Effect of FK506 administration in alpha motorneurons after primary and delayed repair of the sciatic nerve

Objectives:FK506 is an effective immunosuppressive drug for treating graft rejection in transplants patients. However, theneuroregenerative effect of FK506 has been well described in the literature. The aim of this study was to investigate the effectsof FK506 in alpha motor neurons after primary and delayed repair of sciatic nerve. Methods: Rats (n=72) were divided into 6 groups. Control, sham-operated, primary repair FK506 (-), primary repair FK506(+), delayed repair FK506 (-), and delayed repair FK506 (+) groups. Results: After injury, the normal structure of the motor neuron perikarya was maintained by primary repair in the FK506 (+)group. In the delayed repair group, beneficial effect of FK506 was found to be less effective. The SFI value reached -50 recovery level in the FK506-treated group earlier than those of not FK506-treated groups. Conclusion:Beneficial effect of FK506 has been approved by functional and ultrastructural data in both of primary anddelayed repair groups.

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Aldskogius H, Kozlova EN. Central neuron-glial and glial-glial interactions following axon injury. Prog Neurobiol 1998;55:1-26.

Bisby MA, Tetzlaff W. Changes in cytoskeletal protein synthesis fol- lowing axon injury and during axon regeneration. Mol Neurobiol 1992;6:107-23.

de la Cruz RR, Pastor AM, Delgado-Garcia JM. Influence of the postsynaptic target on the functional properties of neurons in the adult mammalian central nervous system. Rev Neurosci 1996;7:115- 49.

Lowrie MB, Vrbova G. Dependence of postnatal motoneurones on their targets: review and hypothesis. Trends Neurosci 1992;15:80-4.

Hefti F. Pharmacology of neurotrophic factors. Annu Rev Pharmacol Toxicol 1997;37:239-67.

Lindsay RM. Neurotrophins and receptors. Prog Brain Res 1994;103:3-14.

Muller HW. Gene expression in nerve regeneration. Diabet Med 1996;13:682.

Sendtner M. Neurotrophic factors for experimental treatment of motoneuron disease. Prog Brain Res 1996;109:365-71.

Terenghi G. Peripheral nerve regeneration and neurotrophic fac- tors. J Anat 1999;194:1-14.

Snider WD, Elliott JL, Yan Q. Axotomy-induced neuronal death during development. J Neurobiol 1992;23:1231-46.

Hoffmann CF, Choufoer H, Marani E, Thomeer RT. Ultrastructural study on avulsion effects of the cat cervical moto- axonal pathways in the spinal cord. Clin Neurol Neurosurg 1993;95: S39-47.

Martin LJ, Kaiser A, Price AC. Motor neuron degeneration after sci- atic nerve avulsion in adult rat evolves with oxidative stress and is apoptosis. J Neurobiol 1999;40:185-201.

Novikov L, Novikova L, Kellerth JO. Brain-derived neurotrophic factor promotes survival and blocks nitric oxide synthase expression in adult rat spinal motoneurons after ventral root avulsion. Neurosci Lett 1995;200:45-8.

Wu W. Expression of nitric-oxide synthase (NOS) in injured CNS neurons as shown by NADPH diaphorase histochemistry. Exp Neurol 1993;120:153-9.

Tandrup T, Woolf CJ, Coggeshall RE. Delayed loss of small dorsal root ganglion cells after transection of the rat sciatic nerve. J Comp Neurol 2000;422:172-80.

Johnson IP, Duberley RM. Motoneuron survival and expression of neuropeptides and neurotrophic factor receptors following axotomy in adult and ageing rats. Neuroscience 1998;84:141-50.

Mattsson P, Meijer B, Svensson M. Extensive neuronal cell death following intracranial transection of the facial nerve in the adult rat. Brain Res Bull 1999;49:333-41.

Tornqvist E, Aldskogius H. Motoneuron survival is not affected by the proximo-distal level of axotomy but by the possibility of regen- erating axons to gain access to the distal nerve stump. J Neurosci Res 1994;39:159-65.

Yu WH. Regulation of nitric oxide synthase expression in motoneu- rons following nerve injury. Dev Neurosci 1997;19:247-54.

Arvidsson J, Aldskogius H. Effect of repeated hypoglossal nerve lesions on the number of neurons in the hypoglossal nucleus of adult rats. Exp Neurol 1982;75:520-4.

