J Reconstr Microsurg 2013; 29(03): 141-148
DOI: 10.1055/s-0032-1333314
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

FK506 and Nerve Regeneration: Past, Present, and Future

Petros Konofaos
1   Department of Plastic Surgery, University of Tennessee, Memphis, Tennessee, USA
,
Julia K. Terzis
2   Department of Plastic Surgery, New York University Medical Center and the International Institute of Reconstructive Microsurgery, Long Island City, New York, USA
› Author Affiliations
Further Information

Publication History

08 May 2012

05 October 2012

Publication Date:
15 January 2013 (online)

Abstract

Promoting neurological recovery requires strategies that simultaneously provide protection to injured neurons and increase the numbers of neurons that extend axons while inducing more rapid and extensive axon regeneration across long nerve gaps. An agent that facilitates the speed and success of reinnervation will have direct applicability to the clinical management of severe peripheral nerve injuries. The immunosuppressive drug FK506 has been proven to have neuroprotective and neurotrophic actions in experimental models, increasing neurite elongation and accelerating the rate of nerve regeneration in vitro and in vivo. This review examines the role played by FK506, with primary focus on its role as a neurotrophic agent and its potential clinical use as a promoter of neurological recovery following peripheral nerve injuries.

 
  • References

  • 1 Paulus Aegineta. De re medica. Paulou Aiginetou iatrou aristou, biblia hepta. En arche hekastou ton biblion deiknytai ta en ekeino pereichomena. Pavli Aeginetae medici optimi, libri septem. In principio singvlorvm librorvm omnia indicantvr, qvae in eo libro continentvr [title romanized; text in Greek]. Venetiis, In aedibvs Aldi, 1528
  • 2 Sunderland S. Nerve Injuries and Their Repair. A Critical Appraisal. NY: Churchill Livingstone; 1991
  • 3 Kobayashi J, Mackinnon SE, Watanabe O , et al. The effect of duration of muscle denervation on functional recovery in the rat model. Muscle Nerve 1997; 20: 858-866
  • 4 Angelov DN, Neiss WF, Streppel M, Andermahr J, Mader K, Stennert E. Nimodipine accelerates axonal sprouting after surgical repair of rat facial nerve. J Neurosci 1996; 16: 1041-1048
  • 5 Badalamente MA, Hurst LC, Stracher A. Neuromuscular recovery using calcium protease inhibition after median nerve repair in primates. Proc Natl Acad Sci U S A 1989; 86: 5983-5987
  • 6 Birge RB, Wadsworth S, Akakura R , et al. A role for schwann cells in the neuroregenerative effects of a non-immunosuppressive fk506 derivative, jnj460. Neuroscience 2004; 124: 351-366
  • 7 Campana WM, Mohiuddin L, Misasi R, O'Brien JS, Calcutt NA. Prosaposin-derived peptides enhanced sprouting of sensory neurons in vitro and induced sprouting at motor endplates in vivo. J Peripher Nerv Syst 2000; 5: 126-130
  • 8 Gold BG, Villafranca JE. Neuroimmunophilin ligands: the development of novel neuroregenerative/ neuroprotective compounds. Curr Top Med Chem 2003; 3: 1368-1375
  • 9 Myckatyn TM, Ellis RA, Grand AG , et al. The effects of rapamycin in murine peripheral nerve isografts and allografts. Plast Reconstr Surg 2002; 109: 2405-2417
  • 10 Lassner F, Schaller E, Steinhoff G, Wonigeit K, Walter GF, Berger A. Cellular mechanisms of rejection and regeneration in peripheral nerve allografts. Transplantation 1989; 48: 386-392
