title: Short-duration treatment with the calpain inhibitor MDL-28170 does not protect axonal transport in an in vivo model of traumatic axonal injury.
abstract: Traumatic axonal injury is characterized by early cytoskeletal proteolysis and disruption of axonal transport. Calpain inhibition has been shown to protect axons in rodent models of traumatic brain injury. However, in these models, both white and gray matter are injured, making it difficult to determine if calpain inhibitors are directly protecting injured axons. To address this issue, we used our rat optic nerve stretch model to test the hypothesis that early calpain inhibition directly protects central nervous system (CNS) axons following stretch injury. Rats were given an intravenous bolus of the calpain inhibitor MDL-28170 (30 mg/kg) 30 min prior to unilateral optic nerve stretch, followed by a 15 mg/kg/h intravenous infusion over the next 2.5 h. Immunohistochemical analysis of optic nerves 30 min after stretch injury revealed variable increases of calpain-cleaved α-spectrin that appeared less evident in stretched nerves from drug-treated rats, although this difference was not statistically significant. Retrograde axonal transport measured by Fluorogold® labeling of retinal ganglion cells was significantly impaired after stretch injury. However, there was no difference in the number of Fluorogold-labeled cells in the vehicle vs. drug treatment groups. These results suggest that early short-duration calpain inhibitor therapy with MDL-28170 is not an effective strategy to prevent disruption of axonal transport following isolated axonal stretch injury in the CNS.
authors.affiliation: Department of Emergency Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. mamarek@uphs.upenn.edu
authors.forename: Marek
authors.initials: M
authors.lastname: Ma
authors.forename: Luchuan
authors.initials: L
authors.lastname: Li
authors.forename: Xinran
authors.initials: X
authors.lastname: Wang
authors.forename: Diana L
authors.initials: DL
authors.lastname: Bull
authors.forename: Frances S
authors.initials: FS
authors.lastname: Shofer
authors.forename: David F
authors.initials: DF
authors.lastname: Meaney
authors.forename: Robert W
authors.initials: RW
authors.lastname: Neumar
mesh_terms: D000818:Animals; D001370:Axonal Transport / Q000187:drug effects* / Q000502:physiology; D002154:Calpain / Q000037:antagonists & inhibitors*; D015853:Cysteine Proteinase Inhibitors / Q000008:administration & dosage*; D020833:Diffuse Axonal Injury / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D004151:Dipeptides / Q000494:pharmacology*; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D008297:Male; D018696:Neuroprotective Agents / Q000008:administration & dosage; D051381:Rats; D020318:Rats, Long-Evans; D013997:Time Factors; D017211:Treatment Failure
chemical_list: D015853:Cysteine Proteinase Inhibitors; D004151:Dipeptides; D018696:Neuroprotective Agents; D002154:Calpain; C058076:calpain inhibitor III
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