PEG minocycline-liposomes ameliorate CNS autoimmune disease

Wei Hu, Josbert Metselaar, Li Hong Ben, Petra D. Cravens, Mahendra P. Singh, Elliot Frohman, Todd N. Eagar, Michael K. Racke, Bernd C. Kieseier, Olaf Stuve

Research output: Contribution to journalArticle

35 Scopus citations

Abstract

Background: Minocycline is an oral tetracycline derivative with good bioavailability in the central nervous system (CNS). Minocycline, a potent inhibitor of matrix metalloproteinase (MMP)-9, attenuates disease activity in experimental autoimmune encephatomyelitis (EAE), an animal model of multiple sclerosis (MS). Potential adverse effects associated with long-term daily minocycline therapy in human patients are concerning. Here, we investigated whether less frequent treatment with long-circulating polyethylene glycol (PEG) minocycline liposomes are effective in treating EAE. Findings: Performing in vitro time kinetic studies of PEG minocycline-liposomes in human peripheral blood mononuclear cells (PBMCs), we determined that PEG minocycline-liposome preparations stabilized with CaCl2 are effective in diminishing MMP-9 activity. Intravenous injections of PEG minocycline-liposomes every five days were as effective in ameliorating clinical EAE as daily intraperitoneal injections of minocycline. Treatment of animals with PEG minocycline-liposomes significantly reduced the number of CNS-infiltrating leukocytes, and the overall expression of MMP-9 in the CNS. There was also a significant suppression of MMP-9 expression and proteolytic activity in splenocytes of treated animals, but not in CNS-infiltrating leukocytes. Thus, leukocytes gaining access to the brain and spinal cord require the same absolute amount of MMP-9 in all treatment groups, but minocycline decreases the absolute cell number. Conclusions: Our data indicate that less frequent injections of PEG minocycline-liposomes are an effective alternative pharmacotherapy to daily minocycline injections for the treatment of CNS autoimmune diseases. Also, inhibition of MMP-9 remains a promising treatment target in EAE and patients with MS.

Original languageEnglish (US)
Article numbere4151
JournalPloS one
Volume4
Issue number1
DOIs
StatePublished - Jan 7 2009

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Hu, W., Metselaar, J., Ben, L. H., Cravens, P. D., Singh, M. P., Frohman, E., Eagar, T. N., Racke, M. K., Kieseier, B. C., & Stuve, O. (2009). PEG minocycline-liposomes ameliorate CNS autoimmune disease. PloS one, 4(1), [e4151]. https://doi.org/10.1371/journal.pone.0004151