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J Reconstr Microsurg 2005; 21(6): 383-389
DOI: 10.1055/s-2005-915206
Copyright © 2005 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Early Effect of Gene Therapy on a Direct Muscle Neurotization Model

Konstantinos C. Papakonstantinou1 , Julia K. Terzis1 , Elizabeth Kamin2 , Janos Luka3
  • 1Microsurgery Research Center, Division of Plastic and Reconstructive Surgery
  • 2Eastern Virginia Medical School
  • 3Department of Pathology, Eastern Virginia Medical School
Further Information

Publication History

Accepted: April 26, 2005

Publication Date:
12 August 2005 (online)

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ABSTRACT

Direct nerve-to-muscle neurotization has been the subject of both clinical and experimental studies. In this study, the authors report a new animal model to test the regenerative properties of a nerve (musculocutaneous) implanted in a muscle (biceps). They also report the early effects of the application at the implantation site of exogenously administered Brain Derived Nerve Factor (BDNF) and of endogenously produced BDNF, via the administration of an adenoviral construct with a tissue-specific promotor for muscle cells (AdRSV), and containing the BDNF gene. Evaluation included behavioral testing (grooming test), electrical stimulation, Western blot analysis of the distal implanted nerve to determine the presence of locally produced BDNF, and motor end-plate staining of the biceps muscle. At the early time point of 1 week following the musculocutaneous nerve to biceps muscle implantation, there was no increased production of recombinant BDNF at the distal implanted musculocutaneous nerve, as assessed by Western blot analysis. Therefore, there was no significant difference in the behavioral evaluation of the animals at 1 week; the Terzis grooming test showed no statistical difference among groups, but a trend toward better function for the BDNF and the high-dose AdRSV-BDNF groups, compared to the control groups. There was also no difference in the histologic appearance and number of the motor end-plates at the implantation site, compared to the controls. The electrical stimulation of the MC nerve did not produce statistically significant results among the experimental groups. In this direct nerve to muscle neurotization model, the application of AdRSV-BDNF at 3 × 109 pfu/ul did not show enhanced production of BDNF at 1 week.

