Skip to main content

Advertisement

SpringerLink
Log in

Minocycline Development for Acute Ischemic Stroke

  • Original Article
  • Published:
Translational Stroke Research Aims and scope Submit manuscript

Abstract

Minocycline, a tetracycline antibiotic, has shown anti-inflammatory, anti-apoptotic, and neuroprotective effects in many models of cerebral ischemia and neurodegenerative disease. Its high penetration of the blood–brain barrier, good safety profile, and delayed therapeutic window make it an ideal candidate for use in stroke. In animal models, minocycline reduced infarct size and improved neurologic outcome when administered acutely, with similar neuroprotective benefits seen following delayed administration. To date, two early phase clinical trials have shown minocycline to be safe and potentially effective in acute ischemic stroke, alone or in combination with tissue plasminogen activator. A large efficacy clinical trial is now needed to confirm previous studies, allow for subgroup analysis, and pinpoint the potential place for minocycline in acute stroke therapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Matsukawa N, Yasuhara T, Hara K, Xu L, Maki M, Yu G, et al. Therapeutic targets and limits of minocycline neuroprotection in experimental ischemic stroke. BMC Neurosci. 2009;10(1):126.

    Article  PubMed  Google Scholar 

  2. Kleindorfer D, Xu Y, Moomaw CJ, Khatri P, Adeoye O, Hornung R. US geographic distribution of rt-PA utilization by hospital for acute ischemic stroke. Stroke. 2009;40(11):3580–4.

    Article  PubMed  Google Scholar 

  3. Saivin S, Houin G. Clinical pharmacokinetics of doxycycline and minocycline. Clin Pharmacokinet. 1988;15(6):355–66.

    Article  PubMed  CAS  Google Scholar 

  4. Coskey R. Acne: treatment with minocycline. Cutis. 1976;17(4):799–801.

    PubMed  CAS  Google Scholar 

  5. Tilley BC, Alarcon GS, Heyse SP, Trentham DE, Neuner R, Kaplan DA, et al. Minocycline in rheumatoid arthritis: a 48-week, double-blind, placebo-controlled trial. Ann Intern Med. 1995;122(2):81–9.

    PubMed  CAS  Google Scholar 

  6. Yrjänheikki J, Keinänen R, Pellikka M, Hökfelt T, Koistinaho J. Tetracyclines inhibit microglial activation and are neuroprotective in global brain ischemia. Proc Natl Acad Sci USA. 1998;95(26):15769–74.

    Article  PubMed  Google Scholar 

  7. Yrjänheikki J, Tikka T, Keinänen R, Goldsteins G, Chan PH, Koistinaho J. A tetracycline derivative, minocycline, reduces inflammation and protects against focal cerebral ischemia with a wide therapeutic window. Proc Natl Acad Sci USA. 1999;96(23):13496–500.

    Article  PubMed  Google Scholar 

  8. Lin S, Zhang Y, Dodel R, Farlow MR, Paul SM, Du Y. Minocycline blocks nitric oxide-induced neurotoxicity by inhibition p38 MAP kinase in rat cerebellar granule neurons. Neurosci Lett. 2001;315(1–2):61–4.

    Article  PubMed  CAS  Google Scholar 

  9. Zhu S, Stavrovskaya IG, Drozda M, Kim BYS, Ona V, Li M, et al. Minocycline inhibits cytochrome c release and delays progression of amyotrophic lateral sclerosis in mice. Nature. 2002;417(6884):74–8. doi:10.1038/417074a.

    Article  PubMed  CAS  Google Scholar 

  10. Tikka T, Fiebich BL, Goldsteins G, Keinanen R, Koistinaho J. Minocycline, a tetracycline derivative, is neuroprotective against excitotoxicity by inhibiting activation and proliferation of microglia. J Neurosci. 2001;21(8):2580–8.

    PubMed  CAS  Google Scholar 

  11. He Y, Appel S, Le W. Minocycline inhibits microglial activation and protects nigral cells after 6-hydroxydopamine injection into mouse striatum. Brain Res. 2001;909(1–2):187–93.

