Nerve Growth Potential of FK 506 and Its Analogues – A Systematic review of Controlled Trials in Rats

Abstract

French

Background

Nerve injuries of the upper extremity seldom regain full preinjury function. Delay in nerve repair, nerve gap and ischemic local conditions are some of the factors attributed as the cause. The proximal axonal segment regenerates in the presence of neuronotrophic factors present in nerve tissue. FK 506 and its nonimmunosuppressive analogues have been shown to influence the growth of axons experimentally. Parallel studies of animals and human beings have demonstrated strong, toxic effects of these agents.

Purpose

To review systematically data on the role of FK 506 and its analogues in peripheral nerve regeneration of randomized, controlled trials in rats. Reports dealing with the toxic effects of these agents all were reviewed as well.

Methods

Articles and reviews were identified through a computerized search of MEDLINE from January 1966 to September 1999 by using the terms “FK 506”, “FKBP-12 ligands”, “peripheral nerve regeneration” and “nephrotoxicity, cardiotoxicity and neurotoxicity in FK 506”. Two reviewers assessed the trials independently.

Results

FK 506 caused dose-related enhancement of axonal growth in all animals that were tested and for all routes of drug administration. Effects of FK 506 when used locally and of its analogues occurred in the same order as those of the parent drug.

Conclusions

FK 506 and its analogues have been experimentally proven to be potent nerve stimulators. Further studies are warranted in view of the pathological and clinical potential for nephrotoxicity and cardiotoxicity of these agents. The authors proposed an experimental model incorporating a nerve conduit filled with slow release FK 506 at the site of nerve gap or crush, thus decreasing its systemic effects.

Keywords

FK 506 FK 506 ligands Immunophillin ligands Nephrotoxicity Peripheral nerve regeneration

Get full access to this article

View all access options for this article.

References

Wong

A.Y.

, Scott

J.J.

. Functional recovery following direct or graft repair of nerve gaps in the rat. Exp Neurol 1991; 114: 364–6.

Novak

C.B.

, MacKinnon

S.E.

, Kelly

. Correlation of two-point discrimination and hand function following median nerve injury. Ann Plast Surg 1993; 31: 495–8.

Whitworth

I.H.

, Brown

R.A.

, Dore

C.J.

, Anand

, Green

C.J.

, Terenghi

. Nerve growth factor enhances nerve regeneration through fibronectin grafts. J Hand Surg [Br] 1996; 21: 514–22.

Gold

B.G.

, Dickerson

T.S.

, Austin

D.R.

, The immunosuppressant FK 506 increases functional recovery and nerve regeneration following peripheral nerve injury. Restor Neurol Neurosci 1994; 6:287–96.

Shapiro

, Fung

J.J.

, Jain

A.B.

, Parks

, Todo

, Strazl

T.E.

. The side effects of FK 506 in humans. Transplant Proc 1990; 22: 35–6.

Nielsen

F.T.

, Leyssac

P.P.

, Kemp

, Starklint

, Dieperink

. Nephrotoxicity of FK-506 in the rat. Studies on glomerular and tubular function, and on the relationship between efficacy and toxicity. Nephrol Dial Transplant 1995; 10: 334–40.

Steiner

J.P.

, Connolly

M.A.

, Valentine

H.L.

. Neurotrophic actions of nonimmunosuppressive analogues of immunosuppressive drugs FK 506, rapamycin, and cyclosporin A. Nat Med 1997; 3: 421–8.

Gold

B.G.

, Zeleny-Pooley

, Wang

M.S.

, Chaturvedi

, Armistead

D.M.

. A nonimmunosuppressant FKBP-12 ligand increases nerve regeneration. Exp Neurol 1997; 147: 269–78.

Fansa

, Keilhoff

, Altmann

, Plogmeier

, Wolf

, Schneider

. The effect of the immunosuppressant FK 506 on peripheral nerve regeneration following nerve grafting. J Hand Surg [Br] 1999; 24: 38–42.

10.

Doolabh

V.B.

, Mackinnon

S.E.

. FK 506 accelerates functional recovery following nerve grafting in a rat model. Plast Reconstr Surg 1999; 103: 1928–36.

11.

Levi-Montalcini

. The nerve growth factor: thirty-five years later. EMBO J 1987; 6: 1145–54.

12.

Gundersen

R.W.

, Barrett

J.N.

. Characterization of the turning response of dorsal root neurites toward nerve growth factor. J Cell Biol 1980; 87: 546–54.

13.

Lander

A.D.

. Molecules that make axons grow. Mol Neurobiol 1987; 1: 213–45.

14.

Akers

R.M.

, Mosher

D.F.

, Lilien

J.E.

. Promotion of retinal neurite outgrowth by substratum-bound fibronectin. Dev Biol 1981; 86: 179–88.

15.

Gundersen

R.W.

. Response of sensory neurites and growth cones to patterned substrata of laminin and fibronectin in vitro. Dev Biol 1987; 121: 423–31.

16.

Dodd

, Jessell

T.M.

. Axon guidance and the patterning of neuronal projections in vertebrates. Science 1988; 242: 692–9.

17.

Gold

B.G.

, Katoh

, Storm-Dickerson

. The immunosuppressant FK 506 increases the rate of axonal regeneration in rat sciatic nerve. J Neurosci 1995; 15: 7509–16.

18.

Wang

M.S.

, Zeleny-Pooley

, Gold

B.G.

. Comparative dose-dependence study of FK 506 and cyclosporin A on the rate of axonal regeneration in the rat sciatic nerve. J Pharmacol Exp Ther 1997; 282: 1084–93.

19.

Gold

B.G.

, Zeleny-Pooley

, Chaturvedi

, Wang

M.S.

. Oral administration of a nonimmunosuppressant FKBP-12 ligand speeds nerve regeneration. Neuroreport 1998; 9: 553–8.

20.

Steiner

J.P.

, Hamilton

G.S.

, Ross

D.T.

. Neurotrophic immunophillin ligands stimulate structural and functional recovery in neurodegenerative animal models. Proc Natl Acad Sci USA 1997; 94: 2019–24.

21.

Dumont

F.J.

, Staruch

M.J.

, Koprak

S.L.

. The immunosuppressive and toxic effects of FK-506 are mechanistically related: pharmacology of a novel antagonist of FK-506 and rapamycin. J Exp Med 1992; 176: 751–60.

22.

A comparison of tacrolimus (FK 506) and cyclosporin for immunosuppression in liver transplantation. The US Multicenter FK 506 Liver Study Group. N Engl J Med 1994; 331:1110–5.

23.

Uchida

, Miura

, Yamanaka

. Renal endothelin in FK 506-induced nephrotoxicity in spontaneously hypertensive rats. Jpn J Pharmacol 1998; 76: 39–49.

24.

Nomoto

, Fujiwara

, Ban

, Ohara

. Cardiotoxicity of long-term intravenous administration of FK 506 in rabbits: dose relationship and recovery after discontinuance. Transplant Proc 1994; 26: 855–7.

25.

Mizisin

A.P.

, Powell

H.C.

. Toxic neuropathies. Curr Opin Neurol 1995; 8: 367–71.

26.

Lyons

W.E.

, George

E.B.

, Dawson

T.M.

, Steiner

J.P.

, Snyder

S.H.

. Immunosuppressant FK 506 promotes neurite outgrowth in cultures of PC 12 cells and sensory ganglia. Proc Natl Acad Sci USA. 1994; 91: 3191–5.