Intravenous hedgehog agonist induces proliferation of neural and oligodendrocyte precursors in rodent spinal cord injury.
BACKGROUND
Sonic hedgehog (Shh) is a glycoprotein molecule that upregulates the transcription factor gli-1 and plays a critical role in the proliferation of endogenous neural precursor cells when directly injected into adult rodent spinal cords after injury.


OBJECTIVE
To use small-molecule agonists of the hedgehog pathway in an attempt to replicate these findings with intravenous administration.


METHODS
Forty Sprague-Dawley rats were randomly divided into 4 groups. Saline treatment control groups were divided into a contusion injury group and a noninjury sham group; Shh agonist treatment groups were divided into an injury group and a noninjury sham group. Shh agonist Ag11.1 was administered to the treatment groups and saline to the control groups. Injections were performed on days 1 and 4 after surgery. On day 14, 1 group was sacrificed, and injured spinal cord portions were removed for explant cultures. After 7 days in culture, specimens were fixed for immunostaining neural precursor cells, and cell counts were taken.


RESULTS
Histological analysis demonstrated cystic cavitary lesions with a rim of white-matter sparing in all specimens. In animals treated with hedgehog agonist for a contusion injury, a significant increase in the number of nestin- and musashi-1-positive neural precursor cells at the rim of the cavity was noted.


CONCLUSIONS
There was a significant increase in the number of O4-positive oligodendrocyte precursors compared with uninjured controls and BrdU-positive cells, reproducing the findings of previous studies using direct Shh protein injection, which demonstrated spared white matter and increased recovery.
Neurosurgery Research Laboratory, Division of Neurological Surgery, Barrow Neurological Institute, St Joseph's Hospital and Medical Center, Phoenix, Arizona, USA. kimberly.duvall@uhhospitals.org
Nicholas C
NC
Bambakidis
Xukui
X
Wang
Ronald J
RJ
Lukas
Robert F
RF
Spetzler
Volker K H
VK
Sonntag
Mark C
MC
Preul
D000818:Animals; D001973:Bromodeoxyuridine / Q000378:metabolism; D002452:Cell Count / Q000379:methods; D049109:Cell Proliferation / Q000187:drug effects*; D004195:Disease Models, Animal; D053823:Hedgehog Proteins / Q000819:agonists* / Q000378:metabolism; D007381:Intermediate Filament Proteins / Q000378:metabolism; D039902:Multipotent Stem Cells / Q000187:drug effects*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D064231:Nestin; D009474:Neurons / Q000187:drug effects*; D019081:O Antigens / Q000378:metabolism; D009836:Oligodendroglia / Q000187:drug effects*; D009924:Organ Culture Techniques; D016601:RNA-Binding Proteins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000166:cytology; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000473:pathology; D013997:Time Factors
D053823:Hedgehog Proteins; D007381:Intermediate Filament Proteins; C104786:Msi1h protein, mouse; D009419:Nerve Tissue Proteins; C577485:Nes protein, mouse; C577486:Nes protein, rat; D064231:Nestin; D019081:O Antigens; D016601:RNA-Binding Proteins; D001973:Bromodeoxyuridine