PEG minocycline-liposomes ameliorate CNS autoimmune disease

Research output: Contribution to journalArticle

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

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

PMID: 19127301

PMCID: PMC2613526

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PEG minocycline-liposomes ameliorate CNS autoimmune disease. / Hu, Wei; Metselaar, Josbert; Ben, Li Hong; Cravens, Petra D.; Singh, Mahendra P.; Frohman, Elliot M.; Eagar, Todd N.; Racke, Michael K.; Kieseier, Bernd C.; Stüve, Olaf.

In: PloS one, Vol. 4, No. 1, e4151, 07.01.2009.

Research output: Contribution to journalArticle

Harvard

Hu, W, Metselaar, J, Ben, LH, Cravens, PD, Singh, MP, Frohman, EM, Eagar, TN, Racke, MK, Kieseier, BC & Stüve, O 2009, 'PEG minocycline-liposomes ameliorate CNS autoimmune disease' PloS one, vol. 4, no. 1, e4151. https://doi.org/10.1371/journal.pone.0004151

APA

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

Vancouver

Hu W, Metselaar J, Ben LH, Cravens PD, Singh MP, Frohman EM et al. PEG minocycline-liposomes ameliorate CNS autoimmune disease. PloS one. 2009 Jan 7;4(1). e4151. https://doi.org/10.1371/journal.pone.0004151

Author

Hu, Wei ; Metselaar, Josbert ; Ben, Li Hong ; Cravens, Petra D. ; Singh, Mahendra P. ; Frohman, Elliot M. ; Eagar, Todd N. ; Racke, Michael K. ; Kieseier, Bernd C. ; Stüve, Olaf. / PEG minocycline-liposomes ameliorate CNS autoimmune disease. In: PloS one. 2009 ; Vol. 4, No. 1.

BibTeX

@article{99d19f9f703541c1a722c5a7c4715b8a,
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 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.",
author = "Wei Hu and Josbert Metselaar and Ben, {Li Hong} and Cravens, {Petra D.} and Singh, {Mahendra P.} and Frohman, {Elliot M.} and Eagar, {Todd N.} and Racke, {Michael K.} and Kieseier, {Bernd C.} and Olaf St{\"u}ve",
year = "2009",
month = "1",
day = "7",
doi = "10.1371/journal.pone.0004151",
language = "English (US)",
volume = "4",
journal = "PLoS ONE",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "1",

}

RIS

TY - JOUR

T1 - PEG minocycline-liposomes ameliorate CNS autoimmune disease

AU - Hu, Wei

AU - Metselaar, Josbert

AU - Ben, Li Hong

AU - Cravens, Petra D.

AU - Singh, Mahendra P.

AU - Frohman, Elliot M.

AU - Eagar, Todd N.

AU - Racke, Michael K.

AU - Kieseier, Bernd C.

AU - Stüve, Olaf

PY - 2009/1/7

Y1 - 2009/1/7

N2 - 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.

AB - 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.

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UR - http://www.scopus.com/inward/citedby.url?scp=58349110811&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0004151

DO - 10.1371/journal.pone.0004151

M3 - Article

VL - 4

JO - PLoS ONE

T2 - PLoS ONE

JF - PLoS ONE

SN - 1932-6203

IS - 1

M1 - e4151

ER -

ID: 16838246