    Article  PubMed  CAS  Google Scholar 

  12. Wu DC, Jackson-Lewis V, Vila M, Tieu K, Teismann P, Vadseth C, et al. Blockade of microglial activation is neuroprotective in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson disease. J Neurosci. 2002;22(5):1763–71.

    PubMed  CAS  Google Scholar 

  13. Sanchez Mejia RO, Ona VO, Li M, Friedlander RM. Minocycline reduces traumatic brain injury-mediated caspase-1 activation, tissue damage, and neurological dysfunction. Neurosurgery. 2001;48(6):1393–401.

    PubMed  CAS  Google Scholar 

  14. Alano CC, Kauppinen TM, Valls AV, Swanson RA. Minocycline inhibits poly(ADP-ribose) polymerase-1 at nanomolar concentrations. Proc Natl Acad Sci. 2006;103(25):9685–90.

    Article  PubMed  CAS  Google Scholar 

  15. Machado L, Kozak A, Ergul A, Hess D, Borlongan C, Fagan S. Delayed minocycline inhibits ischemia-activated matrix metalloproteinases 2 and 9 after experimental stroke. BMC Neurosci. 2006;7(1):56.

    Article  PubMed  Google Scholar 

  16. Elewa H, Hilali H, Hess D, Machado L, Fagan S. Minocycline for short-term neuroprotection. Pharmacotherapy. 2006;26(4):15–21.

    Article  Google Scholar 

  17. Du Y, Ma Z, Lin S, Dodel RC, Gao F, Bales KR, et al. Minocycline prevents nigrostriatal dopaminergic neurodegeneration in the MPTP model of Parkinson’s disease. Proc Natl Acad Sci USA. 2001;98(25):14669–74.

    Article  PubMed  CAS  Google Scholar 

  18. Chen M, Ona VO, Li M, Ferrante RJ, Fink KB, Zhu S, et al. Minocycline inhibits caspase-1 and caspase-3 expression and delays mortality in a transgenic mouse model of Huntington disease. Nat Med. 2000;6(7):797–801. doi:10.1038/77528.

    Article  PubMed  CAS  Google Scholar 

  19. Wang C, Yang T, Noor R, Shuaib A. Delayed minocycline but not delayed mild hypothermia protects against embolic stroke. BMC Neurol. 2002;2(1):2.

    Article  PubMed  Google Scholar 

  20. Arvin KL, Han BH, Du Y, Lin S-Z, Paul SM, Holtzman DM. Minocycline markedly protects the neonatal brain against hypoxic–ischemic injury. Ann Neurol. 2002;52(1):54–61.

    Article  PubMed  CAS  Google Scholar 

  21. Wang CX, Yang T, Shuaib A. Effects of minocycline alone and in combination with mild hypothermia in embolic stroke. Brain Res. 2003;963(1–2):327–9.

    Article  PubMed  CAS  Google Scholar 

  22. Wells JEA, Hurlbert RJ, Fehlings MG, Yong VW. Neuroprotection by minocycline facilitates significant recovery from spinal cord injury in mice. Brain. 2003;126(7):1628–37.

    Article  PubMed  Google Scholar 

  23. Power C, Henry S, Del Bigio MR, Larsen PH, Corbett D, Imai Y, et al. Intracerebral hemorrhage induces macrophage activation and matrix metalloproteinases. Ann Neurol. 2003;53(6):731–42.

    Article  PubMed  CAS  Google Scholar 

  24. Nagel S, Su Y, Horstmann S, Heiland S, Gardner H, Koziol J, et al. Minocycline and hypothermia for reperfusion injury after focal cerebral ischemia in the rat—effects on BBB breakdown and MMP expression in the acute and subacute phase. Brain Res. 2008;1188:198–206.

    Article  PubMed  CAS  Google Scholar 

  25. Zhang W, Narayanan M, Friedlander RM. Additive neuroprotective effects of minocycline with creatine in a mouse model of ALS. Ann Neurol. 2003;53(2):267–70.

