Arun et al. Targeting ASIC1 in primary progressive multiple sclerosis: evidence of neuroprotection with amiloride. Brain. 2013 136:106-15.
Background: Neurodegeneration is the main cause for permanent disability in MS. 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 MSers.
Methods: In this translational study, they tested the neuroprotective effects of amiloride in MSers with primary progressive multiple sclerosis (PPMS). First, they assessed ASIC1 expression in chronic brain lesions from post-mortem of MSers with progressive multiple sclerosis to identify the target process for neuroprotection. Second, they tested the neuroprotective effect of amiloride in a cohort of 14 MSers with primary progressive MS using MRI markers of neurodegeneration as outcome measures of neuroprotection. MSers with PPMS underwent serial MRI 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.
“There is already advanced plans for a clinical trial in progressive MS as part of the SMART study and another trial in optic neuritis is happening. These were discussed by Drs Toosey and Dr Chataway at our research day and will be on this blog for you to see in ~2-3 weeks time.”