Combination of Hydroxychloroquine and Indapamide Attenuates Neurodegeneration in Models Relevant to Multiple...

As the underlying pathophysiology of progressive forms of multiple sclerosis (MS) remains unclear, current treatment strategies are inadequate. Progressive MS is associated with increased oxidative stress and neuronal damage in lesions along with an extensive representation of activated microglia/macrophages. To target these disease mechanisms, we tested the novel combination of generic medications, hydroxychloroquine (HCQ), and indapamide, in tissue culture and in mice. HCQ is an anti-malarial medication found to inhibit microglial activation and to ameliorate disease activity in experimental autoimmune encephalomyelitis. We are currently completing a phase II trial of HCQ in primary progressive MS ( ClinicalTrials.gov Identifier: NCT02913157). Indapamide is an antihypertensive previously discovered in our laboratory drug screen to be an anti-oxidant. As these medications have a different spectrum of activities on disease mechanisms relevant to progressive MS, their use in combination may be more effective than either alone. We thus sought preclinical data for the effectiveness of this combination. In vitro, indapamide had robust hydroxyl scavenging activity, while HCQ and indapamide alone and in combination protected against iron-induced neuronal killing; TNF-α levels in activated microglia were reduced by either drug alone, without additional combination effects. In mice with a lysolecithin lesion that manifests demyelination and axonal loss in the spinal cord, the combination but not individual treatment of HCQ and indapamide reduced CD68⁺ microglia/macrophage representation in lesions, attenuated axonal injury, and lowered levels of lipid peroxidation. Our study supports the combination of indapamide and HCQ as a new treatment strategy targeting multiple facets of progressive MS.