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Animal models demonstrate anti\u2010ganglioside antibodies (AGAb) induce axolemmal complement pore formation through which calcium flux activates the intra\u2010axonal calcium\u2010dependent proteases, calpains. We previously showed protection of axonal components using soluble calpain inhibitors in ex vivo GBS mouse models, and herein, we assess the potential of axonally\u2010restricted calpain inhibition as a neuroprotective therapy operating in vivo. Using transgenic mice that over\u2010express the endogenous human calpain inhibitor calpastatin (<jats:italic>hCAST<\/jats:italic>) neuronally, we assessed distal motor nerve integrity in our established GBS models. We induced immune\u2010mediated injury with monoclonal AGAb plus a source of human complement. The calpain substrates neurofilament and AnkyrinG, nerve structural proteins, were assessed by immunolabelling and in the case of neurofilament, by single\u2010molecule arrays (Simoa). As the distal intramuscular portion of the phrenic nerve is prominently targeted in our in vivo model, respiratory function was assessed by whole\u2010body plethysmography as the functional output in the acute and extended models.<jats:italic>hCAST<\/jats:italic>expression protects distal nerve structural integrity both ex and in vivo, as shown by attenuation of neurofilament breakdown by immunolabelling and Simoa. In an extended in vivo model, while mice still initially undergo respiratory distress owing to acute conduction failure, the recovery phase was accelerated by<jats:italic>hCAST<\/jats:italic>expression. Axonal calpain inhibition can protect the axonal integrity of the nerve in an in vivo GBS paradigm and hasten recovery. These studies reinforce the strong justification for developing further animal and human clinical studies using exogenous calpain inhibitors.<\/jats:p>","DOI":"10.1111\/jns.12520","type":"journal-article","created":{"date-parts":[[2022,11,6]],"date-time":"2022-11-06T15:29:48Z","timestamp":1667748588000},"page":"4-16","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["The endogenous calpain inhibitor calpastatin attenuates axon degeneration in murine<scp>Guillain\u2010Barr\u00e9<\/scp>syndrome"],"prefix":"10.1111","volume":"28","author":[{"given":"Rhona","family":"McGonigal","sequence":"first","affiliation":[{"name":"School of Infection &amp; Immunity University of Glasgow Glasgow United Kingdom"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Madeleine E.","family":"Cunningham","sequence":"additional","affiliation":[{"name":"School of Infection &amp; Immunity University of Glasgow Glasgow United 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