Calpain inhibitors protect against axonal degeneration in a model of anti-ganglioside antibody-mediated motor nerve terminal injury.
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.
O'Hanlon
Graham M
GM
University Department of Neurology, Institute of Neurological Sciences, Southern General Hospital, Glasgow, UK.
Humphreys
Peter D
PD
Goldman
Rebecca S
RS
Halstead
Susan K
SK
Bullens
Roland W M
RW
Plomp
Jaap J
JJ
Ushkaryov
Yuri
Y
Willison
Hugh J
HJ
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D002118:Calcium / Q000494:pharmacology; D003165:Complement System Proteins / Q000494:pharmacology; D046508:Culture Techniques; D003599:Cytoskeleton / Q000187:drug effects / Q000648:ultrastructure; D003964:Diaphragm; D004151:Dipeptides / Q000494:pharmacology; D005089:Exocytosis / Q000187:drug effects; D005732:Gangliosides / Q000276:immunology*; D006023:Glycoproteins / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008854:Microscopy, Electron; D019846:Miller Fisher Syndrome / Q000276:immunology*; D009046:Motor Neurons / Q000187:drug effects / Q000276:immunology / Q000648:ultrastructure; D009414:Nerve Growth Factors / Q000276:immunology; D016900:Neurofilament Proteins / Q000378:metabolism; D009469:Neuromuscular Junction / Q000187:drug effects* / Q000276:immunology / Q000648:ultrastructure; D013111:Spider Venoms / Q000494:pharmacology
D000911:Antibodies, Monoclonal; D004151:Dipeptides; D005732:Gangliosides; D006023:Glycoproteins; D009414:Nerve Growth Factors; D016900:Neurofilament Proteins; D013111:Spider Venoms; C039304:calpain inhibitors; C071482:calpeptin; C020763:alpha-latrotoxin; C039129:GQ1b ganglioside; D003165:Complement System Proteins; D002118:Calcium