title: PEG minocycline-liposomes ameliorate CNS autoimmune disease.
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 encephalomyelitis (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.
  
  
  RESULTS
  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 CaCl(2) 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.
authors.affiliation: Department of Neurology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, United States of America.
authors.forename: Wei
authors.initials: W
authors.lastname: Hu
authors.forename: Josbert
authors.initials: J
authors.lastname: Metselaar
authors.forename: Li-Hong
authors.initials: LH
authors.lastname: Ben
authors.forename: Petra D
authors.initials: PD
authors.lastname: Cravens
authors.forename: Mahendra P
authors.initials: MP
authors.lastname: Singh
authors.forename: Elliot M
authors.initials: EM
authors.lastname: Frohman
authors.forename: Todd N
authors.initials: TN
authors.lastname: Eagar
authors.forename: Michael K
authors.initials: MK
authors.lastname: Racke
authors.forename: Bernd C
authors.initials: BC
authors.lastname: Kieseier
authors.forename: Olaf
authors.initials: O
authors.lastname: Stüve
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000276:immunology; D005260:Female; D006801:Humans; D008081:Liposomes; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008911:Minocycline / Q000008:administration & dosage* / Q000627:therapeutic use; D020721:Nervous System Autoimmune Disease, Experimental / Q000188:drug therapy / Q000276:immunology; D011092:Polyethylene Glycols / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D008081:Liposomes; D061965:Matrix Metalloproteinase Inhibitors; D011092:Polyethylene Glycols; D020782:Matrix Metalloproteinases; D020780:Matrix Metalloproteinase 9; D008911:Minocycline