title: The Evaluation of Magnesium Chloride within a Polyethylene Glycol Formulation in a Porcine Model of Acute Spinal Cord Injury.
abstract: A porcine model of spinal cord injury (SCI) was used to evaluate the neuroprotective effects of magnesium chloride (MgCl2) within a polyethylene glycol (PEG) formulation, called "AC105" (Acorda Therapeutics Inc., Ardsley, NY). Specifically, we tested the hypothesis that AC105 would lead to greater tissue sparing at the injury site and improved behavioral outcome when delivered in a clinically realistic time window post-injury. Four hours after contusion/compression injury, Yucatan minipigs were randomized to receive a 30-min intravenous infusion of AC105, magnesium sulfate (MgSO4), or saline. Animals received 4 additional infusions of the same dose at 6-h intervals. Behavioral recovery was tested for 12 weeks using two-dimensional (2D) kinematics during weight-supported treadmill walking and the Porcine Injury Behavior Scale (PTIBS), a 10-point locomotion scale. Spinal cords were evaluated ex vivo by diffusion-weighted magnetic resonance imaging (MRI) and subjected to histological analysis. Treatment with AC105 or MgSO4did not result in improvements in locomotor recovery on the PTIBS or in 2D kinematics on weight-supported treadmill walking. Diffusion weighted imaging (DWI) showed severe loss of tissue integrity at the impact site, with decreased fractional anisotropy and increased mean diffusivity; this was not improved with AC105 or MgSO4treatment. Histological analysis revealed no significant increase in gray or white matter sparing with AC105 or MgSO4treatment. Finally, AC105 did not result in higher Mg2+levels in CSF than with the use of standard MgSO4. In summary, when testing AC105 in a porcine model of SCI, we were unable to reproduce the promising therapeutic benefits observed previously in less-severe rodent models of SCI.
authors.affiliation: 1 International Collaboration on Repair Discoveries (ICORD), University of British Columbia , Blusson Spinal Cord Center, Vancouver, British Columbia, Canada .
authors.forename: Femke
authors.initials: F
authors.lastname: Streijger
authors.affiliation: 1 International Collaboration on Repair Discoveries (ICORD), University of British Columbia , Blusson Spinal Cord Center, Vancouver, British Columbia, Canada .
authors.forename: Jae H T
authors.initials: JH
authors.lastname: Lee
authors.affiliation: 1 International Collaboration on Repair Discoveries (ICORD), University of British Columbia , Blusson Spinal Cord Center, Vancouver, British Columbia, Canada .
authors.forename: Neda
authors.initials: N
authors.lastname: Manouchehri
authors.affiliation: 1 International Collaboration on Repair Discoveries (ICORD), University of British Columbia , Blusson Spinal Cord Center, Vancouver, British Columbia, Canada .
authors.forename: Elena B
authors.initials: EB
authors.lastname: Okon
authors.affiliation: 1 International Collaboration on Repair Discoveries (ICORD), University of British Columbia , Blusson Spinal Cord Center, Vancouver, British Columbia, Canada .
authors.forename: Seth
authors.initials: S
authors.lastname: Tigchelaar
authors.affiliation: 1 International Collaboration on Repair Discoveries (ICORD), University of British Columbia , Blusson Spinal Cord Center, Vancouver, British Columbia, Canada .
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Anderson
authors.affiliation: 2 Robarts Research Institute, Western University , London, Ontario, Canada .
authors.forename: Greg A
authors.initials: GA
authors.lastname: Dekaban
authors.affiliation: 3 Brain Imaging Center, Montreal Neurological Hospital and Institute , Montreal, Quebec, Canada .
authors.forename: David A
authors.initials: DA
authors.lastname: Rudko
authors.affiliation: 4 Center for Functional and Metabolic Mapping, the University of Western Ontario , London, Ontario, Canada .
authors.forename: Ravi S
authors.initials: RS
authors.lastname: Menon
authors.affiliation: 5 Acorda Therapeutics Inc. , Ardsley, New York.
authors.forename: Jennifer F
authors.initials: JF
authors.lastname: Iaci
authors.affiliation: 5 Acorda Therapeutics Inc. , Ardsley, New York.
authors.forename: Donald C
authors.initials: DC
authors.lastname: Button
authors.affiliation: 5 Acorda Therapeutics Inc. , Ardsley, New York.
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Vecchione
authors.affiliation: 5 Acorda Therapeutics Inc. , Ardsley, New York.
authors.forename: Andrey
authors.initials: A
authors.lastname: Konovalov
authors.affiliation: 5 Acorda Therapeutics Inc. , Ardsley, New York.
authors.forename: Patrick D
authors.initials: PD
authors.lastname: Sarmiere
authors.affiliation: 5 Acorda Therapeutics Inc. , Ardsley, New York.
authors.forename: Chi
authors.initials: C
authors.lastname: Ung
authors.affiliation: 5 Acorda Therapeutics Inc. , Ardsley, New York.
authors.forename: Anthony O
authors.initials: AO
authors.lastname: Caggiano
authors.affiliation: 1 International Collaboration on Repair Discoveries (ICORD), University of British Columbia , Blusson Spinal Cord Center, Vancouver, British Columbia, Canada .|6 Department of Orthopedics, Vancouver Spine Surgery Institute, University of British Columbia , Blusson Spinal Cord Center, Vancouver, British Columbia, Canada .
authors.forename: Brian K
authors.initials: BK
authors.lastname: Kwon
mesh_terms: D000208:Acute Disease; D000818:Animals; D004195:Disease Models, Animal; D004339:Drug Compounding; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D008124:Locomotion / Q000187:drug effects / Q000502:physiology; D015636:Magnesium Chloride / Q000008:administration & dosage* / Q000737:chemistry; D011092:Polyethylene Glycols / Q000008:administration & dosage* / Q000737:chemistry; D011897:Random Allocation; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology; D013119:Spinal Cord Injuries / Q000000981:diagnostic imaging* / Q000503:physiopathology / Q000517:prevention & control*; D013552:Swine; D013556:Swine, Miniature; D013904:Thoracic Vertebrae
chemical_list: D015636:Magnesium Chloride; D011092:Polyethylene Glycols
keywords: AC105; magnesium; polyethylene glycol; porcine; spinal cord injury