Yong, Voon WeeBrown, Dennis2020-06-162020-06-162020-06-11Brown, 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.http://hdl.handle.net/1880/112197As 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.engUniversity 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.multiple sclerosisneurodegenerationmicrogliahydroxychloroquineindapamideoxidative stressneuroprotectionlysolecithindemyelinationmacrophageBiology--CellBiology--MolecularNeuroscienceImmunologyChemistry--Pharmaceuticalmaster thesis10.11575/PRISM/37931