The effects of cold preservation and subimmunosuppressive doses of FK506 on axonal regeneration in murine peripheral nerve isografts

Abstract

Background

FK506 is a frequently used immunosuppressant with neuroregenerative effects. The neuroregenerative and immunosuppressive mechanisms of FK506, however, are distinct, suggesting that FK506 may stimulate nerve regeneration at lower doses than are needed to induce immunosuppression. The effects of cold preservation, a technique known to improve axonal regeneration through nerve allografts, are not well studied in nerve isografts and are also reported here.

Objectives

To determine the effects of subimmunosuppressive doses of FK506 and cold preservation on nerve regeneration in isografts.

Methods

The neuroregenerative properties of immunosuppressive and subimmunosuppressive doses of FK506 were compared in a murine model receiving either fresh or cold preserved nerve isografts. Sixty female BALB/cJ mice were randomized into six groups. Animals in groups I, III and V received fresh nerve isografts. Animals in groups II, IV and VI received cold-preserved nerve isografts. Mice in groups I and II received no medical therapy, while those in groups III and IV received subimmunosuppressive doses of FK506, and those in groups V and VI received immunosuppressive doses as confirmed by mixed lymphocyte reactivity assays. Nerve regeneration was evaluated with histomorphometry and functional recovery was evaluated with walking track analysis.

Results

Pretreatment with cold preservation did not significantly affect neural regeneration. The potent neuroregenerative effect of immunosuppressive doses of FK506 was confirmed, and the ability of subimmunosuppressive doses of FK506 to stimulate axonal regeneration in murine nerve isografts is reported.

Conclusions

Less toxic subimmunosuppressive doses of FK506 retaining some neuroregenerative properties may have a clinical role in treating extensive nerve injuries.