Cyclosporin A limits calcium-induced axonal damage following traumatic brain injury.
In traumatic axonal injury, Ca2+ influx across a focally damaged axolemma precipitates local mitochondrial failure, degradation of the subaxolemmal spectrin network and compaction of neurofilaments, which collectively contribute to axonal failure. In previous studies, cyclosporin A pretreatment preserved mitochondrial integrity and attenuated axonal failure following trauma. Here we investigate whether this CsA-linked protection was related to the concomitant blunting of intra-axonal, Ca2+-induced cytoskeletal changes in traumatic axonal injury, assessed with antibodies targeting spectrin proteolysis and neurofilament compaction. CsA pretreatment dramatically reduced Ca2+-induced cytoskeletal damage following injury; CsA-treated rats, compared with vehicle-treated rats, displayed a 70% decrease in immunoreactive/damaged profiles. We suggest that CsA-mediated preservation of mitochondrial integrity enables the restoration of ionic and metabolic homeostasis thereby short-circuiting Ca2+-induced proteolysis in injured axons.
Okonkwo
D O
DO
Department of Anatomy, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298-0709, USA.
Büki
A
A
Siman
R
R
Povlishock
J T
JT
D000818:Animals; D001369:Axons / Q000187:drug effects* / Q000473:pathology; D015415:Biomarkers; D001921:Brain / Q000473:pathology; D001930:Brain Injuries / Q000473:pathology*; D002118:Calcium / Q000502:physiology*; D002154:Calpain / Q000502:physiology; D016572:Cyclosporine / Q000494:pharmacology*; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D008297:Male; D010447:Peptide Hydrolases / Q000378:metabolism; D011712:Pyramidal Tracts / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013049:Spectrin / Q000378:metabolism
D015415:Biomarkers; D013049:Spectrin; D016572:Cyclosporine; D010447:Peptide Hydrolases; D002154:Calpain; D002118:Calcium