KEYWORDS

Nerve-to-muscle neurotization - BDNF - adenoviral construct

REFERENCES

  • 1 Heineke D. Die directe Enipflanzung des Nerven in den Muskel.  Zentralb Chir. 1914;  41 465-466
    PubMedSearch in Google Scholar
  • 2 Brunelli G A, Brunelli G R. Direct muscle neurotization.  J Reconstr Microsurgery. 1993;  9 81-90
    Thieme ConnectPubMedSearch in Google Scholar
  • 3 MacKinnon S, Hunter G. Neurotization of the rat soleus muscle. A quantitative analysis of reinnervation.  J Hand Surg. 1993;  9 77-80
    PubMedSearch in Google Scholar
  • 4 Terenghi G. Peripheral nerve regeneration and neurotrophic factors.  J Anat. 1999;  14 1-14
    PubMedSearch in Google Scholar
  • 5 Yin Q, Kemp J, Frostnick S. Neurotrophins, neurons and peripheral nerve regeneration.  J Hand Surg. 1988;  23B 433-437
    PubMedSearch in Google Scholar
  • 6 Kishino A, Ishige Y, Tatsuno T, Nakayamo C, Noguchi H. BDNF prevents and reverses adult motor neuron degeneration and induces axonal outgrowth. Exp Neurol. 1997;  144 273-286
    PubMedSearch in Google Scholar
  • 7 Lewin S L, Utley D S, Cheng E T, Verity A N, Terris D J. Simultaneous treatment with BDNF and CNTF after peripheral nerve transection and repair enhances rate of functional recovery compared with BDNF treatment alone.  Laryngoscope. 1997;  107 992-999
    CrossrefPubMedSearch in Google Scholar
  • 8 Sendter M, Dittrich F, Hughes R A, Thoenen H. Actions of CNTF and neurotrophins on degenerating motor neurons: preclinical studies and clinical implications.  J Neurol Sci. 1994;  124 (Suppl) 77-83
    PubMedSearch in Google Scholar
  • 9 Tonra J R, Curtis R, Wong V et al.. Axotomy upregulates the anterograde transport and expression of Brain-Derived Neurotrophic Factor by sensory neurons.  J Neurosci. 1998;  18 4374-4383
    PubMedSearch in Google Scholar
  • 10 Altar C A, DiStefano P S. Neurotrophin trafficking by anterograde transport. Trends Neurosci.  1998;  21 433-437
    PubMedSearch in Google Scholar
  • 11 Reynolds A J, Hendry I A. A technique for 125I-labelling of neurotrophins and the use of retrograde axonal transport as a bioassay.  Brain Res Brain Res Protoc. 1999;  3 308-312
    CrossrefPubMedSearch in Google Scholar
  • 12 Curtis R, Tonra J R, Stark J L et al.. Neuronal injury increases retrograde axonal transport of the neurotrophins to spinal sensory neurons and motor neurons via multiple receptor mechanisms.  Mol Cell Neurosci. 1998;  12 105-118
    CrossrefPubMedSearch in Google Scholar
  • 13 Haase G, Pettman B, Vigne E, Castlenau-Ptakine L, Schmalbruch H, Kahn A. Adenovirus mediated transfer of neurotrophin-3 gene into skeletal muscle of pmn mice: therapeutic effects and mechanisms of action.  J Neurol Sci. 1998;  160 suppl 1 S97-S105
    CrossrefPubMedSearch in Google Scholar
  • 14 Gimenez Y, Ribotta M, Revah F, Pradier L, Loquet I, Mallet J. Prevention of motor neuron death by adenovirus mediated neurotrophic factors.  J Neurosci Res. 1997;  483 281-285
    PubMedSearch in Google Scholar
  • 15 Baumgartner B J, Shine D H. Targeted transduction of CNS neurons with adenoviral vectors carrying neurotrophic factor genes confers neuroprotection that exceeds the transduced population.  J Neurosci. 1997;  17 6504-6511
    PubMedSearch in Google Scholar
  • 16 Rabinovsky E D, Papakonstantinou K, Nichols T, Shenaq S M. The peripheral nerve as a target for gene therapy. In: Proceedings of the Society for Neuroscience San Diego, California; November 11-16, 1995
    Search in Google Scholar
  • 17 Akli S, Caillud C, Vigne E et al.. Transfer of a foreign gene into the brain using adenoviral vectors.  Nat Genet. 1993;  3 224-228
    CrossrefPubMedSearch in Google Scholar
  • 18 Inciong J, Marrocco W, Terzis J****k. Efficacy of intervention strategies in a brachial plexus global avulsion model in the rat.  Plast Reconstr Surg. 2000;  105 2059-2071
    CrossrefPubMedSearch in Google Scholar
  • 19 Gorio A. Muscular reinnervation - II. Sprouting, synapse formation and repression.  J Neurosci. 1983;  8 403-416
    CrossrefPubMedSearch in Google Scholar
  • 20 Brunelli G. Direct neurotization of severely damaged muscles.  J Hand Surg. 1982;  7 572-579
    PubMedSearch in Google Scholar
  • 21 Sakellarides H T, James L, Sorbie C. Reinnervation of denervated muscles by nerve transplantation.  Clin Orthop. 1972;  83 194-201
    PubMedSearch in Google Scholar
  • 22 Payne S H, Brushart T M. Neurotization of the rat soleus muscle: a quantitative analysis of reinnervation.  J Hand Surg. 1997;  22A 640-643
    PubMedSearch in Google Scholar
  • 23 Park D M, Shon S K, Kim Y J. Direct muscle neurotization in rat soleus muscle.  J Reconstr Microsurg. 2000;  16 135-139
    Thieme ConnectPubMedSearch in Google Scholar
  • 24 Papalia I, Lacroix C, Brunelli F, Stagno d' Alcontres F. Direct muscle neurotization after end-to-side neurorrhaphy.  J Reconstr Microsurg. 2001;  17 237-246
    Thieme ConnectPubMedSearch in Google Scholar
  • 25 Mousavi K, Parry D J, Jasmin B J. BDNF rescues myosin heavy chain IIB muscle fibers after neonatal nerve injury.  Am J Physiol Cell Physiol. 2004;  287 C22-C29
    CrossrefPubMedSearch in Google Scholar
  • 26 Nakaizumi T, Kawamoto K, Minoda R, Raphael Y. Adenovirus-mediated expression of brain-derived neurotrophic factor protects spiral ganglion neurons from ototoxic damage.  Audiol Neurootol. 2004;  9 135-143
    CrossrefPubMedSearch in Google Scholar

Julia K TerzisM.D. Ph.D. 

Microsurgery Research Center, EVMS

700 Olney Road, Lewis Hall, Room 2055

Norfolk, VA 23501