Crews LL, Wigston DJ. The dependence of motoneurons on their target muscle during postnatal development of the mouse. J Neurosci 1990;10:1643-53.

Johnson IP, Sears TA, Hunter AS. Retrograde response to axotomy of motoneurons in the thoracic spinal cord of the aging cat. Neurobiol Aging 1991;12:151-60.

Kuzis K, Coffin JD, Eckenstein FP. Time course and age depend- ence of motor neuron death following facial nerve crush injury: role of fibroblast growth factor. Exp Neurol 1999;157:77-87.

Anneser JM, Berthele A, Borasio GD, Castro-Lopes JM, Zieglgansberger W, Tolle TR. Axotomy of the sciatic nerve differ- entially affects expression of metabotropic glutamate receptor mRNA in adult rat motoneurons. Brain Res 2000;868:215-21.

Vanden Noven S, Wallace N, Muccio D, Turtz A, Pinter MJ. Adult spinal motoneurons remain viable despite prolonged absence of functional synaptic contact with muscle. Exp Neurol 1993;123:147- 56.

Kim HS, Park YI. Isolation and identification of a novel microor- ganism producing the immunosuppressant tacrolimus. J Biosci Bioeng 2008;105:418-21.

Abraham RT, Wiederrecht GJ. Immunopharmacology of rapamycin. Annu Rev Immunol 1996;14:483-510.

Dumont FJ, Ok H, Lin S, Kastner CA, Cryan J, Martin MM, Wiederrecht G, Staruch MJ. Mixed agonist/antagonist activity of an FK-506-related immunosuppressant: biological and biochemical characterization. J Pharmacol Exp Ther 1996;276:1078-88.

Brenner MJ, Fox IK, Kawamura DH, Yu VM, Lowe JB 3rd, Hunter DA, Mackinnon SE. Delayed nerve repair is associated with dimin- ished neuroenhancement by FK506. Laryngoscope 2004;114:570-6.

Costantini LC, Chaturvedi P, Armistead DM, McCaffrey PG, Deacon TW, Isacson O. A novel immunophilin ligand: distinct branching effects on dopaminergic neurons in culture and neu- rotrophic actions after oral administration in an animal model of Parkinson's disease. Neurobiol Dis 1998;5:97-106.

Arii T, Kamiya T, Arii K, Ueda M, Nito C, Katsura KI, Katayama Y. Neuroprotective effect of immunosuppressant FK506 in transient focal ischemia in rat: therapeutic time window for FK506 in transient focal ischemia. Neurol Res 2001;23:755-60.

Ebisu T, Katsuta K, Fujikawa A, Aoki I, Umeda M, Naruse S, Tanaka C. Early and delayed neuroprotective effects of FK506 on experimental focal ischemia quantitatively assessed by diffusion- weighted MRI. Magn Reson Imaging 2001;19:153-60.

Sharkey J, Butcher SP. Immunophilins mediate the neuroprotective effects of FK506 in focal cerebral ischaemia. Nature 1994;371:336-9.

Bavetta S, Hamlyn PJ, Burnstock G, Lieberman AR, Anderson PN. The effects of FK506 on dorsal column axons following spinal cord injury in adult rats: neuroprotection and local regeneration. Exp Neurol 1999;158:382-93.

Madsen JR, MacDonald P, Irwin N, Goldberg DE, Yao GL, Meiri KF, Rimm IJ, Stieg PE, Benowitz LI. Tacrolimus (FK506) increases neuronal expression of GAP-43 and improves functional recovery after spinal cord injury in rats. Exp Neurol 1998;154:673-83.

Gold BG, Yew JY, Zeleny-Pooley M. The immunosuppressant FK506 increases GAP-43 mRNA levels in axotomized sensory neu- rons. Neurosci Lett 1998;241:25-8.

Lyons WE, George EB, Dawson TM, Steiner JP, Snyder SH. Immunosuppressant FK506 promotes neurite outgrowth in cultures of PC12 cells and sensory ganglia. Proc Natl Acad Sci USA 1994;91:3191-5.

Gold BG, Gordon HS, Wang MS. Efficacy of delayed or discontin- uous FK506 administrations on nerve regeneration in the rat sciatic nerve crush model: lack of evidence for a conditioning lesion-like effect. Neurosci Lett 1999;267:33-6.

