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The possibility of secondary axotomy\u2014a delayed and potentially reversible form of disconnection\u2014has not been evaluated. Here, we investigated secondary axotomy in a rat model of sciatic nerve stretch injury. We also evaluated whether axon sparing and functional improvement results from pharmacological blockade of the sodium\u2010calcium exchanger 1 (NCX1), which is widely believed to contribute to traumatic axon degeneration but was previously only investigated in vitro.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We studied peripheral nerve secondary axotomy in a clinically relevant rat model of sciatic nerve rapid stretch injury with immunolabeling and fluorescence microscopy. The role of NCX1 in secondary axotomy was studied with pharmacological inhibition with SEA0400 and immunolabeling, immunoblot, and behavioral assays.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We found that early after injury, many axons remained in\u2010continuity and that degeneration of axons was delayed, consistent with the occurrence of secondary axotomy. \u03b2APP, a marker of secondary axotomy, accumulated at regions of axon swelling and disconnection, and NCX1 was upregulated and co\u2010localized to \u03b2APP axonal swellings. Pharmacological blockade of NCX1 after injury reduced calpain activation, proteolytic degradation of neurofilaments, \u03b2APP accumulation, distal axon degeneration, and improved hindlimb function.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>Our data demonstrate a major role for secondary axotomy in peripheral nerve stretch injury and identify NCX1 as a promising therapeutic target to reduce secondary axotomy and improve functional outcome after nerve injury.<\/jats:p><\/jats:sec>","DOI":"10.1111\/jns.12663","type":"journal-article","created":{"date-parts":[[2024,10,15]],"date-time":"2024-10-15T05:11:32Z","timestamp":1728969092000},"page":"555-566","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["The <scp>NCX1<\/scp> calcium exchanger is implicated in delayed axotomy after peripheral nerve stretch injury"],"prefix":"10.1111","volume":"29","author":[{"given":"Bradley","family":"Wilhelmy","sequence":"first","affiliation":[{"name":"Department of Neurosurgery University of Maryland School of Medicine  Baltimore Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Volodymyr","family":"Gerzanich","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery University of Maryland School of Medicine  Baltimore Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J. 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