Abstract
Mitochondrial dysfunction is thought to be a hallmark of traumatic brain injury (TBI) and plays a pivotal role in the resulting cellular injury. Cyclophilin D–mediated activation of the mitochondrial permeability transition pore has been suggested to contribute to this secondary injury cascade. Cyclosporine possesses neuroprotective properties that have been attributed to the desensitization of mitochondrial permeability transition pore activation. In vivo animal experiments have demonstrated neuroprotective effects of cyclosporine in more than 20 independent experimental studies in a multitude of different experimental models. However, the majority of these studies have been carried out in rodents. The aim of the present study was to evaluate the efficacy of a novel and cremophor/kolliphor EL–free lipid emulsion formulation of cyclosporine in a translational large animal model of TBI. A mild-to-moderate focal contusion injury was induced in piglets using a controlled cortical impact device. After initial step-wise analyses of pharmacokinetics and comparing with exposure of cyclosporine in clinical TBI trials, a 5-day dosing regimen with continuous intravenous cyclosporine infusion (20 mg/kg/day) was evaluated in a randomized and blinded placebo-controlled setting. Cyclosporine reduced the volume of parenchymal injury by 35%, as well as improved markers of neuronal injury, as measured with magnetic resonance spectroscopic imaging. Further, a consistent trend toward positive improvements in brain metabolism and mitochondrial function was observed in the pericontusional tissue. In this study, we have demonstrated efficacy using a novel cyclosporine formulation in clinically relevant and translatable outcome metrics in a large animal model of focal TBI.
Highlights
Traumatic brain injury (TBI) is caused by physical trauma to the head or a rapid acceleration-deceleration
Stable concentrations were obtained by 3–6 h after initiation of treatment until animals were terminated at 24 h (Fig. 2A,B)
The brain/blood concentration ratio appeared to increase with increasing dose in piglets, which partly may be caused by the deviation from dose proportionality in the blood concentrations (Table 1)
Summary
Traumatic brain injury (TBI) is caused by physical trauma to the head or a rapid acceleration-deceleration. TBI is a leading cause of death and disability, and in the United States alone, 2.8 million people sustain a TBI each year, resulting in nearly 50,000 deaths.[1] Those that survive may suffer from long-term physical disabilities, and cognitive disorders, including depression, drug and alcohol abuse, and increased risk of suicide.[2,3] Despite the enormous medical need, there is currently no approved neuroprotective treatment for TBI. Mitochondrial dysfunction and oxidative stress are thought to play a pivotal role in this secondary injury cascade.[4] the opening of the mitochondrial permeability transition pore (mPTP), as a result of excitotoxicity and calcium overload, has been proposed to be a decisive pathophysiological mechanism of the secondary injury.[5,6,7,8] The opening of the mPTP leads to loss of mitochondrial inner membrane integrity and adenosine triphosphate (ATP) production, generation of reactive oxygen species
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