A neuroprotective role of glial cell line-derived neurotrophic factor following moderate spinal cord contusion injury.
The present study investigated neuroprotective effects of glial cell line-derived neurotrophic factor (GDNF), a distant member of the transforming growth factor-beta (TGF-beta) superfamily, following moderate contusive spinal cord injury (SCI) in adult rats. A T11 spinal cord contusion injury was made using an Infinite Horizon impactor (IH; impact force=150 kDyn) and recombinant human GDNF at two concentrations (rhGDNF; 1 or 5 microg/microl), or saline vehicle was delivered intrathecally for 28 days using an Alzet miniosmotic pump. We demonstrated that, at 7 weeks postinjury, GDNF infusion significantly reduced the total lesion volume by 34-42% (assessed stereologically) and increased the percentage of white matter sparing by 10-13% (measured at the injury epicenter), as compared to the vehicle infusion. Retrograde tracing revealed that GDNF infusion resulted in a significant increase in the number of FluoroGold (FG)-labeled neurons in propriospinal regions as well as in two supraspinal regions, that is, the medullary and pontine reticular formation, and the lateral vestibular nucleus. Immunofluorescent staining confirmed that the spared white matter contained neurofilament-positive axons. However, transcranial magnetic motor-evoked potential (tcMMEP) assessment revealed no significant difference in onset latency and amplitude between the GDNF- and vehicle-infused groups. These results suggest that GDNF has a strong neuroprotective effect on white matter sparing and the sparing of a subset of proprio- and supraspinal axons following injury. However, a return of tcMMEPs requires the sparing and/or myelination of axons in a defined region of the white matter which was either not spared or remyelinated at this level of injury severity.
Iannotti
Christopher
C
Kentucky Spinal Cord Injury Research Center, Department of Neurological Surgery, University of Louisville School of Medicine, Louisville, KY 40292, USA.
Ping Zhang
Y
Y
Shields
Christopher B
CB
Han
Yingchun
Y
Burke
Darlene A
DA
Xu
Xiao-Ming
XM
D000818:Animals; D001369:Axons / Q000187:drug effects / Q000502:physiology; D002452:Cell Count; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004525:Efferent Pathways / Q000187:drug effects / Q000502:physiology; D019054:Evoked Potentials, Motor / Q000187:drug effects / Q000502:physiology; D005456:Fluorescent Dyes; D051100:Glial Cell Line-Derived Neurotrophic Factor; D007278:Injections, Spinal; D009410:Nerve Degeneration / Q000188:drug therapy* / Q000473:pathology / Q000517:prevention & control; D009413:Nerve Fibers, Myelinated / Q000187:drug effects / Q000502:physiology; D009414:Nerve Growth Factors / Q000494:pharmacology* / Q000627:therapeutic use; D009431:Neural Conduction / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects / Q000502:physiology; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology; D013116:Spinal Cord / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D013266:Stilbamidines; D016896:Treatment Outcome
C049774:2-hydroxy-4,4'-diamidinostilbene, methanesulfonate salt; D005456:Fluorescent Dyes; C495041:Gdnf protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D018696:Neuroprotective Agents; D013266:Stilbamidines