The clinical response to minocycline in multiple sclerosis is accompanied by                 beneficial immune changes: a pilot study

Zabad, Rana; Metz, Luanne M.; Todoruk, Tiona R.; Zhang, Y.; Mitchell, J. Ross; Patry, David G.; Bell, Robert B.; Yong, V. Wee

doi:10.1177/1352458506070319

Cited by 114 publications

(74 citation statements)

References 33 publications

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“…[91][92][93] In addition, minocycline was found to reduce relapse rate and gadolinium-enhancing magnetic resonance imaging lesions in a pilot trial in relapsing-remitting MS patients. 94,95 These results are encouraging. Although it is tempting to state that the effectiveness of minocycline in MS is related to its MMP inhibitory actions, it is important to point out that minocycline possesses a multitude of immunomodulatory and anti-apoptosis functions 96 so that its potential usefulness in MS may even be unrelated to its MMP inhibitory activity.…”

Section: Figsupporting

confidence: 69%

Targeting MMPs in Acute and Chronic Neurological Conditions

2007

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Summary:The matrix metalloproteinases (MMPs) are important enzymes that regulate developmental processes, maintain normal physiology in adulthood and have reparative roles at specific stages after an insult to the nervous system. Conversely, the concordant presence and significant upregulation of several MMP members in virtually all neurological conditions result in pathology. Thus, the MMPs have diverse functions, capable of mediating repair and recovery on the one hand and being involved in producing injury on the other. Therefore, targeting MMPs in neurological conditions has become a complicated challenge. This article highlights the beneficial roles of MMPs in normal and reparative processes within the nervous system and discusses the detriments of MMPs encountered in pathology. We review the availability of MMP inhibitors for clinical use and propose that an important consideration for these inhibitors is timing and duration of their use. With acute injuries where a massive upregulation of several MMPs are observed in the early periods after the insult, early and short-term use of broad spectrum MMP inhibitors would seem logical. In chronic conditions where recurrent insults to the CNS are accompanied by prolonged upregulation of MMPs, thereby necessitating the chronic use of medications, the beneficial effects of MMPs in repair may be compromised by the long-term application of MMP inhibitors. In this review we have used spinal cord injury and multiple sclerosis as examples of acute and chronic neurological conditions, respectively, and we consider the use of MMP inhibitors in these states.

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Section: Figsupporting

confidence: 69%

Targeting MMPs in Acute and Chronic Neurological Conditions

2007

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“…This tetracycline antibiotic that inhibits MMP activity and reduces the severity of animals immunized for EAE (22)(23)(24) has shown promise in relapsing-remitting MS in early clinical trials (25)(26)(27)(28) and, more recently, was found to be effective in a phase III trial in early MS (L. M. Metz et al, submitted for publication). We find that both murine and human T cells were reduced in the expression level (MFI) of EMMPRIN by minocycline, as well as in the percentage of T cells with EMMPRIN expression.…”

Section: Discussionmentioning

confidence: 99%

“…We focus on the potential MS medication minocycline, a tetracycline antibiotic that inhibits MMP activity (21) and reduces the severity of animals immunized for EAE (22)(23)(24). From these animal studies, minocycline was tested and found to have promise in relapsing-remitting MS as suggested by early clinical trials (25)(26)(27)(28). More recently, a phase III trial in patients with a first demyelinating event (clinically isolated syndrome) found that minocycline reduced the acquisition of a second event to become clinically definite MS (L. M. Metz, D. K. B. Li, A. Traboulsee, P. Duquette, M. Eliasziw, G. Cerchiaro, J. Greenfield, A. Riddehough, M. Yeung, M. Kremenchutzky, et al, submitted for publication).…”

mentioning

confidence: 99%

Impact of Minocycline on Extracellular Matrix Metalloproteinase Inducer, a Factor Implicated in Multiple Sclerosis Immunopathogenesis