  • 11 Gold BG, Katoh K, Storm-Dickerson T. The immunosuppressant FK506 increases the rate of axonal regeneration in rat sciatic nerve. J Neurosci 1995; 15: 7509-7516
  • 12 Katsube K, Doi K, Fukumoto T, Fujikura Y, Shigetomi M, Kawai S. Successful nerve regeneration and persistence of donor cells after a limited course of immunosuppression in rat peripheral nerve allografts. Transplantation 1998; 66: 772-777
  • 13 Wang MS, Zeleny-Pooley M, Gold BG. Comparative dose-dependence study of FK506 and cyclosporin A on the rate of axonal regeneration in the rat sciatic nerve. J Pharmacol Exp Ther 1997; 282: 1084-1093
  • 14 Doolabh VB, Mackinnon SE. FK506 accelerates functional recovery following nerve grafting in a rat model. Plast Reconstr Surg 1999; 103: 1928-1936
  • 15 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
  • 16 Hontanilla B, Aubá C, Arcocha J, Gorría O. Nerve regeneration through nerve autografts and cold preserved allografts using tacrolimus (FK506) in a facial paralysis model: a topographical and neurophysiological study in monkeys. Neurosurgery 2006; 58: 768-779 , discussion 768–779
  • 17 Wang J, Liu X, Zhu J, Li W, Xiang J. Study in vitro of populating autogenous Schwann cells into chemical extracted allogenous nerve. Chin J Traumatol 2002; 5: 326-328
  • 18 Udina E, Ceballos D, Verdú E, Gold BG, Navarro X. Bimodal dose-dependence of FK506 on the rate of axonal regeneration in mouse peripheral nerve. Muscle Nerve 2002; 26: 348-355
  • 19 Lee M, Doolabh VB, Mackinnon SE, Jost S. FK506 promotes functional recovery in crushed rat sciatic nerve. Muscle Nerve 2000; 23: 633-640
  • 20 Kline DG. Nerve surgery as it is now and as it may be. Neurosurgery 2000; 46: 1285-1293
  • 21 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: 905-915
  • 22 Büttemeyer R, Rao U, Jones NF. Peripheral nerve allograft transplantation with FK506: functional, histological, and immunological results before and after discontinuation of immunosuppression. Ann Plast Surg 1995; 35: 396-401
  • 23 Johnson EO, Zoubos AB, Soucacos PN. Regeneration and repair of peripheral nerves. Injury 2005; 36 (Suppl. 04) S24-S29
  • 24 Terzis JK, Sun DD, Thanos PK. Historical and basic science review: past, present, and future of nerve repair. J Reconstr Microsurg 1997; 13: 215-225
  • 25 Levi-Montalcini R, Hamburger V. A diffusable agent of mouse sarcoma producing hyperplasia of sympathetic ganglia and hypernemotization of viscera in the chick embryo. J Exp Zool 1953; 123: 233-278
  • 26 Miyauchi A, Kanje M, Danielsen N, Dahlin LB. Role of macrophages in the stimulation and regeneration of sensory nerves by transposed granulation tissue and temporal aspects of the response. Scand J Plast Reconstr Surg Hand Surg 1997; 31: 17-23
  • 27 Rosenfield J, Paksima N. Peripheral nerve injuries and repair in the upper extremity. Bull Hosp Jt Dis 2001– 2002; 60: 155-161
  • 28 Kino T, Hatanaka H, Hashimoto M , et al. FK-506, a novel immunosuppressant isolated from a Streptomyces. I. Fermentation, isolation, and physico-chemical and biological characteristics. J Antibiot (Tokyo) 1987; a; 40: 1249-1255
  • 29 Kino T, Hatanaka H, Miyata S , et al. FK-506, a novel immunosuppressant isolated from a Streptomyces. II. Immunosuppressive effect of FK-506 in vitro. J Antibiot (Tokyo) 1987; b; 40: 1256-1265
  • 30 Starzl TE, Todo S, Fung J, Demetris AJ, Venkataramman R, Jain A. FK 506 for liver, kidney, and pancreas transplantation. Lancet 1989; 2: 1000-1004
