acute ischemic stroke. Acta Neurol Scand. 2005;111:360–5.PubMedCrossRefGoogle Scholar
  6. 6.
    Tuttolomondo A, Pecoraro R, Pinto A, Licata G. A precise stroke classification for evaluation of ischemic stroke subtypes and their relation with diabetes: is toast the best? Stroke. 2011;42:e10.PubMedCrossRefGoogle Scholar
  7. 7.
    Sotgiu S, Barone R, Zanda B, Arru G, Fois ML, Arru A, Rosati G, Marchetti B, Musumeci S. Chitotriosidase in patients with acute ischemic stroke. Eur Neurol. 2005;54:149–53.PubMedCrossRefGoogle Scholar
  8. 8.
    Rallidis LS, Vikelis M, Panagiotakos DB, Rizos I, Zolindaki MG, Kaliva K, Kremastinos DT. Inflammatory markers and in-hospital mortality in acute ischaemic stroke. Atherosclerosis. 2006;189:193–7.PubMedCrossRefGoogle Scholar
  9. 9.
    Licata G, Tuttolomondo A, Di Raimondo D, Corrao S, Di Sciacca R, Pinto A. Immuno-inflammatory activation in acute cardio-embolic strokes in comparison with other subtypes of ischaemic stroke. Thromb Haemost. 2009;101:929–37.PubMedGoogle Scholar
  10. 10.
    Castellanos M, Sobrino T, Pedraza S, Moldes O, Pumar JM, Silva Y, Serena J, Garcia-Gil M, Castillo J, Davalos A. High plasma glutamate concentrations are associated with infarct growth in acute ischemic stroke. Neurology. 2008;71:1862–8.PubMedCrossRefGoogle Scholar
  11. 11.
    Basic Kes V, Simundic AM, Nikolac N, Topic E, Demarin V. Pro-inflammatory and anti-inflammatory cytokines in acute ischemic stroke and their relation to early neurological deficit and stroke outcome. Clin Biochem. 2008;41:1330–4.PubMedCrossRefGoogle Scholar
  12. 12.
    Fassbender K, Rossol S, Kammer T, Daffertshofer M, Wirth S, Dollman M, Hennerici M. Proinflammatory cytokines in serum of patients with acute cerebral ischemia: kinetics of secretion and relation to the extent of brain damage and outcome of disease. J Neurol Sci. 1994;122:135–9.PubMedCrossRefGoogle Scholar
  13. 13.
    Yrjanheikki J, Keinanen R, Pellikka M, Hokfelt T, Koistinaho J. Tetracyclines inhibit microglial activation and are neuroprotective in global brain ischemia. Proc Natl Acad Sci U S A. 1998;95:15769–74.PubMedCrossRefGoogle Scholar
  14. 14.
    Emsley HC, Smith CJ, Gavin CM, Georgiou RF, Vail A, Barberan EM, Hallenbeck JM, del Zoppo GJ, Rothwell NJ, Tyrrell PJ, Hopkins SJ. An early and sustained peripheral inflammatory response in acute ischaemic stroke: relationships with infection and atherosclerosis. J Neuroimmunol. 2003;139:93–101.PubMedCrossRefGoogle Scholar
  15. 15.
    Salobir B, Sabovic M. Possible vascular-bed-specific role of interleukin-6 in young women with a history of myocardial infarction, lacunar cerebral infarction and deep vein thrombosis. Cytokine. 2004;25:265–72.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Jeffrey A. Switzer
    • 1
    Email author
  • Andrea Sikora
    • 4
  • Adviye Ergul
    • 2
    • 3
    • 4
    • 5
  • Jennifer L. Waller
    • 3
  • David C. Hess
    • 1
    • 4
  • Susan C. Fagan
    • 1
    • 4
    • 5
  1. 1.Department of NeurologyGeorgia Health Sciences UniversityAugustaUSA
  2. 2.Department of PhysiologyGeorgia Health Sciences UniversityAugustaUSA
  3. 3.Department of BiostatisticsGeorgia Health Sciences UniversityAugustaUSA
  4. 4.Program in Clinical and Experimental Therapeutics, College of PharmacyUniversity of GeorgiaAugustaUSA
  5. 5.Charlie Norwood VA Medical CenterAugustaUSA

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