IGF-I and End-to-Side Nerve Repair: A Dose-Response Study

ABSTRACT

End-to-side nerve repair allows for target-muscle reinnervation, with simultaneous preservation of donor-nerve function. Local administration of insulin-like growth factor-I (IGF-I) has been shown to increase the rate of axon regeneration in crush-injured and freeze-injured rat sciatic nerve. The purpose of the current project was to determine the effects of IGF-I in a rat model of end-to-side nerve repair. The left musculocutaneous nerve of 18 adult male Sprague-Dawley rats was fully transected to induce biceps-muscle paralysis. The distal stump of the musculocutaneous nerve was then coapted by end-to-side neurorrhaphy through a perineurial window to the ipsilateral median nerve. All animals were randomly assigned to three groups: Group A received 100 μg/ml IGF-I; Group B received 50 μg/ml IGF-I; and control Group C received 10 mM acetic acid vehicle solution. Infusions were regulated by the Alzet model 2004 mini-osmotic pump, with an attached catheter directed at the coaptation site. Weekly postoperative behavioral evaluations revealed significantly increased functional return over control in both experimental groups as early as 3 weeks. After 28 days, histology evaluations revealed statistically significantly higher musculocutaneous nerve axon counts and myelin thickness/axon diameter ratios in both experimental groups vs. controls. The three groups were not significantly different in motor endplate counts of the biceps muscle. Groups A and B were not significantly different in all parameters tested. This study suggests that local infusion of IGF-I may expedite the functional recovery of a paralyzed muscle, by increasing the rate of axon regeneration through an end-to-side nerve graft.

KEYWORD

Insulin-like growth factor-I - end-to-side nerve repair - dose-response - nerve regeneration - neurotrophins

