Dose-response of cyclosporin A in attenuating traumatic axonal injury in rat

David O. Okonkwo*, David E. Melon, Anthony J. Pellicane, Leman K. Mutlu, David G. Rubin, James R. Stone, Gregory A. Helm

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

62 Scopus citations


Cyclosporin A has emerged as a promising therapeutic agent in traumatic brain injury (TBI), although its precise neuroprotective mechanism is unclear. Cyclosporin A, given as a single-dose intrathecal bolus, has previously been shown to attenuate mitochondrial damage and reduce axonal injury in experimental TBI. We assessed the effect of a range of intravenous cyclosporin A doses upon axonal injury attenuation to determine the ideal dose. Rats were subjected to experimental TBI and given one of five intravenous doses of cyclosporin A. At 3 h post-injury, brains were processed for brain tissue cyclosporin A concentration. In a second set of animals, at 24 h postinjury, brains were processed for amyroid precursor protein immunoreactivity, a widely used marker of axonal injury. Intravenous administration produced therapeutic levels of cyclosporin A in brain parenchyma. Higher concentrations were achieved with equivalent doses given intrathecally; this is consistent with the reported poor blood-brain barrier permeability of cyclosporin A. Cyclosporin A 10 mg/kg i.v. produced the greatest degree of neuroprotection against diffuse axonal injury; cyclosporin A 50 mg/kg i.v. was toxic. Intravenous cyclosporin A administration achieves therapeutic levers in brain parenchyma and 10 mg/kg is the most effective dose in attenuating axonal damage after traumatic brain injury.

Original languageEnglish
Pages (from-to)463-466
Number of pages4
Issue number3
StatePublished - 3 Mar 2003
Externally publishedYes


  • Calcineurin
  • Cyclosporin A
  • Diffuse axonal injury
  • Mitochondria
  • Traumatic brain injury


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