minocycline and Multiple-Sclerosis

Multiple sclerosis (MS) is the most common inflammatory demyelinating disease of the central nervous system (CNS). Although there are several approved drugs for MS, not all patients respond optimally to these drugs. More effective, well-tolerated therapeutic strategies for MS are necessary, either through the development of new medication or combination of existing ones. Minocycline is a traditional antibiotic with profound anti-inflammatory and neuroprotective effects and good tolerance for long-term use. The encouraging results from the animal model and clinical experiments on minocycline make it a promising candidate for MS treatment whether used alone or combined with other drugs. In this review, we summarized the pharmacological actions of minocycline and focused on its therapeutic effects and safety in experimental autoimmune encephalomyelitis (EAE) and MS. The data obtained here showed that minocycline would be an effective and safe therapy for MS.

Topics: Animals; Encephalomyelitis, Autoimmune, Experimental; Humans; Microglia; Minocycline; Multiple Sclerosis

Multiple sclerosis (MS) is an autoimmune/ inflammatory disease of the central nervous system (CNS). MS affects more than two million people worldwide and has been recognized as the leading cause of neurological disability in young adults. MS has long been considered as a CNS disease of demyelination and inflammation. Axonal degeneration has however been increasingly accepted as a key pathogenetic element. Certain noninvasive tests such as optic coherence tomography (OCT), magnetization transfer imaging (MTI), and proton magnetic resonance spectroscopy (MRS) might be superior in early detection of axonal loss and neurodegeneration as compared to conventional neuroimaging studies. New therapeutic strategies targeting the neurodegenerative process in MS provide hope to the MS community. A number of phase II or III clinical trials that are designed to target such specific pathogenetic mechanisms include sodium channel blockers, matrix metalloproteinases (MMP) inhibitors, c-AMP selective phosphodiesterase inhibitors, NMDA receptor antagonists, amongst others. In the current review, we will discuss the current understanding of the mechanisms of neurodegeneration in MS, agents with neuroprotective properties, patents currently available and, their possible application in the treatment of MS.

Topics: Humans; Immunity, Innate; Magnetic Resonance Spectroscopy; Magnetics; Minocycline; Multiple Sclerosis; Nerve Degeneration; Neuroprotective Agents; Sodium Channel Blockers; Tomography, Optical Coherence

In 1993, interferon beta-1b, the first clinically proven disease-modifying agent for multiple sclerosis, was approved, with several comparable agents following close behind. These agents have been beneficial in reducing relapse events and MRI lesions, but all require parenteral administration, leading some otherwise eligible patients to decline such therapies. Oral agents have been studied for decades with mixed results, but a small number of medications currently being tested in phase II/III clinical trials have shown promise in efficacy and tolerability. This review assesses the results of the more thoroughly studied of these agents, some of which may soon be approved for use in multiple sclerosis.

Topics: Administration, Oral; Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Cladribine; Clinical Trials as Topic; Dimethyl Fumarate; Fingolimod Hydrochloride; Fumarates; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Immunosuppressive Agents; Interferon beta-1b; Interferon-beta; Isoxazoles; Leflunomide; Minocycline; Multiple Sclerosis; Mycophenolic Acid; Propylene Glycols; Pyridones; Quinolones; Sphingosine

