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Brain Advance Access published online on August 22, 2003
Brain, doi:10.1093/brain/awg254
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© 2003 The Guarantors of Brain

Article

Calpain inhibitors protect against axonal degeneration in a model of anti-ganglioside antibody-mediated motor nerve terminal injury

Graham M. O'Hanlon 1, Peter D. Humphreys 1, Rebecca S. Goldman 1, Susan K. Halstead 1, Roland W. M. Bullens 2, Jaap J. Plomp 2, Yuri Ushkaryov 3, and Hugh J. Willison 1*

1 University Department of Neurology, Institute of Neurological Sciences, Southern General Hospital, Glasgow, G51 4TF, UK
2 Neurophysiology, Leiden University Medical Centre, The Netherlands; Neurology, Leiden University Medical Centre, The Netherlands
3 Department of Biological Sciences, Imperial College, London, UK

* Corresponding author. E-mail: h.j.willison{at}udcf.gla.ac.uk.

Received 29 April 2003 ; revised 4 June 2003 ; accepted 5 June 2003

Abstract

Miller Fisher syndrome-associated anti-GQ1b ganglioside antibodies produce an acute complement-dependent neuroexocytic effect at the mouse neuromuscular junction (NMJ) that closely resembles the effect of {alpha}-latrotoxin (LTx). This pathophysiological effect is accompanied by morphological disruption of the nerve terminal involving the loss of major cytoskeletal components, including neurofilament. Both LTx and the membrane attack complex of complement form membrane pores that allow free ionic movement and we have previously hypothesized that Ca2+ ingress and the subsequent activation of Ca2+-dependent proteases, calpains, may lead to substrate degradation resulting in structural disorganization of the terminal. Here, we treated mouse NMJs in hemidiaphragm preparations with anti-GQ1b antibodies and complement, or with LTx in the presence and absence of extracellular Ca2+, and studied possible neuroprotective effects of the calpain inhibitors calpeptin and calpain inhibitor V. Both Ca2+ depletion and calpain inhibition protected the cytoskeleton from degradation, as assessed by immunohistological and ultrastructural analysis. Calpain inhibitors may therefore be useful therapeutically in limiting nerve terminal and axonal injury in autoimmune peripheral neuropathy and in human latrodectism.

Keywords: Miller Fisher syndrome; neuromuscular junction; anti-ganglioside antibody; {alpha}-latrotoxin; calpain inhibitor
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