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Cyclosporin‐A treatment attenuates delayed cytoskeletal alterations and secondary axotomy following mild axonal stretch injury
Author(s) -
Staal J.A.,
Dickson T.C.,
Chung R.S.,
Vickers J.C.
Publication year - 2007
Publication title -
developmental neurobiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.716
H-Index - 129
eISSN - 1932-846X
pISSN - 1932-8451
DOI - 10.1002/dneu.20552
Subject(s) - axotomy , neurofilament , axon , cytoskeleton , biology , diffuse axonal injury , spectrin , microbiology and biotechnology , pathology , anatomy , central nervous system , neuroscience , traumatic brain injury , medicine , immunology , immunohistochemistry , biochemistry , cell , psychiatry
Following central nervous system trauma, diffuse axonal injury and secondary axotomy result from a cascade of cellular alterations including cytoskeletal and mitochondrial disruption. We have examined the link between intracellular changes following mild/moderate axonal stretch injury and secondary axotomy in rat cortical neurons cultured to relative maturity (21 days in vitro ). Axon bundles were transiently stretched to a strain level between 103% and 106% using controlled pressurized fluid. Double‐immunohistochemical analysis of neurofilaments, neuronal spectrin, α‐internexin, cytochrome‐c, and ubiquitin was conducted at 24‐, 48‐, 72‐, and 96‐h postinjury. Stretch injury resulted in delayed cytoskeletal damage, maximal at 48‐h postinjury. Accumulation of cytochrome‐c and ubiquitin was also evident at 48 h following injury and colocalized to axonal regions of cytoskeletal disruption. Pretreatment of cultures with cyclosporin‐A, an inhibitor of calcineurin and the mitochondrial membrane transitional pore, reduced the degree of cytoskeletal damage in stretch‐injured axonal bundles. At 48‐h postinjury, 20% of untreated cultures demonstrated secondary axotomy, whereas cyclosporin A‐treated axon bundles remained intact. By 72‐h postinjury, 50% of control preparations and 7% of cyclosporin A‐treated axonal bundles had progressed to secondary axotomy, respectively. Statistical analyses demonstrated a significant ( p < 0.05) reduction in secondary axotomy between treated and untreated cultures. In summary, these results suggest that cyclosporin‐A reduces progressive cytoskeletal damage and secondary axotomy following transient axonal stretch injury in vitro . © 2007 Wiley Periodicals, Inc. Develop Neurobiol, 2007