NEUROPHARMACOLOGY AND NEUROTOXICOLOGYDose–response of cyclosporin A in attenuating traumatic axonal injury in ratOkonkwo, David O.1 CA; Melon, David E.; Pellicane, Anthony J.; Mutlu, Leman K.; Rubin, David G.; Stone, James R.; Helm, Gregory A.Author Information Departments of 1Neuroscience and Neurological Surgery, University of Virginia, PO Box 800212, Charlottesville, VA 22908, USA CACorresponding Author: firstname.lastname@example.org Received 12 November 2002; accepted 12 December 2002 NeuroReport: March 3rd, 2003 - Volume 14 - Issue 3 - p 463-466 Buy SDC 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. © 2003 Lippincott Williams & Wilkins, Inc.