On the basis of encouraging preliminary results, we conducted a randomized, controlled trial to determine whether minocycline reduces the risk of conversion from a first demyelinating event (also known as a clinically isolated syndrome) to multiple sclerosis.. During the period from January 2009 through July 2013, we randomly assigned participants who had had their first demyelinating symptoms within the previous 180 days to receive either 100 mg of minocycline, administered orally twice daily, or placebo. Administration of minocycline or placebo was continued until a diagnosis of multiple sclerosis was established or until 24 months after randomization, whichever came first. The primary outcome was conversion to multiple sclerosis (diagnosed on the basis of the 2005 McDonald criteria) within 6 months after randomization. Secondary outcomes included conversion to multiple sclerosis within 24 months after randomization and changes on magnetic resonance imaging (MRI) at 6 months and 24 months (change in lesion volume on T. A total of 142 eligible participants underwent randomization at 12 Canadian multiple sclerosis clinics; 72 participants were assigned to the minocycline group and 70 to the placebo group. The mean age of the participants was 35.8 years, and 68.3% were women. The unadjusted risk of conversion to multiple sclerosis within 6 months after randomization was 61.0% in the placebo group and 33.4% in the minocycline group, a difference of 27.6 percentage points (95% confidence interval [CI], 11.4 to 43.9; P=0.001). After adjustment for the number of enhancing lesions at baseline, the difference in the risk of conversion to multiple sclerosis within 6 months after randomization was 18.5 percentage points (95% CI, 3.7 to 33.3; P=0.01); the unadjusted risk difference was not significant at the 24-month secondary outcome time point (P=0.06). All secondary MRI outcomes favored minocycline over placebo at 6 months but not at 24 months. Trial withdrawals and adverse events of rash, dizziness, and dental discoloration were more frequent among participants who received minocycline than among those who received placebo.. The risk of conversion from a clinically isolated syndrome to multiple sclerosis was significantly lower with minocycline than with placebo over 6 months but not over 24 months. (Funded by the Multiple Sclerosis Society of Canada; ClinicalTrials.gov number, NCT00666887 .).

Topics: Actuarial Analysis; Administration, Oral; Adult; Anti-Bacterial Agents; Demyelinating Diseases; Disease Progression; Dizziness; Double-Blind Method; Exanthema; Female; Humans; Intention to Treat Analysis; Life Tables; Magnetic Resonance Imaging; Male; Middle Aged; Minocycline; Multiple Sclerosis; Risk; Tooth Discoloration

Combining different therapies may improve disease control in patients with relapsing-remitting multiple sclerosis (RRMS). This study assessed the efficacy and safety of minocycline added to subcutaneous (sc) interferon (IFN) β-1a therapy.. This was a double-blind, randomized, placebo-controlled multicentre study. Within 3 months (±1 month) of starting sc IFN β-1a 44 μg three times weekly, patients with RRMS were randomized to minocycline 100 mg twice daily or placebo, added to sc IFN β-1a, for 96 weeks. The primary efficacy endpoint was the time to first qualifying relapse. Secondary efficacy endpoints were the annualized relapse rate for qualifying relapses, the number of new/enlarging T2-weighted lesions and change in brain volume [magnetic resonance imaging (MRI) was performed only in a few selected centres]. In addition, a number of tertiary efficacy endpoints were assessed.. One hundred and forty-nine patients received minocycline and 155 received placebo; MRI data were available for 23 and 27 patients, respectively. The time to first qualifying relapse did not differ significantly for minocycline versus placebo (hazard ratio 0.85; 95% confidence interval 0.53, 1.35; log-rank = 0.50; P = 0.48). There were no statistically significant differences between the two groups on other efficacy endpoints, although some numerical trends in favour of minocycline were observed. No unexpected adverse events were reported, but more patients discontinued because of adverse events with minocycline versus placebo.. Minocycline showed no statistically significant beneficial effect when added to sc IFN β-1a therapy.

Topics: Adolescent; Adult; Anti-Bacterial Agents; Brain; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Interferon beta-1a; Magnetic Resonance Imaging; Male; Middle Aged; Minocycline; Multiple Sclerosis; Organ Size; Treatment Outcome; Young Adult

The 2005 and 2010 McDonald criteria utilize magnetic resonance imaging (MRI) to provide evidence of disease dissemination in space (DIS) and time (DIT) for the diagnosis of multiple sclerosis (MS) in patients who have clinically isolated syndromes (CIS).. Data from 109 CIS patients not satisfying the 2005 criteria at entry into a randomized controlled minocycline trial were analyzed to determine the proportion who would have been diagnosed with MS at screening based on 2010 criteria. The impact of including symptomatic, as well as asymptomatic, MRI lesions to confirm DIT was also explored.. Thirty percent (33/109) of patients, retrospectively, met the 2010 criteria for a diagnosis of MS at baseline. When both symptomatic and asymptomatic lesions were used to confirm DIT, three additional patients met the 2010 criteria. There was a significant 10.1% increase in the proportion of patients who met the 2010 DIS criteria, compared with the 2005 DIS criteria; however, two patients satisfied the 2005 DIS but not 2010 DIS criteria.. Using 2010 McDonald criteria, 30% of the CIS patients could be diagnosed with MS using a single MRI scan. Inclusion of symptomatic lesions in the DIT criteria further increases this proportion to 33%.

