Advanced

Neuroprotective Effects of Cyclosporine in a Porcine Pre-Clinical Trial of Focal Traumatic Brain Injury

Karlsson, Michael LU ; Pukenas, Bryan; Chawla, Sanjeev; Ehinger, Johannes K. LU ; Plyler, Ross; Stolow, Madeline; Gabello, Melissa; Hugerth, Matilda; Elmér, Eskil LU and Hansson, Magnus J. LU , et al. (2019) In Journal of Neurotrauma 36(1). p.14-24
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... (More)

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.

(Less)
Please use this url to cite or link to this publication:
author
, et al. (More)
(Less)
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
magnetic resonance imaging, magnetic resonance spectroscopy imaging, mitochondria, traumatic brain injury
in
Journal of Neurotrauma
volume
36
issue
1
pages
11 pages
publisher
Mary Ann Liebert, Inc.
external identifiers
  • scopus:85058665382
ISSN
0897-7151
DOI
10.1089/neu.2018.5706
language
English
LU publication?
yes
id
7fa20862-b43f-4141-9496-6a3026f36a57
date added to LUP
2019-01-03 07:39:58
date last changed
2019-01-04 03:00:09
@article{7fa20862-b43f-4141-9496-6a3026f36a57,
  abstract     = {<p>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.</p>},
  author       = {Karlsson, Michael and Pukenas, Bryan and Chawla, Sanjeev and Ehinger, Johannes K. and Plyler, Ross and Stolow, Madeline and Gabello, Melissa and Hugerth, Matilda and Elmér, Eskil and Hansson, Magnus J. and Margulies, Susan and Kilbaugh, Todd},
  issn         = {0897-7151},
  keyword      = {magnetic resonance imaging,magnetic resonance spectroscopy imaging,mitochondria, traumatic brain injury},
  language     = {eng},
  number       = {1},
  pages        = {14--24},
  publisher    = {Mary Ann Liebert, Inc.},
  series       = {Journal of Neurotrauma},
  title        = {Neuroprotective Effects of Cyclosporine in a Porcine Pre-Clinical Trial of Focal Traumatic Brain Injury},
  url          = {http://dx.doi.org/10.1089/neu.2018.5706},
  volume       = {36},
  year         = {2019},
}