Hahn

Kaushik

Mishra

et al. 2016

The Journal of Immunology

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Extracellular matrix metalloproteinase inducer (EMMPRIN, CD147) is a transmembrane glycoprotein that is upregulated on leukocytes in active lesions in multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Administration of anti-EMMPRIN Abs reduces the severity of EAE. Minocycline is a tetracycline antibiotic with immune-modulatory properties that decreases the severity of EAE; it was recently found to attenuate the conversion from a first demyelinating event to clinically definite MS in a phase III trial. We investigated whether and how minocycline affects the expression of EMMPRIN on T cells in culture and in mice afflicted with EAE. EMMPRIN expression in cultures of mouse splenocytes or human PBMCs was elevated upon polyclonal T cell activation, and this was reduced by minocycline correspondent with decreased P-Akt levels. An established MS medication, IFN-β, also diminished EMMPRIN levels on human cells whereas this was not readily observed for fingolimod or monomethylfumarate. In EAE-afflicted mice, minocycline treatment significantly reduced EMMPRIN levels on splenic lymphocytes at the presymptomatic (day 7) phase, and prevented the development of disease. Day 7 spleen transcripts from minocycline-treated EAE mice had a significantly lower MMP-9/TIMP-1 ratio, and significantly lower MCT-1 and CD98 levels, factors associated with EMMPRIN function. Day 16 (peak clinical severity) CNS samples from EAE mice had prominent representation of inflammatory perivascular cuffs, inflammatory molecules and EMMPRIN, and these were abrogated by minocycline. Overall, minocycline attenuated the activation-induced elevation of EMMPRIN on T cells in culture and in EAE mice, correspondent with reduced immune function and EAE CNS pathology.

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“…These include anti-oxidant [1], anti-apoptotic [2], anti-metastatic [3] and most notably anti-inflammatory effects [2,[4][5][6]. Tetracyclines are inexpensive, have a very good safety profile and have been investigated in the treatment of a number of inflammatory diseases including rheumatoid arthritis [6,7], periodontitis [8], cardiac ischaemia-reperfusion injury [9] and a wide range of central nervous system pathologies including Parkinson's disease [10], multiple sclerosis [11], amylotrophic sclerosis [12,13], and both global and focal cerebral ischaemia [4,5].…”

Section: Introductionmentioning

confidence: 99%

Proteomic analysis of the anti‐inflammatory action of minocycline

Dunston¹,

Griffiths²,

Lambert³

et al. 2011

Proteomics Clinical Apps

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Minocycline possesses anti-inflammatory properties independently of its antibiotic activity although the underlying molecular mechanisms are unclear. Lipopolysaccharide (LPS)-induced cytokines and pro-inflammatory protein expression are reduced by minocycline in cultured macrophages. Here, we tested a range of clinically important tetracycline compounds (oxytetracycline, doxycycline, minocycline and tigecycline) and showed that they all inhibited LPS-induced nitric oxide production. We made the novel finding that tigecycline inhibited LPS-induced nitric oxide production to a greater extent than the other tetracycline compounds tested. To identify potential targets for minocycline, we assessed alterations in the macrophage proteome induced by LPS in the presence or absence of a minocycline pretreatment using 2-DE and nanoLC-MS. We found a number of proteins, mainly involved in cellular metabolism (ATP synthase b-subunit and aldose reductase) or stress response (heat shock proteins), which were altered in expression in response to LPS, some of which were restored, at least in part, by minocycline. This is the first study to document proteomic changes induced by minocycline. The observation that minocycline inhibits some, but not all, of the LPS-induced proteomic changes shows that minocycline specifically affects some signalling pathways and does not completely inhibit macrophage activation.

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The clinical response to minocycline in multiple sclerosis is accompanied by beneficial immune changes: a pilot study

Cited by 114 publications

References 33 publications

Targeting MMPs in Acute and Chronic Neurological Conditions

Targeting MMPs in Acute and Chronic Neurological Conditions

Impact of Minocycline on Extracellular Matrix Metalloproteinase Inducer, a Factor Implicated in Multiple Sclerosis Immunopathogenesis

Proteomic analysis of the anti‐inflammatory action of minocycline

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