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The Journal of Neuroscience, December 10, 2003, 23(36):11479-11488

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 Previous Article

Development/Plasticity/Repair
Effects of Neurotoxic and Neuroprotective Agents on Peripheral Nerve Regeneration Assayed by Time-Lapse Imaging In Vivo

Y. Albert Pan, Thomas Misgeld, Jeff W. Lichtman, and Joshua R. Sanes

Department of Anatomy and Neurobiology, Washington University Medical School, St. Louis, Missouri 63110

A direct histological assay of axonal regeneration would have many advantages over currently available behavioral, electrophysiological, and radiometric assays. We show that peripheral sensory axons marked with the yellow fluorescent protein in transgenic mice can be viewed transcutaneously in superficial nerves. Degenerating and regenerating axons can be followed in live animals with a dissecting microscope and then, after fixation, studied at high resolution by confocal microscopy. Using this approach, we document differences in regenerative ability after nerve transection, crush injury, and crush injury after a previous "conditioning" lesion. We also show that the chemotherapeutic drug vincristine rapidly but transiently blocks regeneration and that the immunosuppressive drug FK506 modestly enhances regeneration. Moreover, FK506 nearly restores normal regenerative ability in animals treated with submaximal doses of vincristine. Because neuropathy is the major dose-limiting side effect of vincristine, we propose that its efficacy could be enhanced by coadministration of FK506 analogs that are neuroactive but not immunosuppressive.

Key words: regeneration; conditioning lesion; FK506; transgenic mice; vincristine; Wallerian degeneration

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Received Aug 26, 2003; revised October 19, 2003; accepted October 22, 2003.

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