Topics: Adolescent; Adult; Canada; Demyelinating Diseases; Disease Progression; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Minocycline; Multiple Sclerosis; Neuroprotective Agents; Practice Guidelines as Topic; Young Adult

Minocycline has immunomodulatory and neuroprotective activities in vitro and in an animal model of multiple sclerosis (MS). We have previously reported that minocycline decreased gadolinium-enhancing activity over six months in a small trial of patients with active relapsing-remitting MS (RRMS). Here we report the impact of oral minocycline on clinical and magnetic resonance imaging (MRI) outcomes and serum immune molecules in this cohort over 24 months of open-label minocycline treatment. Despite a moderately high pretreatment annualized relapse rate (1.3/year pre-enrolment; 1.2/year during a three-month baseline period) prior to treatment, no relapses occurred between months 6 and 24. Also, despite very active MRI activity pretreatment (19/40 scans had gadolinium-enhancing activity during a three-month run-in), the only patient with gadolinium-enhancing lesions on MRI at 12 and 24 months was on half-dose minocycline. Levels of the p40 subunit of interleukin (IL)-12, which at high levels might antagonize the proinflammatory IL-12 receptor, were elevated over 18 months of treatment, as were levels of soluble vascular cell adhesion molecule-1. The activity of matrix metalloproteinase-9 was decreased by treatment. Thus, clinical and MRI outcomes are supported by systemic immunological changes and call for further investigation of minocycline in MS.

Topics: Adult; Cytokines; Female; Follow-Up Studies; Humans; Immunologic Factors; Magnetic Resonance Imaging; Male; Minocycline; Multiple Sclerosis; Neuroprotective Agents; Pilot Projects

In the trial of Minocycline in Clinically Isolated Syndrome (MinoCIS), minocycline significantly reduced the risk of conversion to clinically definite multiple sclerosis (CDMS). Neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) are emerging biomarkers in MS, and minocycline modulates matrix metalloproteinases (MMPs).. To assess the value of blood NfL and GFAP as a biomarker of baseline and future disease activity and its utility to monitor treatment response in minocycline-treated patients with clinically isolated syndrome (CIS).. We measured NfL, GFAP, and MMPs in blood samples from 96 patients with CIS from the MinoCIS study and compared biomarkers with clinical and radiologic characteristics and outcome.. At baseline, NfL levels correlated with T. Blood NfL levels are associated with measures of disease activity in CIS and have prognostic value. Minocycline increased NfL levels at month 3, but reduced GFAP and MMP-7 levels.

Topics: Biomarkers; Demyelinating Diseases; Gadolinium; Glial Fibrillary Acidic Protein; Humans; Intermediate Filaments; Matrix Metalloproteinase 7; Minocycline; Multiple Sclerosis; Neurofilament Proteins

Multiple sclerosis (MS) is a chronic demyelinating inflammatory disorder with variable clinical and pathologic characteristics reflecting multiple underlying pathophysiologic mechanisms. Repositioning of existing drugs for the new indications offers several advantages including significant reduction in the cost and time of drug development and exemption from early phase clinical trials. Minocycline has been reported to exhibit immunomodulation in several pre-clinical and clinical studies through suppression of migratory inflammatory cells, modulation of peripheral immune response, and inhibition of microglial activation within the CNS.. Here, the authors review the repositioning potential of minocycline for the treatment of MS along with appraisal of the evidence obtained from preclinical and clinical research. The authors also discuss the advantages and potential safety concerns related to the use of minocycline for the management of MS.. Minocycline offers several distinct advantages in terms of well-known safety profile, lower cost of therapy, widespread availability, and being available as an oral formulation. The authors call upon the public and private funders to facilitate well designed and adequately powered randomized clinical trials that can provide conclusive evidence regarding the safety and efficacy of minocycline in patients with MS.

