T. Miura et al., Partial functional recovery of paraplegic rat by adenovirus-mediated gene delivery of constitutively active MEK1, EXP NEUROL, 166(1), 2000, pp. 115-126
Spinal cord injury in adult mammals results in little axonal regeneration,
although the mechanism of regeneration failure still remains elusive. Recen
t research has revealed that activation of the extracellular-signal-regulat
ed kinases (ERKs) plays an important role in the neurite outgrowth. In the
present study, we constructed a replication-defective adenovirus vector car
rying mutated form of MEK1 (CA-MEK virus), which constitutively activate ER
K pathway, and investigated its effect on thoracic spinal cord injury model
in young adult rats as well as neurite outgrowth in vitro. In rat pheocrom
ocytoma cell line PC12 cells, CA-MEK virus infection induced sustained acti
vation of ERKs and stimulated neurite outgrowth in the absence of neurotrop
hic factors. In rat spinal cord transection model, injection of CA-MEK viru
s into the completely transected spinal cord efficiently activated ERKs in
the supraspinal neurons and induced axonal regeneration across the transect
ion site, which was confirmed by anterograde labeling with wheat-germ-agglu
tinin conjugated peroxidase (WGA-HRP). Spinal cord evoked potentials (SCEP)
showed that these regenerated axone were electroconductive. Most important
ly, CA-MEK virus-treated rats showed significant recovery of hind limb func
tion 2 weeks after operation compared to the control rats treated with no v
irus or LacZ virus. These results suggest that adenovirus-mediated CA-MEK g
ene transduction offers a novel strategy for the gene therapy of spinal cor
d injury. (C) 2000 Academic Press.