Exploring the neuroregenerative potential of tacrolimus

ABSTRACT

Introduction: The clinical use of tacrolimus is characterized by many side effects which include neurotoxicity. In contrast, tacrolimus has also shown to have neuroregenerative properties. On a molecular level, the mechanisms of action could provide us more insight into understanding the neurobiological effects. The aim of this article is to review current evidence regarding the use of tacrolimus in peripheral nerve injuries.

Areas covered: Available data on tacrolimus’ indications were summarized and molecular mechanisms were elucidated to possibly understand the conflicting neurotoxic and neuroregenerative effects. The potential clinical applications of tacrolimus, as immunosuppressant and enhancer of nerve regeneration in peripheral nerve injuries, are discussed. Finally, concepts of delivery are explored.

Expert opinion: It is unclear what the exact neurobiological effects of tacrolimus are. Besides its known calcineurin inhibiting properties, the mechanism of action of tacrolimus is mediated by its binding to FK506-binding protein-52, resulting in a bimodal dose response. Experimental models found that tacrolimus administration is preferred up to three days prior to or within 10 days post-nerve reconstruction. Moreover, the indication for the use of tacrolimus has been expanding to fields of dermatology, ophthalmology, orthopedic surgery and rheumatology to improve outcomes after various indications.

KEYWORDS:

• Calcineurin inhibitor
• nerve injury
• neuroregeneration
• neurotoxicity
• allograft rejection
• tacrolimus
• transplantation

Article highlights

• There are contradictory reports on the neurobiological effects of tacrolimus, as both neuroregenerative and neurotoxic properties have been described.

• On a molecular level, the calcineurin inhibiting property of tacrolimus seems to play a major role in its neuroregenerative and neurotoxic effects.

• The mechanism of action of tacrolimus is suggested to be mediated by binding to FK506-binding protein-52, resulting in a bimodal dose response.

• The bimodal dose response causes low and high concentrations to result in similar increased neuroregenerative effects whereas intermediate doses were not shown to be neuroregenerative.

• Both systemic and locally administered tacrolimus appear to have beneficial effects on recovery in nerve injuries. Local delivery is theoretically more favorable as it results in fewer systemic side effects.

• For optimal timing between nerve injury, microsurgical repair and the initiation of tacrolimus administration, it should preferably be administered up to three days prior to or within 10 days post-nerve reconstruction.

Acknowledgments

We would like to thank Jim Postier for the artwork of Figure 3.

Declaration of interest

DA Hesselink has received grant and lecture support from Astellas Pharma and Chiesi Farmaceutici SpA. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.