Topics: Drug Repositioning; Humans; Immunomodulation; Minocycline; Multiple Sclerosis

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.. As minocycline and hydroxychloroquine have been shown to inhibit microglia, we evaluated their effects on other outcomes relevant for progression.. Medications were evaluated in culture and in mice with acute and chronic experimental autoimmune encephalomyelitis (EAE).. 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.. 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.

Topics: Animals; B-Lymphocytes; Cell Proliferation; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Humans; Hydroxychloroquine; Lymphocyte Activation; Mice; Mice, Biozzi; Mice, Inbred C57BL; Minocycline; Multiple Sclerosis; Neurons; Neuroprotective Agents; T-Lymphocytes

Topics: Minocycline; Multiple Sclerosis

Topics: Demyelinating Diseases; Humans; Magnetic Resonance Imaging; Minocycline; Multiple Sclerosis

Topics: Demyelinating Diseases; Humans; Magnetic Resonance Imaging; Minocycline; Multiple Sclerosis

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.

Topics: Animals; Anti-Bacterial Agents; Basigin; Central Nervous System; Clinical Trials, Phase III as Topic; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Fingolimod Hydrochloride; Fumarates; Humans; Interferon-beta; Lymphocyte Activation; Maleates; Matrix Metalloproteinase 9; Mice; Mice, Inbred C57BL; Minocycline; Monocytes; Multiple Sclerosis; T-Lymphocytes; Tissue Inhibitor of Metalloproteinase-1

Premature infants are at an increased risk of developing cognitive and motor handicaps due to chronic hypoxia. Although the current therapies have reduced the incidence of these handicaps, untoward side effects abound. Using a murine model of sublethal hypoxia, we demonstrated reduction in several transcription factors that modulate expression of genes known to be involved in several neural functions. We demonstrate the induction of these genes by minocycline, a tetracycline antibiotic with noncanonical functions, in both in vitro and in vivo studies. Specifically, there was induction of genes, including Sox10, Hif1a, Hif2a, Birc5, Yap1, Epo, Bdnf, Notch1 (cleaved), Pcna, Mag, Mobp, Plp1, synapsin, Adgra2, Pecam1, and reduction in activation of caspase 3, all known to affect proliferation, apoptosis, synaptic transmission, and nerve transmission. Minocycline treatment of mouse pups reared under sublethal hypoxic conditions resulted in improvement in open field testing parameters. These studies demonstrate beneficial effects of minocycline treatment following hypoxic insult, document up-regulation of several genes associated with improved cognitive function, and support the possibility of minocycline as a potential therapeutic target in the treatment of neurodevelopmental handicaps observed in the very premature newborn population. Additionally, these studies may aid in further interpretation of the effects of minocycline in the treatment trials and animal model studies of fragile X syndrome and multiple sclerosis.

Topics: Adaptor Proteins, Signal Transducing; Animals; Apoptosis; Cell Cycle Proteins; Disease Models, Animal; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Inhibitor of Apoptosis Proteins; Mice, Inbred C57BL; Minocycline; Multiple Sclerosis; Phosphoproteins; Repressor Proteins; SOXE Transcription Factors; Survivin; Up-Regulation; YAP-Signaling Proteins

