Combination of Hydroxychloroquine and Indapamide to Attenuate Neurodegeneration in Models of Multiple Sclerosis

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dc.contributor.advisorYong, Voon Wee
dc.contributor.authorBrown, Dennis
dc.contributor.committeememberOusman, Shalina S.
dc.contributor.committeememberKoch, Marcus A.
dc.date2020-11
dc.date.accessioned2020-06-16T16:06:29Z
dc.date.available2020-06-16T16:06:29Z
dc.date.issued2020-06-11
dc.description.abstractAs the underlying pathophysiology of progressive forms of multiple sclerosis (MS) are unclear, current treatment strategies remain inadequate. Progressive MS is associated with increased oxidative stress and neuronal damage in lesions along with an extensive representation of activated microglia/macrophages. We tested a novel combination of generic medications, hydroxychloroquine (HCQ) and indapamide, to target the aforementioned pathologies associated with progressive MS. HCQ is an anti-malarial known to inhibit microglial activation, ameliorate EAE disease activity, and is currently in a Phase II trial in primary progressive MS. Indapamide is an antihypertensive previously discovered in our laboratory drug screen to be an antioxidant. Indapamide was also found to be neuroprotective in vitro and in the lysolecithin model of demyelination. As MS disease activity is ongoing or episodic, I employed a pre-treatment paradigm prior to inducing a demyelinating spinal cord lesion in mice with lysolecithin. I found the combination but not individual treatment of HCQ and indapamide to reduce microglia/macrophage CD68+ representation in lesion, and to attenuate neuronal impairment as determined by amyloid precursor protein accumulation in axons that traverse the area of injury. In vitro, HCQ and indapamide in combination had robust neuroprotective and antioxidant effects, in addition to attenuating microglial activation. With a lack of pharmaceutical treatments currently available for the progressive forms of MS, it is critical that research is focused on improving therapeutics for this unmet need of MS. With the promising results of the combination treatment of HCQ and indapamide in neuroprotection in vitro and in vivo, this thesis hopes to provide the preclinical rationale for a new and affordable combination treatment strategy targeting multiple facets of progressive MS.en_US
dc.identifier.citationBrown, D. (2020). Combination of Hydroxychloroquine and Indapamide to Attenuate Neurodegeneration in Models of Multiple Sclerosis (Master's thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.en_US
dc.identifier.doihttp://dx.doi.org/10.11575/PRISM/37931
dc.identifier.urihttp://hdl.handle.net/1880/112197
dc.language.isoengen_US
dc.publisher.facultyCumming School of Medicineen_US
dc.publisher.institutionUniversity of Calgaryen
dc.rightsUniversity of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission.en_US
dc.subjectmultiple sclerosisen_US
dc.subjectneurodegenerationen_US
dc.subjectmicrogliaen_US
dc.subjecthydroxychloroquineen_US
dc.subjectindapamideen_US
dc.subjectoxidative stressen_US
dc.subjectneuroprotectionen_US
dc.subjectlysolecithinen_US
dc.subjectdemyelinationen_US
dc.subjectmacrophageen_US
dc.subject.classificationBiology--Cellen_US
dc.subject.classificationBiology--Molecularen_US
dc.subject.classificationNeuroscienceen_US
dc.subject.classificationImmunologyen_US
dc.subject.classificationChemistry--Pharmaceuticalen_US
dc.titleCombination of Hydroxychloroquine and Indapamide to Attenuate Neurodegeneration in Models of Multiple Sclerosisen_US
dc.typemaster thesisen_US
thesis.degree.disciplineMedicine – Neuroscienceen_US
thesis.degree.grantorUniversity of Calgaryen_US
thesis.degree.nameMaster of Science (MSc)en_US
ucalgary.item.requestcopytrueen_US
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