    Article  PubMed  CAS  Google Scholar 

  26. Ravina BM, Fagan SC, Hart RG, Hovinga CA, Murphy DD, Dawson TM, Marler JR. Neuroprotective agents for clinical trials in Parkinson’s disease: a systematic assessment. Neurology. 2003;60(8):1234–40.

    PubMed  CAS  Google Scholar 

  27. Kim H-S, Suh Y-H. Minocycline and neurodegenerative diseases. Behav Brain Res. 2009;196(2):168–79.

    Article  PubMed  CAS  Google Scholar 

  28. Parashos SA, Swearingen CJ, Biglan KM, Bodis-Wollner I, Liang GS, Ross GW, et al. Determinants of the timing of symptomatic treatment in early Parkinson disease: The National Institutes of Health Exploratory Trials in Parkinson disease (NET-PD) experience. Arch Neurol. 2009;66(9):1099–104.

    Article  PubMed  Google Scholar 

  29. Gordon PH, Gelinas DF, Qualls C, Meister ME, Werner J, Mendoza M, et al. Placebo controlled phase I/II studies of minocycline in amyotrophic lateral sclerosis. Neurology. 2004;62(10):1845–7.

    PubMed  CAS  Google Scholar 

  30. Xu L, Fagan SC, Waller J, Edwards D, Borlongan C, Zheng J, et al. Low dose intravenous minocycline is neuroprotective after middle cerebral artery occlusion-reperfusion in rats. BMC Neurol. 2004;4(1):7.

    Article  PubMed  Google Scholar 

  31. Fagan SC, Waller JL, Nichols FT, Edwards DJ, Pettigrew LC, Clark WM, et al. Minocycline to improve neurologic outcome in stroke (MINOS): a dose-finding study. Stroke. 2010;41(10):2283–7.

    Article  PubMed  CAS  Google Scholar 

  32. Hayakawa K, Mishima K, Nozako M, Hazekawa M, Mishima S, Fujioka M, et al. Delayed treatment with minocycline ameliorates neurologic impairment through activated microglia expressing a high-mobility group box1-inhibiting mechanism. Stroke. 2008;39(3):951–8.

    Article  PubMed  CAS  Google Scholar 

  33. Liu Z, Fan Y, Won SJ, Neumann M, Hu D, Zhou L, et al. Chronic treatment with minocycline preserves adult new neurons and reduces functional impairment after focal cerebral ischemia. Stroke. 2007;38(1):146–52.

    Article  PubMed  CAS  Google Scholar 

  34. Hewlett KA, Corbett D. Delayed minocycline treatment reduces long-term functional deficits and histological injury in a rodent model of focal ischemia. Neuroscience. 2006;141(1):27–33.

    Article  PubMed  CAS  Google Scholar 

  35. Lampl Y, Boaz M, Gilad R, Lorberboym M, Dabby R, Rapoport A, et al. Minocycline treatment in acute stroke. Neurology. 2007;69(14):1404–10.

    Article  PubMed  CAS  Google Scholar 

  36. Wang J, Wei Q, Wang C-Y, Hill WD, Hess DC, Dong Z. Minocycline up-regulates Bcl-2 and protects against cell death in mitochondria. J Biol Chem. 2004;279(19):19948–54.

    Article  PubMed  CAS  Google Scholar 

  37. Colovic M, Caccia S. Liquid chromatographic determination of minocycline in brain-to-plasma distribution studies in the rat. J Chromatogr B. 2003;791(1–2):337–43.

    Article  CAS  Google Scholar 

  38. Drew TM, Altman R, Black K, Goldfield M. Minocycline for prophylaxis of infection with Neisseria meningitidis: high rate of side effects in recipients. J Infect Dis. 1976;133(2):194–8.

    Article  PubMed  CAS  Google Scholar 

  39. Clark BJ, Dornbush AC, Hutchinson J. Minocycline administered intravenously: pharmacological activity and clinical experience. Curr Ther Res. 1974;16(9):865–77.

