Sage Journals: Discover world-class research

Abstract

Background:

Most multiple sclerosis (MS) patients succumb to a progressive phenotype. Continued lymphocyte activity in the brain, microglia-mediated injury, iron deposition, and oxidative stress are characteristics of progressive MS.

Objective:

As minocycline and hydroxychloroquine have been shown to inhibit microglia, we evaluated their effects on other outcomes relevant for progression.

Methods:

Medications were evaluated in culture and in mice with acute and chronic experimental autoimmune encephalomyelitis (EAE).

Results:

Both medications individually reduced iron neurotoxicity and a combination effect was not observed. Hydroxyl radical scavenging activity was manifested by minocycline only. Minocycline reduced T-cell proliferation more prominently than hydroxychloroquine; an aggregate effect occurred at low but not high concentrations. B-cell proliferation was mitigated to a greater extent by hydroxychloroquine and an additive effect was not evident. In EAE, suboptimal doses of minocycline and hydroxychloroquine individually delayed onset of clinical signs, while their combination suppressed clinical manifestations until treatment was stopped. In Biozzi ABH mice, a model of progressive MS, the chronic phase was beneficially altered using the combination.

Conclusion:

While minocycline and hydroxychloroquine did not manifest additive effects in most culture assays, their combination at suboptimal doses in EAE unexpectedly exceeded their individual activity. Minocycline and hydroxychloroquine combined are candidate treatments for progressive MS.

Keywords

Generic medication neuroprotection antioxidant progressive multiple sclerosis

Get full access to this article

View all access options for this article.

References

Ransohoff

Hafler

Lucchinetti

. Multiple sclerosis: A quiet revolution. Nat Rev Neurol 2015; 11: 134–142.

Lassmann

van Horssen

Mahad

. Progressive multiple sclerosis: Pathology and pathogenesis. Nat Rev Neurol 2012; 8: 647–656.

Komori

Blake

Greenwood

et al . Cerebrospinal fluid markers reveal intrathecal inflammation in progressive multiple sclerosis. Ann Neurol 2015; 78: 3–20.

Fischer

Sharma

Lim

et al . NADPH oxidase expression in active multiple sclerosis lesions in relation to oxidative tissue damage and mitochondrial injury. Brain 2012; 135: 886–899.

Hametner

Wimmer

Haider

et al . Iron and neurodegeneration in the multiple sclerosis brain. Ann Neurol 2013; 74: 848–861.

Serafini

Rosicarelli

Magliozzi

et al . Detection of ectopic B-cell follicles with germinal centers in the meninges of patients with secondary progressive multiple sclerosis. Brain Pathol 2004; 14: 164–174.

Giuliani

Hader

Yong

. Minocycline attenuates T cell and microglia activity to impair cytokine production in T cell-microglia interaction. J Leukoc Biol 2005; 78: 135–143.

Yong

Wells

Giuliani

et al . The promise of minocycline in neurology. Lancet Neurol 2004; 3: 744–751.

Koch

Zabad

Giuliani

et al . Hydroxychloroquine reduces microglial activity and attenuates experimental autoimmune encephalomyelitis. J Neurol Sci 2015; 358: 131–137.

10.

Metz

DKB

Traboulsee

et al . Trial of minocycline in a clinically isolated syndrome of multiple sclerosis. N Engl J Med 2017; 376: 2122–2133.

11.

Brundula

Rewcastle

Metz

et al . Targeting leukocyte MMPs and transmigration: Minocycline as a potential therapy for multiple sclerosis. Brain 2002; 125: 1297–1308.

12.

Scholz

Sobotka

Caramoy

et al . Minocycline counter-regulates pro-inflammatory microglia responses in the retina and protects from degeneration. J Neuroinflammation 2015; 12: 209.

13.

Vecil

Larsen

Corley

et al . Interleukin-1 is a key regulator of matrix metalloproteinase-9 expression in human neurons in culture and following mouse brain trauma in vivo. J Neurosci Res 2000; 61: 212–224.

14.

Keough

Rogers

Zhang

et al . An inhibitor of chondroitin sulfate proteoglycan synthesis promotes central nervous system remyelination. Nat Commun 2016; 7: 11312.

15.

