Targeting ASIC1 in primary progressive multiple sclerosis

Evidence of neuroprotection with amiloride

Tarunya Arun, Valentina Tomassini, Emilia Sbardella, Michiel B. De Ruiter, Lucy Matthews, Maria Isabel Leite, Rose Gelineau-Morel, Ana Cavey, Sandra Vergo, Matt Craner, Lars Fugger, Alex Rovira, Mark Jenkinson, Jacqueline Palace

Research output: Contribution to journalArticle

74 Citations (Scopus)

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 Ca2+ 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.

Original languageEnglish
Pages (from-to)106-115
Number of pages10
JournalBrain
Volume136
Issue number1
DOIs
Publication statusPublished - 2013

Fingerprint

Chronic Progressive Multiple Sclerosis
Amiloride
Multiple Sclerosis
Neuroprotective Agents
Brain
Therapeutics
Potassium Sparing Diuretics
Acid Sensing Ion Channels
Magnetic Resonance Imaging
Neuroprotection
Pyramidal Tracts
Diffusion Tensor Imaging
Corpus Callosum
Wounds and Injuries
Thalamus
Axons
Theoretical Models
Randomized Controlled Trials
Heart Failure
Outcome Assessment (Health Care)

Keywords

  • acid-sensing ion channel
  • amiloride
  • MRI
  • multiple sclerosis
  • neuroprotection

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Arun, T., Tomassini, V., Sbardella, E., De Ruiter, M. B., Matthews, L., Leite, M. I., ... Palace, J. (2013). Targeting ASIC1 in primary progressive multiple sclerosis: Evidence of neuroprotection with amiloride. Brain, 136(1), 106-115. https://doi.org/10.1093/brain/aws325

Targeting ASIC1 in primary progressive multiple sclerosis : Evidence of neuroprotection with amiloride. / Arun, Tarunya; Tomassini, Valentina; Sbardella, Emilia; De Ruiter, Michiel B.; Matthews, Lucy; Leite, Maria Isabel; Gelineau-Morel, Rose; Cavey, Ana; Vergo, Sandra; Craner, Matt; Fugger, Lars; Rovira, Alex; Jenkinson, Mark; Palace, Jacqueline.

In: Brain, Vol. 136, No. 1, 2013, p. 106-115.

Research output: Contribution to journalArticle

Arun, T, Tomassini, V, Sbardella, E, De Ruiter, MB, Matthews, L, Leite, MI, Gelineau-Morel, R, Cavey, A, Vergo, S, Craner, M, Fugger, L, Rovira, A, Jenkinson, M & Palace, J 2013, 'Targeting ASIC1 in primary progressive multiple sclerosis: Evidence of neuroprotection with amiloride', Brain, vol. 136, no. 1, pp. 106-115. https://doi.org/10.1093/brain/aws325
Arun T, Tomassini V, Sbardella E, De Ruiter MB, Matthews L, Leite MI et al. Targeting ASIC1 in primary progressive multiple sclerosis: Evidence of neuroprotection with amiloride. Brain. 2013;136(1):106-115. https://doi.org/10.1093/brain/aws325
Arun, Tarunya ; Tomassini, Valentina ; Sbardella, Emilia ; De Ruiter, Michiel B. ; Matthews, Lucy ; Leite, Maria Isabel ; Gelineau-Morel, Rose ; Cavey, Ana ; Vergo, Sandra ; Craner, Matt ; Fugger, Lars ; Rovira, Alex ; Jenkinson, Mark ; Palace, Jacqueline. / Targeting ASIC1 in primary progressive multiple sclerosis : Evidence of neuroprotection with amiloride. In: Brain. 2013 ; Vol. 136, No. 1. pp. 106-115.
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