    PubMed  CAS  Google Scholar 

  40. Murata Y, Rosell A, Scannevin RH, Rhodes KJ, Wang X, Lo EH. Extension of the thrombolytic time window with minocycline in experimental stroke. Stroke; Journal Cerebral Circulation. 2008;39(12):3372–7.

    CAS  Google Scholar 

  41. Machado LS, Sazonova IY, Kozak A, Wiley DC, El-Remessy AB, Ergul A, et al. Minocycline and tissue-type plasminogen activator for stroke: assessment of interaction potential. Stroke. 2009;40(9):3028–33.

    CAS  Google Scholar 

  42. Fukuda S, Fini CA, Mabuchi T, Koziol JA, Eggleston Jr LL, del Zoppo GJ. Focal cerebral ischemia induces active proteases that degrade microvascular matrix. Stroke. 2004;35(4):998–1004.

    Article  PubMed  CAS  Google Scholar 

  43. Rosenberg GA, Navratil M, Barone F, Feuerstein G. Proteolytic cascade enzymes increase in focal cerebral ischemia in rat. J Cereb Blood Flow Metab. 1996;16(3):360–6.

    Article  PubMed  CAS  Google Scholar 

  44. Heo JH, Lucero J, Abumiya T, Koziol JA, Copeland BR, del Zoppo GJ. Matrix metalloproteinases increase very early during experimental focal cerebral Ischemia. J Cereb Blood Flow Metab. 1999;19(6):624–33.

    Article  PubMed  CAS  Google Scholar 

  45. Gasche Y, Fujimura M, Morita-Fujimura Y, Copin J-C, Kawase M, Massengale J, et al. Early appearance of activated matrix metalloproteinase-9 after focal cerebral ischemia in mice: a possible role in blood–brain barrier dysfunction. J Cereb Blood Flow Metab. 1999;19(9):1020–8.

    Article  PubMed  CAS  Google Scholar 

  46. Weng YC, Kriz J. Differential neuroprotective effects of a minocycline-based drug cocktail in transient and permanent focal cerebral ischemia. Exp Neurol. 2007;204(1):433–42.

    Article  PubMed  CAS  Google Scholar 

  47. Sathasivam S, Grierson AJ, Shaw PJ. Characterization of the caspase cascade in a cell culture model of SOD1-related familial amyotrophic lateral sclerosis: expression, activation and therapeutic effects of inhibition. Neuropathol Appl Neurobiol. 2005;31(5):467–85.

    Article  PubMed  CAS  Google Scholar 

  48. Kasner SE. Clinical interpretation and use of stroke scales. Lancet Neurol. 2006;5(7):603–12.

    Article  PubMed  Google Scholar 

  49. Tilley BC, Marler J, Geller NL, Lu M, Legler J, Brott T, et al. Use of a global test for multiple outcomes in stroke trials with application to the National Institute of Neurological Disorders and Stroke t-PA Stroke Trial. Stroke. 1996;27(11):2136–42.

    PubMed  CAS  Google Scholar 

  50. Li J, McCullough LD. Sex differences in minocycline-induced neuroprotection after experimental stroke. J Cereb Blood Flow Metab. 2009;29(4):670–4.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Program in Clinical and Experimental Therapeutics, University of Georgia College of Pharmacy, HM 1200, 1120 15th St., Augusta, GA, 30912, USA

    Susan C. Fagan, Lydia E. Cronic & David C. Hess

  2. Charlie Norwood VA Medical Center, Augusta, GA, USA

    Susan C. Fagan

  3. Department of Neurology, Georgia Health Sciences University, Augusta, GA, USA

    Susan C. Fagan & David C. Hess

Authors
  1. Susan C. Fagan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lydia E. Cronic
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. David C. Hess
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Susan C. Fagan.

Additional information

SI: Emerging Stroke Therapies

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fagan, S.C., Cronic, L.E. & Hess, D.C. Minocycline Development for Acute Ischemic Stroke. Transl. Stroke Res. 2, 202–208 (2011). https://doi.org/10.1007/s12975-011-0072-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12975-011-0072-6

Keywords

Search

Navigation