To identify response biomarkers for pharmaceutical treatment of multiple sclerosis, we induced experimental autoimmune encephalomyelitis (EAE) in rats and treated symptomatic animals with minocycline. Cerebrospinal fluid (CSF) samples were collected 14 days after EAE induction at the peak of neurological symptoms, and proteomics analysis was performed using nano-LC-Orbitrap mass spectrometry. Additionally, the minocycline concentration in CSF was determined using quantitative matrix-assisted laser desorption/ionization-triple-quadrupole tandem mass spectrometry (MALDI-MS/MS) in the selected reaction monitoring (SRM) mode. Fifty percent of the minocycline-treated EAE animals did not show neurological symptoms on day 14 ("responders"), while the other half displayed neurological symptoms ("nonresponders"), indicating that minocycline delayed disease onset and attenuated disease severity in some, but not all, animals. Neither CSF nor plasma minocycline concentrations correlated with the onset of symptoms or disease severity. Analysis of the proteomics data resulted in a list of 20 differentially abundant proteins between the untreated animals and the responder group of animals. Two of these proteins, complement C3 and carboxypeptidase B2, were validated by quantitative LC-MS/MS in the SRM mode. Differences in the CSF proteome between untreated EAE animals and minocycline-treated responders were similar to the differences between minocycline-treated responders and nonresponders (70% overlap). Six proteins that remained unchanged in the minocycline-treated animals but were elevated in untreated EAE animals may be related to the mechanism of action of minocycline.

Topics: Adjuvants, Immunologic; Animals; Carboxypeptidase B; Cerebrospinal Fluid Proteins; Complement C3; Encephalomyelitis, Autoimmune, Experimental; Freund's Adjuvant; Male; Minocycline; Multiple Sclerosis; Neuroprotective Agents; Proteome; Rats; Rats, Inbred Lew; Tandem Mass Spectrometry

Minocycline is a tetracycline family antibiotic that has anti-inflammatory and immunomodulatory properties. These properties have shown promise in the treatment of conditions such as rheumatoid arthritis, Huntington disease, and multiple sclerosis. As lymphocyte activation is involved in the pathogenesis of many of these diseases, T cells are postulated to be a primary target in minocycline therapy. Previous studies have demonstrated attenuation of CD4(+) T cell activation by minocycline, but a specific mechanism has not been elucidated. In this study, we investigated the effect of minocycline on the activity of three key transcription factors regulating CD4(+) T cell activation: NF-κB, AP-1 (activator protein 1), and NFAT (nuclear factor of activated T) cells. Our data demonstrate that minocycline selectively impairs NFAT-mediated transcriptional activation, a result of increased phosphorylation and reduced nuclear translocation of the isoform NFAT1. Minocycline increased the activity of the NFAT kinase GSK3 and decreased intracellular Ca(2+) flux, both of which facilitate NFAT1 phosphorylation. These findings provide a novel mechanism for minocycline induced suppression of CD4(+) T cell activation and may better inform the application of minocycline as an immunomodulatory agent.

Topics: Active Transport, Cell Nucleus; Anti-Bacterial Agents; Anti-Inflammatory Agents; Arthritis, Rheumatoid; Calcium Signaling; CD4-Positive T-Lymphocytes; Cell Nucleus; Cells, Cultured; Enzyme Activation; Enzyme Activators; Glycogen Synthase Kinase 3; Humans; Huntington Disease; Lymphocyte Activation; Minocycline; Multiple Sclerosis; NF-kappa B; NFATC Transcription Factors; Phosphorylation; Protein Isoforms; Transcription Factor AP-1

The subventricular zone (SVZ) of the brain constitutes a niche for neural stem and progenitor cells that can initiate repair after central nervous system (CNS) injury. In a relapsing-remitting model of experimental autoimmune encephalomyelitis (EAE), the neural stem cells (NSCs) become activated and initiate regeneration during acute disease, but lose this ability during the chronic phases of disease. We hypothesized that chronic microglia activation contributes to the failure of the NSC repair potential in the SVZ.. Using bromodeoxyuridine injections at different time points during EAE, we quantified the number of proliferating and differentiating progenitors, and evaluated the structure of the SVZ by electron microscopy. In vivo minocycline treatment during EAE was used to address the effect of microglia inactivation on SVZ dysfunction.. In vivo treatment with minocycline, an inhibitor of microglia activation, increases stem cell proliferation in both naive and EAE animals. Minocycline treatment decreases cortical and periventricular pathology in the chronic phase of EAE, improving the proliferation of Sox2 stem cells and NG2 oligodendrocyte precursors cells originating in the SVZ and their differentiation into mature oligodendrocytes.. These data suggest that failure of repair observed during chronic EAE correlates with microglia activation and that treatments targeting chronic microglial activation have the potential for enhancing repair in the CNS.

