Oral 9th Venoms to Drugs 2026

Venom peptide inhibitors reveal how acid-sensing ion channel 1a contributes to the pathology of multiple sclerosis (145263)

Lachlan D Rash 1 , Maleeha Waqar 1 , Neville Butcher 1 , Nemat Khan 1
  1. The University of Queensland, St Lucia, QLD, Australia

Introduction: Acid-sensing ion channel 1a (ASIC1a) is a ligand-gated sodium channel activated by acidosis [1]. Expression of ASIC1a protein is increased in damaged axons in spinal cords from EAE-mice and in MS lesions and inhibition of ASIC1a is neuroprotective in EAE [2]. How ASIC1a contributes to axonal damage and whether ASIC1a contributes directly to neuroinflammation in the pathology of EAE/MS is currently unknown. Aims: The aim of this study was to determine the efficacy of the funnel wed spider venom peptide Hi1a [3] in the mouse EAE model and mechanism by which ASIC1a activation leads to axonal damage, and if ASIC1a expression and activation may contribute to astrogliosis. Methods: Acute EAE was induced in wild-type or ASIC1a knockout, female C57BL/6 mice (10 weeks old). Following symptom onset (EAE score 0.5, a.u.) mice were randomized to receive either Hi1a (50 ug/kg) or vehicle once-daily using intraperitoneal injection. Post-mortem tissue analysis was done using immunohistochemistry (IHC) and Western blots to assess changes in ASIC1a expression in relation to markers of necroptosis and astrocyte activation. IHC analysis of human MS lesions was also carried out to compare the results from EAE mice to clinical samples. Results: Genetic knockout or peripheral administration Hi1a significantly reduced motor deficits and paralysis in EAE mice. Post-mortem analysis revealed that proteins in the necroptosis pathway (receptor interacting protein kinase 1 [RIPK1], and mixed lineage kinase domain-like protein [MLKL]) increase in the spinal cord of EAE mice. This was significantly inhibited in both Hi1a-treated and ASIC1a knockout mice. ASIC1a protein strongly colocalised with the necroptosis effector MLKL in damaged (SMI32 positive) axons in the spinal cord. ASIC1a protein expression was absent in astrocytes from naïve mice but appeared and increased with increasing symptom severity in spinal cord astrocytes in EAE mice. Analysis of postmortem human tissues confirmed that ASIC1a expression increases in astrocytes in MS lesions. Conclusion: Tissue acidosis and necroptosis (an inflammation-inducing mechanism of cell death) occur in MS and EAE. Our results suggest that activation of ASIC1a can directly mediate axonal damage by triggering neuronal necroptosis in EAE. Furthermore, we show that ASIC1a protein expression in astrocytes correlates with EAE symptom severity suggesting that its activation may also contribute to directly to neuroinflammation by enhancing astrogliosis, and that this also occurs in human MS lesions.

  1. Rash, L. D. and S. Kellenberger (2026). "Acid-sensing ion channels: structure, function, pharmacology, and clinical significance." Physiol Rev 106(1): 281–362.
  2. Vergo, S., M. J. Craner, R. Etzensperger, K. Attfield, M. A. Friese, J. Newcombe, M. Esiri and L. Fugger (2011). "Acid-sensing ion channel 1 is involved in both axonal injury and demyelination in multiple sclerosis and its animal model." Brain 134(Pt 2): 571–584.
  3. Chassagnon, I. R., C. A. McCarthy, Y. K. Chin, S. S. Pineda, A. Keramidas, M. Mobli, V. Pham, T. M. De Silva, J. W. Lynch, R. E. Widdop, L. D. Rash and G. F. King (2017). "Potent neuroprotection after stroke afforded by a double-knot spider-venom peptide that inhibits acid-sensing ion channel 1a." Proc Natl Acad Sci U S A 114(14): 3750–3755.