  • 31 A comparison of tacrolimus (FK506) and cyclosporine for immunosuppression in liver transplantation. The U.S. Multicentre FK506 Liver Study Group. [No authors listed] N Engl J Med 1994; 331 (17) 1110-1115
  • 32 Mouzaki A, Dai Y, Weil R, Rungger D. Cyclosporin A and FK506 prevent the derepression of the IL-2 gene in mitogen-induced primary T lymphocytes. Cytokine 1992; 4: 151-160
  • 33 Heitman J, Koller A, Kunz J , et al. The immunosuppressant FK506 inhibits amino acid import in Saccharomyces cerevisiae. Mol Cell Biol 1993; 13: 5010-5019
  • 34 Schmidt A, Hall MN, Koller A. Two FK506 resistance-conferring genes in Saccharomyces cerevisiae, TAT1 and TAT2, encode amino acid permeases mediating tyrosine and tryptophan uptake. Mol Cell Biol 1994; 14: 6597-6606
  • 35 Yamamoto S, Jiang H, Kato R. Stimulation of hair growth by topical application of FK506, a potent immunosuppressive agent. J Invest Dermatol 1994; 102: 160-164
  • 36 Francavilla A, Barone M, Todo S, Zeng Q, Porter KA, Starzl TE. Augmentation of rat liver regeneration by FK 506 compared with cyclosporin. Lancet 1989; 2 (8674) 1248-1249
  • 37 Carroll PB, Rilo HL, Abu Elmagd K , et al. Effect of tacrolimus (FK506) in dystrophic epidermolysis bullosa: rationale and preliminary results. Arch Dermatol 1994; 130: 1457-1458
  • 38 Ayres RCS, Dousset B, Wixon S, Buckels JA, McMaster P, Mayer AD. Peripheral neurotoxicity with tacrolimus. Lancet 1994; 343: 862-863
  • 39 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 U S A 1994; 91: 3191-3195
  • 40 Liu J. FK506 and ciclosporin: molecular probes for studying intracellular signal transduction. Trends Pharmacol Sci 1993; 14: 182-188
  • 41 Liu J, Albers MW, Wandless TJ , et al. Inhibition of T cell signaling by immunophilin-ligand complexes correlates with loss of calcineurin phosphatase activity. Biochemistry 1992; 31: 3896-3901
  • 42 Grand AG, Myckatyn TM, Mackinnon SE, Hunter DA. Axonal regeneration after cold preservation of nerve allografts and immunosuppression with tacrolimus in mice. J Neurosurg 2002; 96: 924-932
  • 43 Snyder AK, Fox IK, Nichols CM , et al. Neuroregenerative effects of preinjury FK-506 administration. Plast Reconstr Surg 2006; 118: 360-367
  • 44 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
  • 45 Sabatini DM, Lai MM, Snyder SH. Neural roles of immunophilins and their ligands. Mol Neurobiol 1997; 15: 223-239
  • 46 Tanaka K, Fujita N, Higashi Y, Ogawa N. Neuroprotective and antioxidant properties of FKBP-binding immunophilin ligands are independent on the FKBP12 pathway in human cells. Neurosci Lett 2002; 330: 147-150
  • 47 Gold BG, Yew JY, Zeleny-Pooley M. The immunosuppressant FK506 increases GAP-43 mRNA levels in axotomized sensory neurons. Neurosci Lett 1998; 241: 25-28
  • 48 Gold BG, Densmore V, Shou W, Matzuk MM, Gordon HS. Immunophilin FK506-binding protein 52 (not FK506-binding protein 12) mediates the neurotrophic action of FK506. J Pharmacol Exp Ther 1999; 289: 1202-1210
  • 49 Owens-Grillo JK, Hoffmann K, Hutchison KA , et al. The cyclosporin A-binding immunophilin CyP-40 and the FK506-binding immunophilin hsp56 bind to a common site on hsp90 and exist in independent cytosolic heterocomplexes with the untransformed glucocorticoid receptor. J Biol Chem 1995; 270 (35) 20479-20484