Topics: Animals; Anti-Bacterial Agents; Bromodeoxyuridine; Cell Count; Cell Movement; Cell Proliferation; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Mice; Microglia; Microscopy, Electron, Transmission; Minocycline; Multiple Sclerosis; Myelin Proteolipid Protein; Neural Stem Cells; Oligodendroglia; Peptide Fragments; Secondary Prevention; Stem Cell Niche; Time Factors

The complex manifestations of chronic multiple sclerosis (MS)are due in part to widespread axonal abnormalities that affect lesional and nonlesional areas in the central nervous system. We describe an association between microglial activation and axon/oligodendrocyte pathology at nodal and paranodal domains in normal-appearing white matter (NAWM) of MS cases and in experimental autoimmune encephalomyelitis (EAE). The extent of paranodal axoglial (neurofascin-155(+)/Caspr1(+)) disruption correlated with local microglial inflammation and axonal injury (expression of nonphosphorylated neurofilaments) in MS NAWM. These changes were independent of demyelinating lesions and did not correlate with the density of infiltrating lymphocytes. Similar axoglial alterations were seen in the subcortical white matter of Parkinson disease cases and in preclinical EAE, at a time point when there is microglial activation before the infiltration of immune cells. Disruption of the axoglial unit in adjuvant-immunized animals was reversible and coincided with the resolution of microglial inflammation; paranodal damage and microglial inflammation persisted in chronic EAE. Axoglial integrity could be preserved by the administration of minocycline, which inhibited microglial activation, in actively immunized animals. These data indicate that, in MS NAWM, permanent disruption to axoglial domains in an environment of microglial inflammation is an early indicator of axonal injury that likely affects nerve conduction and may contribute to physiologic dysfunction.

Topics: Adult; Aged; Analysis of Variance; Animals; Anti-Bacterial Agents; Axons; Brain; Calcium-Binding Proteins; Caspase 1; CD3 Complex; DNA-Binding Proteins; Encephalomyelitis, Autoimmune, Experimental; Female; Gene Expression Regulation; Glycoproteins; HLA-DR Antigens; Humans; Indoles; Kv1.2 Potassium Channel; Male; Mice; Mice, Inbred C57BL; Microfilament Proteins; Microglia; Microscopy, Confocal; Middle Aged; Minocycline; Multiple Sclerosis; Myelin-Oligodendrocyte Glycoprotein; NAV1.6 Voltage-Gated Sodium Channel; Nerve Tissue Proteins; Neurofilament Proteins; Nitric Oxide Synthase Type II; Peptide Fragments; Postmortem Changes; Ranvier's Nodes; Sodium Channels; Toll-Like Receptor 4

The effects of Glatiramer Acetate (GA) in combination with Minocycline (MIN), a second-generation tetracycline, have been investigated on the course of EAE in mice, resulting in a significant reduction in disease severity and burden with attenuation of the inflammation, axonal loss and demyelination. Here we investigate the effects of combination therapy with GA and MIN on the induction, maturation and phenotyping of blood monocyte-derived dendritic cells (DCs) in Multiple Sclerosis (MS) patients. Hence the expressions of HLA-DR, CD11c, CD83 and CD1a were studied by flow cytometric analysis on immature (iDCs) and mature DCs (mDCs) from untreated and GA treated MS patients. Thirteen relapsing-remitting MS patients and 13 healthy controls (HCs) were included in the study. Ten of the MS patient group were re-tested after a 2 month period of GA treatment. The marker expressions on DC from untreated MS and HCs were studied in vitro in the absence or presence of GA and GA+MIN; and on DCs from GA treated MS patients without and with the in vitro addition of MIN. We found that in vitro GA alone or in combination with MIN downregulated DCs antigen presentation capability (HLA-DR), whereas the combination treatment only affected also myeloid DCs activation (CD83) in both MS and HCs. Prolonged GA treatment (in vivo for 2 months) affected antigen presentation capability by DCs, whereas when treated in vitro with MIN these cells also tended to reduce activation marker expression and myeloid phenotype acquisition (CD11c). The present data demonstrate possible combination effects of GA and MIN on peripheral blood monocyte-derived DCs in MS patients.

