Systemic polyethylene glycol promotes neurological recovery and tissue sparing in rats after cervical spinal cord injury.
Polyethylene glycol (PEG) has been reported to possess fusogenic properties that may confer neuroprotection after spinal cord injury (SCI), but there is uncertainty regarding the mechanisms of PEG in vivo and the robustness of its protective effects. We hypothesized that PEG promotes preservation of cytoskeletal proteins associated with white matter protection and neurobehavioral recovery after SCI. In proof-of-principle experiments using a pin-drop organotypic culture model of SCI, PEG attenuated neural cell death. Adult rats underwent 35-g clip compression SCI at C8 and were randomized postinjury to receive intravenous 30% PEG or sterile Ringer's lactate solution. Confocal microscopy and high-performance liquid chromatography of fluorescein-conjugated PEG permitted in vivo quantification of PEG concentrations in the injured and uninjured spinal cord. Western blot, immunohistochemistry, and terminal deoxynucleotidyl transferase mediated dUTP nick end labeling staining demonstrated that PEG reduced 200-kd neurofilament degradation and apoptotic cell death. Polyethylene glycol also promoted spinal cord tissue sparing based on retrograde axonal Fluoro-Gold tracing and morphometric histological assessment. Polyethylene glycol also promoted significant, although modest, neurobehavioral recovery after SCI. Collectively, these results indicate that PEG protects key axonal cytoskeletal proteins after SCI, and that the protection is associated with axonal preservation. The modest extent of locomotor recovery after treatment with PEG suggests, however, that this compound may notconfer sufficient neuroprotection to be used clinically as a single treatment.
Baptiste
Darryl C
DC
Division of Genetics & Development, Toronto Western Research Institute and Krembil Neuroscience Centre, Western Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada.
Austin
James W
JW
Zhao
William
W
Nahirny
Adrian
A
Sugita
Shuzo
S
Fehlings
Michael G
MG
D000704:Analysis of Variance; D000818:Animals; D002574:Cervical Vertebrae; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D020287:In Situ Nick-End Labeling / Q000379:methods; D066298:In Vitro Techniques; D007211:Indoles; D009043:Motor Activity / Q000187:drug effects; D016900:Neurofilament Proteins / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D011092:Polyethylene Glycols / Q000494:pharmacology / Q000627:therapeutic use*; D011597:Psychomotor Performance / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D020127:Recovery of Function / Q000187:drug effects; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000473:pathology*; D013266:Stilbamidines; D013997:Time Factors
C049774:2-hydroxy-4,4'-diamidinostilbene, methanesulfonate salt; D003598:Cytoskeletal Proteins; D007211:Indoles; D016900:Neurofilament Proteins; D018696:Neuroprotective Agents; D013266:Stilbamidines; C051774:neurofilament protein H; D011092:Polyethylene Glycols; C007293:DAPI; D010751:Phosphopyruvate Hydratase