  • 50 Czar MJ, Owens-Grillo JK, Yem AW , et al. The hsp56 immunophilin component of untransformed steroid receptor complexes is localized both to microtubules in the cytoplasm and to the same nonrandom regions within the nucleus as the steroid receptor. Mol Endocrinol 1994; 8: 1731-1741
  • 51 Sharkey J, Butcher SP. Immunophilins mediate the neuroprotective effects of FK506 in focal cerebral ischaemia. Nature 1994; 371: 336-339
  • 52 Becker DB, Jensen JN, Myckatyn TM, Doolabh VB, Hunter DA, Mackinnon SE. Effects of FKBP-12 ligands following tibial nerve injury in rats. J Reconstr Microsurg 2000; 16: 613-620
  • 53 Giordani F, Benetolli A, Favero-Filho LA, Lima KC, Cestari Junior L, Milani H. Tacrolimus (FK506) reduces ischemia-induced hippocampal damage in rats: a 7- and 30-day study. Braz J Med Biol Res 2003; 36: 495-502
  • 54 Sosa I, Reyes O, Kuffler DP. Immunosuppressants: neuroprotection and promoting neurological recovery following peripheral nerve and spinal cord lesions. Exp Neurol 2005; 195: 7-15
  • 55 Wang MS, Gold BG. FK506 increases the regeneration of spinal cord axons in a predegenerated peripheral nerve autograft. J Spinal Cord Med 1999; 22: 287-296
  • 56 Sobol JB, Lowe III JB, Yang RK, Sen SK, Hunter DA, Mackinnon SE. Effects of delaying FK506 administration on neuroregeneration in a rodent model. J Reconstr Microsurg 2003; 19: 113-118
  • 57 Brenner MJ, Lowe III JB, Fox IK , et al. Effects of Schwann cells and donor antigen on long-nerve allograft regeneration. Microsurgery 2005; 25: 61-70
  • 58 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: 127-137
  • 59 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: 274-278
  • 60 Gold BG, Storm-Dickerson T, Austin DR. The immunosuppressant FK506 increases functional recovery and nerve regeneration following peripheral nerve injury. Restor Neurol Neurosci 1994; 6: 287-296
  • 61 Gold BG, Zeleny-Pooley M, Chaturvedi P, Wang MS. Oral administration of a nonimmunosuppressant FKBP-12 ligand speeds nerve regeneration. Neuroreport 1998; 9: 553-558
  • 62 Diaz LM, Steele MH, Guerra AB , et al. The role of topically administered FK506 (tacrolimus) at the time of facial nerve repair using entubulation neurorrhaphy in a rabbit model. Ann Plast Surg 2004; 52: 407-413
  • 63 Yeh C, Bowers D, Hadlock TA. Effect of FK506 on functional recovery after facial nerve injury in the rat. Arch Facial Plast Surg 2007; 9: 333-339
  • 64 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: 649-654
  • 65 Felldin M, Bäckman L, Brattström C , et al. Rescue therapy with tacrolimus (FK 506) in renal transplant recipients—a Scandinavian multicenter analysis. Transpl Int 1997; 10: 13-18
  • 66 Yang RK, Lowe III JB, Sobol JB, Sen SK, Hunter DA, Mackinnon SE. Dose-dependent effects of FK506 on neuroregeneration in a rat model. Plast Reconstr Surg 2003; 112: 1832-1840
  • 67 Ellis RA, Brenner MJ, Mackinnon SE, Myckatyn TM, Hunter DA. Use of mixed lymphocyte reaction to identify subimmunosuppressive FK-506 levels in mice. Microsurgery 2003; 23: 276-282
  • 68 Konofaos P, Burns J, Terzis JK. Effect of low-dose FK506 after contralateral C7 transfer to the musculocutaneous nerve: a study in rats. J Reconstr Microsurg 2010; 26: 225-233
  • 69 Terzis JK, Konofaos P. Low-dose FK506 after contralateral C7 transfer to the musculocutaneous nerve using two different tubes: a study in rats. Ann Plast Surg 2010; 64: 622-631
  • 70 Steiner JP, Connolly MA, Valentine HL , et al. Neurotrophic actions of nonimmunosuppressive analogues of immunosuppressive drugs FK506, rapamycin and cyclosporin A. Nat Med 1997; 3: 421-428
