Intravenous hedgehog agonist induces proliferation of neural and oligodendrocyte precursors in rodent spinal cord injury

Abstract

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.

Conclusion: 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.