Topics: Anti-Bacterial Agents; Antigens, CD; Cells, Cultured; Dendritic Cells; Dose-Response Relationship, Drug; Drug Combinations; Flow Cytometry; Gene Expression Regulation; Glatiramer Acetate; HLA-DR Antigens; Humans; Immunosuppressive Agents; Minocycline; Multiple Sclerosis; Peptides

Multiple sclerosis (MS) is the most common inflammatory demyelinating disorder of the central nervous system (CNS). An approach to improve MS treatment is to identify a rational combination of new medications or existing therapies that impact different aspects of the disease process. Statins are effective in the treatment of MS animal models and are promising candidates for future treatment. Minocycline ameliorates clinical severity of experimental autoimmune encephalomyelitis (EAE) and exhibits several anti-inflammatory and neuroprotective activities. In this study, we tested whether the combination of these two drugs could produce beneficial effects in EAE mice immunized with myelin oligodendrocyte protein (MOG). Our findings show that combined treatment, compared to using the medications alone, resulted in a significant reduction in disease severity, in both the acute and chronic phases of the disease, along with attenuation of inflammation, demyelination and axonal loss. Stereological analysis revealed that the combined treatment significantly guarded against neuroinflammation and neurodegeneration. Moreover, a significant suppression of anti-MOG antibody production in animals treated with the two medications was found. In conclusion, our findings prove that this combination of drugs is neuroprotective and suppresses the severity of EAE. Furthermore, this pharmacological approach appears to be promising as a future therapeutic strategy to control MS.

Topics: Animals; Anti-Bacterial Agents; Atorvastatin; Body Weight; Cell Proliferation; Cytokines; Drug Therapy, Combination; Encephalomyelitis, Autoimmune, Experimental; Enzyme-Linked Immunosorbent Assay; Female; Glial Fibrillary Acidic Protein; Glycoproteins; Heptanoic Acids; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Mice; Mice, Inbred C57BL; Minocycline; Multiple Sclerosis; Myelin-Oligodendrocyte Glycoprotein; Neurologic Examination; Peptide Fragments; Pyrroles; Stereotaxic Techniques; T-Lymphocytes; Time Factors

Topics: Clinical Trials as Topic; Clinical Trials, Phase II as Topic; Cost of Illness; Female; Humans; Male; Minocycline; Multiple Sclerosis

There have been significant advances in the treatment of multiple sclerosis (MS) in recent years, but further improvement in therapy is required as not all patients have responded optimally. An approach to enhancing MS treatment is to combine drugs that impact on different aspects of the disease process. We have described that the tetracycline derivative, minocycline, attenuates the severity of experimental autoimmune encephalomyelitis (EAE), a model of MS. Here, we have evaluated the combination of minocycline and glatiramer acetate (GA), a current therapy in MS, on the course of EAE in mice. This combination resulted in a significant reduction of disease severity and disease burden with attenuation of the inflammation, axonal loss and demyelination.

Topics: Analysis of Variance; Animals; Anti-Bacterial Agents; Cytokines; Demyelinating Diseases; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Encephalomyelitis, Autoimmune, Experimental; Glatiramer Acetate; Immunosuppressive Agents; Inflammation; Lymph Nodes; Mice; Mice, Inbred C57BL; Minocycline; Multiple Sclerosis; Myelin Proteins; Myelin-Associated Glycoprotein; Myelin-Oligodendrocyte Glycoprotein; Peptides; Silver Staining; Spleen; Time Factors

