Targeting ASIC1 in primary progressive multiple sclerosis: evidence of neuroprotection with amiloride

Abstract

Neurodegeneration is the main cause for permanent disability in multiple sclerosis. The effect of current immunomodulatory treatments on neurodegeneration is insufficient. Therefore, direct neuroprotection and myeloprotection remain an important therapeutic goal. Targeting acid-sensing ion channel 1 (encoded by the ASIC1 gene), which contributes to the excessive intracellular accumulation of injurious Na(+) and Ca(2+) and is over-expressed in acute multiple sclerosis lesions, appears to be a viable strategy to limit cellular injury that is the substrate of neurodegeneration. While blockade of ASIC1 through amiloride, a potassium sparing diuretic that is currently licensed for hypertension and congestive cardiac failure, showed neuroprotective and myeloprotective effects in experimental models of multiple sclerosis, this strategy remains untested in patients with multiple sclerosis. In this translational study, we tested the neuroprotective effects of amiloride in patients with primary progressive multiple sclerosis. First, we assessed ASIC1 expression in chronic brain lesions from post-mortem of patients with progressive multiple sclerosis to identify the target process for neuroprotection. Second, we tested the neuroprotective effect of amiloride in a cohort of 14 patients with primary progressive multiple sclerosis using magnetic resonance imaging markers of neurodegeneration as outcome measures of neuroprotection. Patients with primary progressive multiple sclerosis underwent serial magnetic resonance imaging scans before (pretreatment phase) and during (treatment phase) amiloride treatment for a period of 3 years. Whole-brain volume and tissue integrity were measured with high-resolution T(1)-weighted and diffusion tensor imaging. In chronic brain lesions of patients with progressive multiple sclerosis, we demonstrate an increased expression of ASIC1 in axons and an association with injury markers within chronic inactive lesions. In patients with primary progressive multiple sclerosis, we observed a significant reduction in normalized annual rate of whole-brain volume during the treatment phase, compared with the pretreatment phase (P = 0.018, corrected). Consistent with this reduction, we showed that changes in diffusion indices of tissue damage within major clinically relevant white matter (corpus callosum and corticospinal tract) and deep grey matter (thalamus) structures were significantly reduced during the treatment phase (P = 0.02, corrected). Our results extend evidence of the contribution of ASIC1 to neurodegeneration in multiple sclerosis and suggest that amiloride may exert neuroprotective effects in patients with progressive multiple sclerosis. This pilot study is the first translational study on neuroprotection targeting ASIC1 and supports future randomized controlled trials measuring neuroprotection with amiloride in patients with multiple sclerosis.

Novel Insights into Acid-Sensing Ion Channels: Implications for Degenerative Diseases

“…These findings collectively support the potential efficacy of ASIC1 as a protective target for axon degeneration associated with active MS. Consistent with the pivotal role of ASIC1 in the animal model of MS, studies by Arun et al [47] showed that amiloride exerts a neuroprotective effect in patients with primary progressive MS. The normalized annual rate of whole-brain volume during the amiloride treatment phase (3 years) was significantly reduced, compared to the pretreatment phase.…”

International Union of Basic and Clinical Pharmacology. XCI. Structure, Function, and Pharmacology of Acid-Sensing Ion Channels and the Epithelial Na+Channel

“…It was further shown that ASIC1a is upregulated in lesions from experimental autoimmune encephalomyelitis in mice and from MS patients (Vergo et al, 2011). Treatment with amiloride was neuroprotective in animal models and in human MS patients (Vergo et al, 2011;Arun et al, 2013). Interestingly, an association between the ASIC2 gene and MS has been shown in a remote human population in Sardinia (Bernardinelli et al, 2007).…”

An In Silico Approach for the Evaluation of Nutraceutical Properties of Pearl Millet as a Brain Food

“…As neurofibrillary tangles and amyloid plaque are also involved in pathology of Parkinson's disease and blocks transmission through cortex region or perforant tracks from areas of association of isocortex to hippocampus and cause memory impairment thus same targets as that of Alzheimer's can work for the treatment of the disease by inhibition by the above mentioned constituents of pearl millet [19]. In multiple sclerosis, MMP9 and ASIC1a elevated levels cause havoc by increasing the ion concentrations and early relapse which can be targeted and inhibited effectively by glycosylorientin, glycosylvetixin and vitexin (for MMP) and pelargonidin and quercetin (for ASIC1a), proving their efficiency to cure this disease [18]. So, our hypothesis of using nutraceutical property of pearl millet as a potential treatment for the majority of neurodegenerative disorders is having a great scope as suggested by our docking results.…”

“…Another one is multiple sclerosis in which levels of MMP9 are elevated and becomes the cause of relapsing condition in short duration [17]. ASIC1a is also known to express increasingly and are a potent target for multiple sclerosis as they are responsible for the accumulation of intracellular ions of sodium and calcium and causes injurious symptoms of the disease [18]. So, we considered MMP9, MMP2, Aquaporin 4, ASIC1a and PKC as major targets for our in silico study on NDs treatment.…”