  • 71 Costantini LC, Isacson O. Immunophilin ligands and GDNF enhance neurite branching or elongation from developing dopamine neurons in culture. Exp Neurol 2000; 164: 60-70
  • 72 Archibald SJ, Wang MS, Gold BG. FK506 accelerates axonal regeneration through an artificial nerve guide in the rat sciatic nerve transection model. J Peripher Nerv Syst 1999; 4: 202
  • 73 Butí M, Verdú E, Labrador RO, Vilches JJ, Forés J, Navarro X. Influence of physical parameters of nerve chambers on peripheral nerve regeneration and reinnervation. Exp Neurol 1996; 137: 26-33
  • 74 Gómez N, Cuadras J, Butí M, Navarro X. Histologic assessment of sciatic nerve regeneration following resection and graft or tube repair in the mouse. Restor Neurol Neurosci 1996; 10: 187-196
  • 75 Rodríguez FJ, Gómez N, Labrador RO , et al. Improvement of regeneration with predegenerated nerve transplants in silicone chambers. Restor Neurol Neurosci 1999; 14: 65-79
  • 76 Kostopoulos E, Konofaos P, Frazer M, Terzis JK. Tubulization techniques in brachial plexus surgery in an animal model for long nerve defects (40 mm): a pilot study. Ann Plast Surg 2010; 64: 614-621
  • 77 Chen L, Gu YD. An experimental study of contralateral C7 root transfer with vascularized nerve grafting to treat brachial plexus root avulsion. J Hand Surg [Br] 1994; 19: 60-66
  • 78 Viterbo F, Trindade JC, Hoshino K, Mazzoni Neto A. Latero-terminal neurorrhaphy without removal of the epineural sheath. Experimental study in rats. Rev Paul Med 1992; 110: 267-275
  • 79 Bertelli JA, dos Santos AR, Calixto JB. Is axonal sprouting able to traverse the conjunctival layers of the peripheral nerve? A behavioral, motor, and sensory study of end-to-side nerve anastomosis. J Reconstr Microsurg 1996; 12: 559-563
  • 80 Noah EM, Williams A, Fortes W, Terzis JK. A new animal model to investigate axonal sprouting after end-to-side neurorrhaphy. J Reconstr Microsurg 1997; 13: 317-325
  • 81 Noah EM, Williams A, Jorgenson C, Skoulis TG, Terzis JK. End-to-side neurorraphy: a histologic and morpho- metric study of axonal sprouting into an end-to-side nerve graft. J Reconstr Microsurg 1997; 12: 99-106
  • 82 Tarasidis G, Watanabe O, Mackinnon SE, Strasberg SR, Haughey BH, Hunter DA. End-to-side neurorraphy: a long-term study of neural regeneration in a rat model. Otolaryngol Head Neck Surg 1998; 119: 337-341
  • 83 Chen B, Song Y, Liu Z. Promotion of nerve regeneration in peripheral nerve by short-course FK506 after end-to-side neurorrhaphy. J Surg Res 2009; 152: 303-310
  • 84 Steiner JP, Hamilton GS, Ross DT , et al. Neurotrophic immunophilin ligands stimulate structural and functional recovery in neurodegenerative animal models. Proc Natl Acad Sci U S A 1997; 94: 2019-2024
  • 85 Gold BG, Zeleny-Pooley M, Wang MS, Chaturvedi P, Armistead DM. A nonimmunosuppressant FKBP-12 ligand increases nerve regeneration. Exp Neurol 1997; 147: 269-278
  • 86 Guo X, Dawson VL, Dawson TM. Neuroimmunophilin ligands exert neuroregeneration and neuroprotection in midbrain dopaminergic neurons. Eur J Neurosci 2001; 13: 1683-1693
  • 87 Klettner A, Baumgrass R, Zhang Y , et al. The neuroprotective actions of FK506 binding protein ligands: neuronal survival is triggered by de novo RNA synthesis, but is independent of inhibition of JNK and calcineurin. Brain Res Mol Brain Res 2001; 97: 21-31