Rezk

Miyazaki

et al . Proinflammatory GM-CSF-producing B cells in multiple sclerosis and B cell depletion therapy. Sci Transl Med 2015; 7: 310ra166.

16.

Číž

Čížová

Denev

et al . Different methods for control and comparison of the antioxidant properties of vegetables. Food Control 2010; 21: 518–523.

17.

Hampsch-Woodill

Flanagan

et al . Novel fluorometric assay for hydroxyl radical prevention capacity using fluorescein as the probe. J Agric Food Chem 2002; 50: 2772–2777.

18.

Giuliani

Metz

Wilson

et al . Additive effect of the combination of glatiramer acetate and minocycline in a model of MS. J Neuroimmunol 2005; 158: 213–221.

19.

Al-Izki

Pryce

Jackson

et al . Immunosuppression with FTY720 is insufficient to prevent secondary progressive neurodegeneration in experimental autoimmune encephalomyelitis. Mult Scler 2011; 17: 939–948.

20.

Goncalves DaSilva

Yong

. Matrix metalloproteinase-12 deficiency worsens relapsing-remitting experimental autoimmune encephalomyelitis in association with cytokine and chemokine dysregulation. Am J Pathol 2009; 174: 898–909.

21.

Friese

Schattling

Fugger

. Mechanisms of neurodegeneration and axonal dysfunction in multiple sclerosis. Nat Rev Neurol 2014; 10: 225–238.

22.

Sloka

Metz

Hader

et al . Reduction of microglial activity in a model of multiple sclerosis by dipyridamole. J Neuroinflammation 2013; 10: 89.

23.

Kutzelnigg

Lucchinetti

Stadelmann

et al . Cortical demyelination and diffuse white matter injury in multiple sclerosis. Brain 2005; 128: 2705–2712.

24.

Hampton

Serio

Pryce

et al . Neurodegeneration progresses despite complete elimination of clinical relapses in a mouse model of multiple sclerosis. Acta Neuropathol Commun 2013; 1: 84.

25.

Metz

Zhang

Yeung

et al . Minocycline reduces gadolinium-enhancing magnetic resonance imaging lesions in multiple sclerosis. Ann Neurol 2004; 55: 756.

26.

Metz

Traboulsee

et al . Glatiramer acetate in combination with minocycline in patients with relapsing–remitting multiple sclerosis: Results of a Canadian, multicenter, double-blind, placebo-controlled trial. Mult Scler 2009; 15: 1183–1194.

27.

van den Borne

Dijkmans

de Rooij

et al . Chloroquine and hydroxychloroquine equally affect tumor necrosis factor-alpha, interleukin 6, and interferon-gamma production by peripheral blood mononuclear cells. J Rheumatol 1997; 24: 55–60.

28.

Sperber

Quraishi

Kalb

et al . Selective regulation of cytokine secretion by hydroxychloroquine: Inhibition of interleukin 1 alpha (IL-1-alpha) and IL-6 in human monocytes and T cells. J Rheumatol 1993; 20: 803–808.

29.

Bertolaccini

Contento

Lennen

et al . Complement inhibition by hydroxychloroquine prevents placental and fetal brain abnormalities in antiphospholipid syndrome. J Autoimmun 2016; 75: 30–38.

30.

Watkins

Neal

Loveless

et al . Complement is activated in progressive multiple sclerosis cortical grey matter lesions. J Neuroinflammation 2016; 13: 161.

31.

Romme Christensen

Bornsen

Ratzer

et al . Systemic inflammation in progressive multiple sclerosis involves follicular T-helper, Th17- and activated B-cells and correlates with progression. PLoS ONE 2013; 8: e57820.

32.

Fitzner

Hecker

Zettl

. Molecular biomarkers in cerebrospinal fluid of multiple sclerosis patients. Autoimmun Rev 2015; 14: 903–913.

33.

Montalban

Hauser

Kappos

et al . Ocrelizumab versus placebo in primary progressive multiple sclerosis. N Engl J Med 2017; 376: 209–220.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

0.25 MB

Unexpected additive effects of minocycline and hydroxychloroquine in models of multiple sclerosis: Prospective combination treatment for progressive disease?

Abstract

Background:

Objective:

Methods:

Results:

Conclusion:

Keywords

Get full access to this article

References

Supplementary Material