Partial functional recovery of paraplegic rat by adenovirus-mediated gene delivery of constitutively active MEK1

Toshiki Miura, Sakae Tanaka, Atsushi Seichi, Makoto Arai, Takahiro Goto, Hideki Katagiri, Tomoichiro Asano, Hiromi Oda, Kozo Nakamura

Research output: Contribution to journalArticlepeer-review

28 Citations (Scopus)

Abstract

Spinal cord injury in adult mammals results in little axonal regeneration, although the mechanism of regeneration failure still remains elusive. Recent research has revealed that activation of the extracellular-signal-regulated kinases (ERKs) plays an important role in the neurite outgrowth. In the present study, we constructed a replication-defective adenovirus vector carrying mutated form of MEK1 (CA-MEK virus), which constitutively activate ERH pathway, and investigated its effect on thoracic spinal cord injury model in young adult rats as well as neurite outgrowth in vitro. In rat pheocromocytoma cell line PC12 cells, CA-MEK virus infection induced sustained activation of ERKs and stimulated neurite outgrowth in the absence of neurotrophic factors. In rat spinal cord transection model, injection of CA-MEK virus into the completely transected spinal cord efficiently activated ERKs in the supraspinal neurons and induced axonal regeneration across the transection site, which was confirmed by anterograde labeling with wheat-germ-agglutinin conjugated peroxidase (WGA-HRP). Spinal cord evoked potentials (SCEP) showed that these regenerated axons were electroconductive. Most importantly, CA-MEK virus-treated rats showed significant recovery of hind limb function 2 weeks after operation compared to the control rats treated with no virus or LacZ virus. These results suggest that adenovirus-mediated CA-MEK gene transduction offers a novel strategy for the gene therapy of spinal cord injury. (C) 2000 Academic Press.

Original languageEnglish
Pages (from-to)115-126
Number of pages12
JournalExperimental Neurology
Volume166
Issue number1
DOIs
Publication statusPublished - 2000

Keywords

  • Adenovirus
  • Gene therapy
  • MEK
  • Spinal cord injury

ASJC Scopus subject areas

  • Neurology
  • Developmental Neuroscience

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