REFERENCES

• 1 Viterbo F, Trindade J C, Hoshino K, Mazzoni Neto A. Latero-terminal neurorrhaphy without removal of the epineurial sheath: experimental study in rats.  Rev Paul Med . 1992;  110 267
• 2 Kennedy R. On the restoration of co-ordinated movement after nerve-crossing with interchange of function of the cerebral cortical centers.  Phil Trans Roy Soc . 1901;  194B 127
• 3 Ballance C A, Ballance H A, Stewart P. Remarks on the operative treatment of chronic facial palsy of peripheral origin.  Br Med J . 1903;  2 1009
• 4 Sherren J. Some points in the surgery of the peripheral nerves.  Edinb Med J . 1906;  20 297
• 5 Viterbo F. A new method for treatment of facial palsy: the cross-face nerve transplantation with end-to-side neurorrhaphy.  Rev Soc Bras Cir Plast Estet Reconstr . 1993;  8 29
• 6 Viterbo F, Trindade J C, Hoshino K, Mazzoni A. Two end-to-side neurorrhaphies and nerve graft with removal of the epineurial sheath: experimental study in rats.  Br J Plast Surg . 1994;  47 75
• 7 Lundborg G, Zhao Q, Kanje M. Can sensory and motor collateral sprouting be induced from intact peripheral nerve by end-to-side anastomosis?.  J Hand Surg . 1994;  19B 277
• 8 Zhao J Z, Chen Z W, Chen T Y. Nerve regeneration after terminolateral neurorrhaphy: experimental study in rats.  J Reconstr Microsurg . 1997;  13 31
• 9 Kalliainen L K, Kuzon Jr M W. Reinnervating skeletal muscle using end-to-side neurorrhaphy.  Can J Plast Surg . 1996;  4 25
• 10 Tarasidis G, Watanabe O, Mackinnon S E. End-to-side neurorrhaphy resulting in limited sensory axonal regeneration in a rat model.  Ann Otol Rhinol Laryngol . 1997;  106 506
• 11 Rovak J M, Cederna P S, Macionis V. Termino-lateral neurorrhaphy: the functional axonal anatomy.  Microsurgery . 2000;  20 6
• 12 Terzis J K. ``Babysitters'': an exciting new concept in facial reanimation, facial nerve. In: Proceedings of the Sixth International Symmposium on the Facial Nerve Rio de Janeiro, Brazil: Kygler and Ghedini Publications 1988
• 13 May M, Sobol S M, Mester S J. Hypoglossal-facial nerve interpositional-jump graft for facial reanimation without tongue atrophy.  Otolaryngol Head Neck Surg . 1991;  104 818
• 14 Noah E M, Williams A, Jorgenson C. End-to-side neurorrhaphy: a histologic and morphometric study of axonal sprouting into an end-to-side nerve graft.  J Reconstr Microsurg . 1997;  13 99
• 15 Noah E M, Williams A, Fortes W, Terzis J K. A new animal model to investigate axonal sprouting after end-to-side neurorrhaphy.  J Reconstr Microsurg . 1997;  13 317
• 16 Kalantarian B, Rice D C, Tiangco D A, Terzis J K. Gains and losses of the XII-VII component of the ``baby-sitter'' procedure: a morphometric analysis.  J Reconstr Microsurg . 1998;  14 459
• 17 Okajima S, Terzis J K. Ultrastructure of early axonal regeneration in an end-to-side neurorrhaphy model.  J Reconstr Microsurg . 2000;  16 313
• 18 Kalliainen L K, Cederna P S, Kuzon Jr M W. Mechanical function of muscle reinnervated by end-to-side neurorrhaphy.  Plast Reconstr Surg . 1999;  103 1919
• 19 Rinderknecht E, Humbel R E. The amino acid sequence of human insulin-like growth factor I and its structural homology with proinsulin.  J Biol Chem . 1978;  253 2769
• 20 Froesch E R, Schmid C, Schwander J, Zapf J. Actions of insulin-like growth factors.  Ann Rev Physiol . 1985;  47 443
• 21 Zapf J, Waldvogel M, Froesch E R. Binding of nonsuppressible insulinlike activity to human serum: evidence for a carrier protein.  Arch Biochem Biophys . 1975;  168 638
• 22 Hardouin S, Gourmelen M, Noguiez P. Molecular forms of serum insulin-like growth factor (IGF)-binding proteins in man: relationships with growth hormone and IGFs and physiological significance.  J Clin Endocrinol Metab . 1989;  69 1291
• 23 Baxter R C, Martin J L. Binding proteins for the insulin-like growth factors: structure, regulation and function.  Prog Growth Factor Res . 1989;  1 49
• 24 Recio-Pinto E, Ishii D N. Effects of insulin, insulin-like growth factor-II and nerve growth factor on neurite outgrowth in cultured human neuroblastoma cells.  Brain Res . 1984;  302 323
• 25 Recio-Pinto E, Ishii D N. Insulin and insulin-like growth factor receptors regulating neurite formation in cultured human neuroblastoma cells.  J Neurosci Res . 1988;  19 312
• 26 Wang C, Li Y, Wible B. Effects of insulin and insulin-like growth factors on neurofilament mRNA and tubulin mRNA content in human neuroblastoma SH-SY5Y cells.  Brain Res Mol Brain Res . 1992;  13 289
• 27 Mulholland M W, Romanchuk G, Simeone D M, Flowe K. Stimulation of myenteric plexus neurite outgrowth by insulin and insulin-like growth factors I and II.  Life Sci . 1992;  51 1789
• 28 Kanje M, Skottner A, Sjorberg J, Lundborg G. Insulin-like growth factor I (IGF-I) stimulates regeneration in rat sciatic nerve.  Brain Res . 1989;  486 396
• 29 Sjoberg J, Kanje M. Insulin-like growth factor (IGF-I) as a stimulator of regeneration in the freeze-injured rat sciatic nerve.  Brain Res . 1989;  485 102
• 30 Svenningsen A F, Kanje M. Insulin and the insulin-like growth factors I and II are mitogenic to cultured rat sciatic nerve segments and stimulate [3H] thymidine incorporation throughout their respective receptors.  Glia . 1996;  18 68
• 31 Cheng H L, Russell J W, Feldman E L. IGF-I promotes peripheral nervous system myelination.  Ann NY Acad Sci . 1999;  883 124
• 32 Fortes W M, Noah E M, Liuzzi F J, Terzis J K. End-to-side neurorrhaphy: evaluation of axonal response and upregulation of IGF-I and IGF-II in a non-injury model.  J Reconstr Microsurg . 1999;  15 449
• 33 Thanos P K, Okajima S, Tiangco D A, Terzis J K. Insulin-like growth factor-I promotes nerve regeneration through a nerve graft in an experimental model of facial paralysis.  Restor Neurol Neurosci . 1999;  15 57
• 34 Lutz B S, Wei F C, Ma S F, Chuang D C. Effects of insulin-like growth factor-I in motor nerve regeneration after nerve transection and repair vs nerve crushing injury in the rat.  Acta Neurochir . 1999;  41 1101
• 35 Vergani L, Di Giulio M A, Losa M. Systemic administration of insulin-like growth factor decreases motor neuron cell death and promotes muscle reinnervation.  J Neurosci Res . 1998;  54 840
• 36 Caplan J, Tiangco D A, Terzis J K. Effects of IGF-II in a new end-to-side model.  J Reconstr Microsurg . 1999;  15 351
• 37 Inciong J G, Marrocco W C, Terzis J K. Efficacy of intervention strategies in a brachial plexus global avulsion model in the rat.  Plast Reconstr Surg . 2000;  105 2059
• 38 Bertelli J A, Mira J C. Behavioral evaluating methods in the objective clinical assessment of motor function after experimental brachial plexus reconstruction in the rat.  J Neurosci Methods . 1993;  46 203-208
• 39 Gorio A. Muscular reinnervation. II: sprouting synapse formation and repression.  J Neurosci . 1983;  3 403
• 40 de Medinaceli L, Freed W J, Wyatt R J. An index of the functional condition of rat sciatic nerve based on measurements made from walking tracks.  Exp Neurol . 1982;  77 634
• 41 Terzis J K, Smith K J. Repair of severed peripheral nerves: comparison of the ``de Medinaceli'' and standard microsuture methods.  Exp Neurology . 1987;  96 672
• 42 Kanaya F, Firrell J C, Breidenbach W C. Sciatic function index, nerve conduction tests, muscle contraction, and axon morphometry as indicators of regeneration.  Plast Reconstr Surg . 1996;  98 1264
• 43 Glazner G W, Morrison A E, Ishii D N. Elevated insulin-like growth factor (IGF) gene expression in sciatic nerves during IGF-supported nerve regeneration.  Brain Res Mol Brain Res . 1994;  25 265
• 44 Pu S F, Zhuang H X, Ishii D N. Differential spatio-temporal expression of the insulin-like growth factor genes in regenerating sciatic nerve.  Brain Res Mol Brain Res . 1995;  34 18
• 45 Pu S F, Zhuang H X, Marsh D J, Ishii D N. Time-dependent alteration of insulin-like growth factor gene expression during nerve regeneration in regions of muscle enriched with neuromuscular junctions.  Brain Res Mol Brain Res . 1999;  63 207
• 46 Near S L, Whalen L R, Miller J A, Ishii D N. Insulin-like growth factor-II stimulates motor nerve regeneration.  Proc Natl Acad Sci USA . 1992;  89 156
• 47 Glazner G W, Lupien S, Miller J A, Ishii D N. Insulin-like growth factor-II increases the rate of sciatic nerve regeneration in rats.  Neuroscience . 1993;  54 791