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

Abstract

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 amyloid 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 levels in brain parenchyma and 10 mg/kg is the most effective dose in attenuating axonal damage after traumatic brain injury.

• Authors: David O Okonkwo, David E Melon, Anthony J Pellicane, Leman K Mutlu, David G Rubin, James R Stone, Gregory A Helm
• Journal: Neuroreport (Neuroreport) Vol. 14 Issue 3 Pg. 463-6 (Mar 03 2003) ISSN: 0959-4965 [Print] England
• PMID: 12634504 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amyloid beta-Protein Precursor
• Cyclosporine

Topics

• Amyloid beta-Protein Precursor (metabolism)
• Animals
• Axons (drug effects, pathology)
• Brain (metabolism, pathology)
• Brain Injuries (drug therapy, metabolism, pathology)
• Cyclosporine (administration & dosage, adverse effects, pharmacokinetics)
• Dose-Response Relationship, Drug
• Immunohistochemistry
• Injections, Intravenous
• Male
• Osmolar Concentration
• Rats
• Rats, Sprague-Dawley
• Seizures (chemically induced)
• Wounds, Nonpenetrating (drug therapy, metabolism, pathology)