Gold BG, Katoh K, Storm-Dickerson T. The immunosuppressant FK506 increases the rate of axonal regeneration in rat sciatic nerve. J Neurosci 1995;15:7509-16.

Lee M, Doolabh VB, Mackinnon SE, Jost S. FK506 promotes func- tional recovery in crushed rat sciatic nerve. Muscle Nerve 2000;23:633-40.

Wang MS, Zeleny-Pooley M, Gold BG. Comparative dose-depend- ence study of FK506 and cyclosporin A on the rate of axonal regen- eration in the rat sciatic nerve. J Pharmacol Exp Ther 1997;282: 1084-93.

Navarro X, Udina E, Ceballos D, Gold BG. Effects of FK506 on nerve regeneration and reinnervation after graft or tube repair of long nerve gaps. Muscle Nerve 2001;24:905-15.

Sarikcioglu L, Duygulu E, Aydin H, Gurer EI, Ozkan O, Tuzuner S. Effects of intrathecal administration of FK506 after sciatic nerve crush injury. J Reconstr Microsurg 2006;22:649-54.

Sobol JB, Lowe IJ, Yang RK, Sen SK, Hunter DA, Mackinnon SE. Effects of delaying FK506 administration on neuroregeneration in a rodent model. J Reconstr Microsurg 2003;19:113-8.

Chunasuwankul R, Ayrout C, Dereli Z, Gal A, Lanzetta M, Owen E. Low dose discontinued FK506 treatment enhances peripheral nerve regeneration. Int Surg 2002;87:274-8.

Jost SC, Doolabh VB, Mackinnon SE, Lee M, Hunter D. Acceleration of peripheral nerve regeneration following FK506 administration. Restor Neurol Neurosci 2000;17:39-44.

Sulaiman OA, Midha R, Munro CA, Matsuyama T, Al-Majed A, Gordon T. Chronic Schwann cell denervation and the presence of a sensory nerve reduce motor axonal regeneration. Exp Neurol 2002;176:342-54.

Sulaiman OA, Voda J, Gold BG, Gordon T. FK506 increases peripheral nerve regeneration after chronic axotomy but not after chronic schwann cell denervation. Exp Neurol 2002;175:127-37.

Pockett S, Gavin RM. Acceleration of peripheral nerve regeneration after crush injury in rat. Neurosci Lett 1985;59:221-4.

Doolabh VB, Mackinnon SE. FK506 accelerates functional recovery following nerve grafting in a rat model. Plast Reconstr Surg 1999; 103:1928-36.

Fansa H, Keilhoff G, Altmann S, Plogmeier K, Wolf G, Schneider W. The effect of the immunosuppressant FK 506 on peripheral nerve regeneration following nerve grafting. J Hand Surg Br 1999; 24:38-42.

Yang RK, Lowe JB, 3rd, Sobol JB, Sen SK, Hunter DA, Mackinnon SE. Dose-dependent effects of FK506 on neuroregeneration in a rat model. Plast Reconstr Surg 2003;112:1832-40.

Buttemeyer R, Rao U, Jones NF. Peripheral nerve allograft trans- plantation with FK506: functional, histological, and immunological results before and after discontinuation of immunosuppression. Ann Plast Surg 1995;35:396-401.

Grand AG, Myckatyn TM, Mackinnon SE, Hunter DA. Axonal regeneration after cold preservation of nerve allografts and immuno- suppression with tacrolimus in mice. J Neurosurg 2002;96:924-32.

Weinzweig N, Grindel S, Gonzalez M, Kuy D, Fang J, Shahani B. Peripheral-nerve allotransplantation in rats immunosuppressed with transient or long-term FK-506. J Reconstr Microsurg 1996;12:451-9.

Bignotti B, Origo C, Schenone A, Ratto S, Mancardi GL, Ferrari ML. Experimental studies on peripheral nerve repair following early or delayed suture. Ital J Orthop Traumatol 1986;12:259-66.

Bolesta MJ, Garrett WE Jr, Ribbeck BM, Glisson RR, Seaber AV, Goldner JL. Immediate and delayed neurorrhaphy in a rabbit model: a functional, histologic, and biochemical comparison. J Hand Surg Am 1988;13:352-7.

Fu SY, Gordon T. Contributing factors to poor functional recovery after delayed nerve repair: prolonged denervation. J Neurosci 1995;15:3886-95.