Apart from its devastating impact on individuals and their families, multiple sclerosis (MS) creates a huge economic burden for society by mainly afflicting young adults in their most productive years. Although effective strategies for symptom management and disease modifying therapies have evolved, there exists no curative treatment yet. Worldwide, MS prevalence parallels the distribution of the Lyme disease pathogen Borrelia (B.) burgdorferi, and in America and Europe, the birth excesses of those individuals who later in life develop MS exactly mirror the seasonal distributions of Borrelia transmitting Ixodes ticks. In addition to known acute infections, no other disease exhibits equally marked epidemiological clusters by season and locality, nurturing the hope that prevention might ultimately be attainable. As minocycline, tinidazole and hydroxychloroquine are reportedly capable of destroying both the spirochaetal and cystic L-form of B. burgdorferi found in MS brains, there emerges also new hope for those already afflicted. The immunomodulating anti-inflammatory potential of minocycline and hydroxychloroquine may furthermore reduce the Jarisch Herxheimer reaction triggered by decaying Borrelia at treatment initiation. Even in those cases unrelated to B. burgdorferi, minocycline is known for its beneficial effect on several factors considered to be detrimental in MS. Patients receiving a combination of these pharmaceuticals are thus expected to be cured or to have a longer period of remission compared to untreated controls. Although the goal of this rational, cost-effective and potentially curative treatment seems simple enough, the importance of a scientifically sound approach cannot be overemphasised. A randomised, prospective, double blinded trial is necessary in patients from B. burgdorferi endemic areas with established MS and/or Borrelia L-forms in their cerebrospinal fluid, and to yield reasonable significance within due time, the groups must be large enough and preferably taken together in a multi-centre study.

Topics: Animals; Anti-Bacterial Agents; Borrelia burgdorferi Group; Chronic Disease; Drug Therapy, Combination; Humans; Hydroxychloroquine; Ixodes; Lyme Disease; Minocycline; Multiple Sclerosis; Prevalence; Seasons; Secondary Prevention; Tinidazole

The objective of the current study was to investigate whether minocycline improves the effect of an existing multiple sclerosis (MS) medication, interferon-beta, on experimental autoimmune encephalomyelitis (EAE) in mice. When used at sub-optimal doses, neither medication affected EAE but their combination at these doses led to the significant alleviation of EAE disease severity scores and histological outcomes. In culture, the toxicity of T cells to neurons was alleviated by their prior exposure to minocycline or interferon-beta and their combination further attenuated neuronal death. Collectively, these results suggest the utility of the combination of minocycline and interferon-beta in MS.

Topics: Adult; Animals; Cell Death; Cell Proliferation; Cells, Cultured; Coculture Techniques; Cytotoxicity, Immunologic; Disease Models, Animal; Drug Therapy, Combination; Encephalomyelitis, Autoimmune, Experimental; Humans; Interferon Type I; Lymphocyte Activation; Mice; Minocycline; Multiple Sclerosis; Neurons; Recombinant Proteins; Severity of Illness Index; T-Lymphocyte Subsets

Multiple sclerosis is characterized by the infiltration of leukocytes into the CNS. As matrix metalloproteinases (MMPs) facilitate the passage of leukocytes across matrix barriers, we tested the hypothesis that targeting MMPs could attenuate neuro-inflammation. We report that minocycline, a widely used generic drug with a good safety record, inhibited MMP activity, reduced production of MMP-9 and decreased the transmigration of T lymphocytes across a fibronectin matrix barrier. In addition, minocycline was efficacious against both mild and severe experimental autoimmune encephalomyelitis (EAE) in mice, an animal model of multiple sclerosis. When severe EAE was produced, minocycline pre-treatment delayed the course of the disease: when maximal disease activity occurred in vehicle-treated EAE mice, minocycline animals were relatively normal and had minimal signs of inflammation and demyelination in the CNS. When tested in mice afflicted with mild EAE, minocycline attenuated the clinical severity of disease throughout the course of treatment. These results indicate that minocycline may constitute a safe and inexpensive therapy for multiple sclerosis.

Topics: Animals; Anti-Bacterial Agents; Cell Movement; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Delivery Systems; Encephalomyelitis, Autoimmune, Experimental; Female; Humans; Injections, Intraperitoneal; Leukocytes, Mononuclear; Matrix Metalloproteinase 9; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Mice; Mice, Inbred C57BL; Minocycline; Multiple Sclerosis