Simon Faissner1, Yasamin Mahjoub2, Manoj Mishra2, Steffen Haupeltshofer3, Jennifer Nancy Hahn2, Ralf Gold3, Marcus Koch2, Luanne M Metz2, Tamir Ben-Hur4, V Wee Yong2. 1. Hotchkiss Brain Institute and Department of Clinical Neurosciences, University of Calgary, Calgary, AB, Canada/St. Josef-Hospital and Department of Neurology, Ruhr-University Bochum, Bochum, Germany. 2. Hotchkiss Brain Institute and Department of Clinical Neurosciences, University of Calgary, Calgary, AB, Canada. 3. St. Josef-Hospital and Department of Neurology, Ruhr-University Bochum, Bochum, Germany. 4. Department of Neurology, Hadassah Medical Center and The Hebrew University of Jerusalem, Jerusalem, Israel.
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.
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 ABHmice, 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.
Authors: Ulrike W Kaunzner; Yeona Kang; Shun Zhang; Eric Morris; Yihao Yao; Sneha Pandya; Sandra M Hurtado Rua; Calvin Park; Kelly M Gillen; Thanh D Nguyen; Yi Wang; David Pitt; Susan A Gauthier Journal: Brain Date: 2019-01-01 Impact factor: 13.501