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.

Multifunctional Drugs for Head Injury

“…177,178 Indeed, compared with FK506, a related immunosuppressant that inhibits calcineurin as effectively as CyA does, 169,179 CyA was superior in protecting against ischemic damage [177][178][179][180] and hypoglycemic brain injury, 181 presumably because of the superior ability of CyA to inhibit the mitochondrial permeability transition. 180 In addition to the suggestion that CyA completely inhibits excitotoxin-induced neuronal cell death, 182 there is also a dose-dependent inhibition of amyloid precursor protein accumulation 183 and of traumatic axonal injury after TBI, 184 which may account for the reduced number of disconnected and dysfunctional axons following impact acceleration TBI. [185][186][187][188] In clinical studies, phase II trials of CyA in TBI 189 have shown in the ascending dose study that patients with TBI demonstrated more rapid clearance and a wider distribution of CyA metabolites than other populations, thus complicating accurate dose determination for further trials.…”

Safety and Tolerability of Cyclosporin A in Severe Traumatic Brain Injury Patients: Results from a Prospective Randomized Trial

“…Recently, the role of cyclosporin A (CsA) as a neuroprotectant has been documented in several animal models of TBI (Alessandri et al, 2002;Okonkwo et al, , 2003Signoretti et al, 2004;Sullivan et al, 1999Sullivan et al, , 2000b. CsA transiently inhibits the opening of the mitochondrial permeability transition pore by unbinding mitochondrial matrix cyclophillin from the pore (Broekemeier et al, 1989;Broekemeier and Pfeiffer, 1995;Szabò and Zoratti, 1991), and thus protects mitochondria in the face of increased intracellular calcium.…”

Detection of Structural and Metabolic Changes in Traumatically Injured Hippocampus by Quantitative Differential Proteomics

“…It is further supported by the role of cyclosporine A and FK506, which inhibit calcineurins to provide neuroprotection and improve outcomes after TBI. 44,48 On the other hand, TBI-induced downregulation of calcineurins may be destructive. Previously we reported that fluid percussion TBI significantly decreased the expression of glial cell line-derived neurotrophic factor (GDNF) in rat hippocampi, whereas grafted human neural stem cells produced GDNF and rescued the cognitive deficit.…”