Grabb WC. Median and ulnar nerve suture. An experimental study comparing primary and secondary repair in monkeys. J Bone Joint Surg Am 1968;50:964-72.

Irintchev A, Draguhn A, Wernig A. Reinnervation and recovery of mouse soleus muscle after long-term denervation. Neuroscience 1990;39:231-43.

Van Beek A, Glover JL, Zook E. Primary versus delayed-primary neurorrhaphy in rat sciatic nerve. J Surg Res 1975;18:335-9.

Wang MS, Gold BG. FK506 increases the regeneration of spinal cord axons in a predegenerated peripheral nerve autograft. J Spinal Cord Med 1999;22:287-96.

Kujawa KA, Jones KJ. Testosterone-induced acceleration of recov- ery from facial paralysis in male hamsters: temporal requirements of hormone exposure. Physiol Behav 1990;48:765-8.

Kujawa KA, Kinderman NB, Jones KJ. Testosterone-induced accel- eration of recovery from facial paralysis following crush axotomy of the facial nerve in male hamsters. Exp Neurol 1989;105:80-5.

de Medinaceli L, Freed WJ, Wyatt RJ. An index of the functional condition of rat sciatic nerve based on measurements made from walking tracks. Exp Neurol 1982;77:634-43.

Carlton JM, Goldberg NH. Quantitating integrated muscle function following reinnervation. Surg Forum 1986;37:611-2.

Bain JR, Mackinnon SE, Hunter DA. Functional evaluation of com- plete sciatic, peroneal, and posterior tibial nerve lesions in the rat. Plast Reconstr Surg 1989;83:129-38.

Fu SY, Gordon T. Contributing factors to poor functional recovery after delayed nerve repair: prolonged axotomy. J Neurosci 1995;15:3876-85.

Kobayashi J, Mackinnon SE, Watanabe O, Ball DJ, Gu XM, Hunter DA, Kuzon WM Jr. The effect of duration of muscle denervation on functional recovery in the rat model. Muscle Nerve 1997;20:858-66.

Totosy de Zepetnek JE, Zung HV, Erdebil S, Gordon T. Innervation ratio is an important determinant of force in normal and reinnervated rat tibialis anterior muscles. J Neurophysiol 1992;67: 1385-403.

Viguie CA, Lu DX, Huang SK, Rengen H, Carlson BM. Quantitative study of the effects of long-term denervation on the extensor digitorum longus muscle of the rat. Anat Rec 1997;248: 346-54.

Gordon T, Fu SY. Long-term response to nerve injury. Adv Neurol 1997;72:185-99.

Sulaiman OA, Gordon T. Effects of short- and long-term Schwann cell denervation on peripheral nerve regeneration, myelination, and size. Glia 2000;32:234-46.

Hizay A, Demirel BM, Gokhan G, Sarikcioglu L, Demir N. Does FK506 reduce the size of the watershed area after vascular injury of the sciatic nerve? Rom J Morphol Embryol 2011;52:1077-80.

Sarikcioglu L, Demir N, Akar Y, Demirtop A. Effect of intrathecal FK506 administration on intraorbital optic nerve crush: an ultra- structural study. Can J Ophthalmol 2009;44:427-30.

Utuk A, Sarikcioglu L, Demirel BM, Demir N. The immunosup- pressive agent FK506 prevents subperineurial degeneration and demyelination on ultrastructural and functional analysis. Curr Neurovasc Res 2009;6:252-8.

Yildirim FB, Sarikcioglu L, Ozsoy U, Demir N, Demirtop A, Ucar Y. Effect of FK506 administration after obturator nerve injury: a functional and ultrastructural study. Acta Neurobiol Exp (Wars) 2008; 68:477-83.

Ma J, Novikov LN, Wiberg M, Kellerth JO. Delayed loss of spinal motoneurons after peripheral nerve injury in adult rats: a quantita- tive morphological study. Exp Brain Res 2001;139:216-23.

Guntinas-Lichius O, Effenberger K, Angelov DN, Klein J, Streppel M, Stennert E, Neiss WF. Delayed rat facial nerve repair leads to accelerated and enhanced muscle reinnervation with reduced collat- eral axonal sprouting during a definite denervation period using a cross-anastomosis paradigm. Exp Neurol 2000;162:98-111.