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

ABSTRACT: 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.

SUBMITTER: Brown D

PROVIDER: S-EPMC8116375 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundThe mechanisms driving multiple sclerosis (MS), the most common cause of non-traumatic disability in young adults, remain unknown despite extensive research. Especially puzzling are the underlying molecular processes behind the two major disease patterns of MS: relapsing-remitting and progressive. The relapsing-remitting course is exemplified by acute inflammatory attacks, whereas progressive MS is characterized by neurodegeneration on a background of mild-moderate inflammation. The molecular and cellular features differentiating the two patterns are still unclear, and the role of inflammation during progressive disease is a subject of active debate.MethodsWe performed a comprehensive analysis of the intrathecal inflammation in two clinically distinct mouse models of MS: the PLP139-151-induced relapsing experimental autoimmune encephalomyelitis (R-EAE) and the chronic progressive, Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD). Microarray technology was first used to examine global gene expression changes in the spinal cord. Inflammation in the spinal cord was further assessed by immunohistochemical image analysis and flow cytometry. Levels of serum and cerebrospinal fluid (CSF) immunoglobulin (Ig) isotypes and chemokines were quantitated using Luminex Multiplex technology, whereas a capture ELISA was used to measure serum and CSF albumin levels. Finally, an intrathecal Ig synthesis index was established with the ratio of CSF and serum test results corrected as a ratio of their albumin concentrations.ResultsMicroarray analysis identified an enrichment of B cell- and Ig-related genes upregulated in TMEV-IDD mice. We also demonstrated an increased level of intrathecal Ig synthesis as well as a marked infiltration of late differentiated B cells, including antibody secreting cells (ASC), in the spinal cord of TMEV-IDD, but not R-EAE mice. An intact blood-brain barrier in TMEV-IDD mice along with higher CSF levels of CXCL13, CXCL12, and CCL19 provides evidence for an intrathecal synthesis of chemokines mediating B cell localization to the central nervous system (CNS).ConclusionsOverall, these findings, showing increased concentrations of intrathecally produced Igs, substantial infiltration of ASC, and the presence of B cell supporting chemokines in the CNS of TMEV-IDD mice, but not R-EAE mice, suggest a potentially important role for Igs and ASC in the chronic progressive phase of demyelinating diseases.

Project description:Some recent studies suggest that in progressive multiple sclerosis, neurodegeneration may occur independently from inflammation. The aim of our study was to analyse the interdependence of inflammation, neurodegeneration and disease progression in various multiple sclerosis stages in relation to lesional activity and clinical course, with a particular focus on progressive multiple sclerosis. The study is based on detailed quantification of different inflammatory cells in relation to axonal injury in 67 multiple sclerosis autopsies from different disease stages and 28 controls without neurological disease or brain lesions. We found that pronounced inflammation in the brain is not only present in acute and relapsing multiple sclerosis but also in the secondary and primary progressive disease. T- and B-cell infiltrates correlated with the activity of demyelinating lesions, while plasma cell infiltrates were most pronounced in patients with secondary progressive multiple sclerosis (SPMS) and primary progressive multiple sclerosis (PPMS) and even persisted, when T- and B-cell infiltrates declined to levels seen in age matched controls. A highly significant association between inflammation and axonal injury was seen in the global multiple sclerosis population as well as in progressive multiple sclerosis alone. In older patients (median 76 years) with long-disease duration (median 372 months), inflammatory infiltrates declined to levels similar to those found in age-matched controls and the extent of axonal injury, too, was comparable with that in age-matched controls. Ongoing neurodegeneration in these patients, which exceeded the extent found in normal controls, could be attributed to confounding pathologies such as Alzheimer's or vascular disease. Our study suggests a close association between inflammation and neurodegeneration in all lesions and disease stages of multiple sclerosis. It further indicates that the disease processes of multiple sclerosis may die out in aged patients with long-standing disease.

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

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