Research Article

Rapid, effective, and long-lasting behavioral recovery produced by microsutures, methylene blue, and polyethylene glycol after completely cutting rat sciatic nerves

  1. G.D. Bittner1,2,3,*,
  2. C.P. Keating4,
  3. J.R. Kane5,
  4. J.M. Britt5,
  5. C.S. Spaeth1,†,
  6. J.D. Fan2,
  7. A. Zuzek1,
  8. R.W. Wilcott1,5,
  9. W.P. Thayer6,
  10. J.M. Winograd4,
  11. F. Gonzalez-Lima3,5,7,
  12. T. Schallert3,5

Article first published online: 3 FEB 2012

DOI: 10.1002/jnr.23023

Issue

Journal of Neuroscience Research

Journal of Neuroscience Research

Volume 90, Issue 5, pages 967–980, May 2012

Additional Information

How to Cite

Bittner, G.D., Keating, C.P., Kane, J.R., Britt, J.M., Spaeth, C.S., Fan, J.D., Zuzek, A., Wilcott, R.W., Thayer, W.P., Winograd, J.M., Gonzalez-Lima, F. and Schallert, T. (2012), Rapid, effective, and long-lasting behavioral recovery produced by microsutures, methylene blue, and polyethylene glycol after completely cutting rat sciatic nerves. J. Neurosci. Res., 90: 967–980. doi: 10.1002/jnr.23023

Author Information

  1. 1

    Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, Texas

  2. 2

    Section of Neurobiology, University of Texas at Austin, Austin, Texas

  3. 3

    Institute for Neuroscience, University of Texas at Austin, Austin, Texas

  4. 4

    Plastic Surgery Research Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts

  5. 5

    Department of Psychology, University of Texas at Austin, Austin, Texas

  6. 6

    Department of Plastic Surgery, Vanderbilt University, Nashville, Tennessee

  7. 7

    Division of Pharmacology and Toxicology, University of Texas at Austin, Austin, Texas

  1. †

    University of Texas Southwest Medical Center, Dallas, TX 75390

*Section of Neurobiology, The University of Texas at Austin, Austin, TX 78712

Publication History

  1. Issue published online: 7 MAR 2012
  2. Article first published online: 3 FEB 2012
  3. Manuscript Accepted: 13 DEC 2011
  4. Manuscript Revised: 4 DEC 2011
  5. Manuscript Received: 2 NOV 2011

Funded by

  • Lone Star Paralysis Foundation (to G.D.B.)
  • Davis Phinney Foundation (to T.S.)
  • NIH (to F.G.-L.)

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Keywords:

  • axotomy;
  • nerve regeneration;
  • nerve repair

Abstract

Behavioral function lost in mammals (including humans) after peripheral nerve severance is slowly (weeks to years) and often poorly restored by 1–2-mm/day, nonspecifically directed outgrowths from proximal axonal stumps. To survive, proximal stumps must quickly repair (seal) plasmalemmal damage. We report that, after complete cut- or crush-severance of rat sciatic nerves, morphological continuity, action potential conduction, and behavioral functions can be consistently (>98% of trials), rapidly (minutes to days), dramatically (70–85% recovery), and chronically restored and some Wallerian degeneration prevented. We assess axoplasmic and axolemmal continuity by intra-axonal dye diffusion and action potential conduction across the lesion site and amount of behavioral recovery by Sciatic Functional Index and Foot Fault tests. We apply well-specified sequences of solutions containing FDA-approved chemicals. First, severed axonal ends are opened and resealing is prevented by hypotonic Ca2+-free saline containing antioxidants (especially methylene blue) that inhibit plasmalemmal sealing in sciatic nerves in vivo, ex vivo, and in rat B104 hippocampal cells in vitro. Second, a hypotonic solution of polyethylene glycol (PEG) is applied to open closely apposed (by microsutures, if cut) axonal ends to induce their membranes to flow rapidly into each other (PEG-fusion), consistent with data showing that PEG rapidly seals (PEG-seals) transected neurites of B104 cells, independently of any known endogenous sealing mechanism. Third, Ca2+-containing isotonic saline is applied to induce sealing of any remaining plasmalemmal holes by Ca2+-induced accumulation and fusion of vesicles. These and other data suggest that PEG-sealing is neuroprotective, and our PEG-fusion protocols that repair cut- and crush-severed rat nerves might rapidly translate to clinical procedures. © 2012 Wiley Periodicals, Inc.

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