Influence of Tacrolimus (FK506) on Nerve Regeneration Using Allografts: A Rat Sciatic Nerve Model

doi:10.1016/j.joms.2015.03.032

Journal of Oral and Maxillofacial Surgery

Volume 73, Issue 7, July 2015, Pages 1438.e1-1438.e9

https://doi.org/10.1016/j.joms.2015.03.032 Get rights and content

Purpose

FK506 is an immunosuppressant agent used to prevent rejection after organ transplantation. The aim of the present study was to assess effects of tacrolimus (FK506) on peripheral nerve regeneration using allografts in a rat sciatic nerve model.

Materials and Methods

Thirty male white Wistar rats were divided randomly into a normal control (NC) group (n = 10), an allograft (ALLO) group (n = 10), and an FK506-treated (ALLO/FK506) group (n = 10). In the NC group, the left sciatic nerve was exposed through a gluteal muscle incision and, after homeostasis, the muscle was sutured. In the ALLO group, the left sciatic nerve was exposed through a gluteal muscle incision and transected proximal to the tibioperoneal bifurcation, where a 10-mm segment was excised. The same procedure was performed in the ALLO/FK506 group. The harvested nerves of the ALLO group served as allografts for the ALLO/FK506 group and vice versa. The NC and ALLO groups received sterile olive oil 300 μL intraperitoneally once a day for 1 week and the ALLO/FK506 group received FK506 300 μL (1 mg/kg) intraperitoneally once a day for 1 week.

Results

Behavioral, functional, and biomechanical recovery and gastrocnemius muscle mass showed earlier regeneration of axons in the ALLO/FK506 than in the ALLO group (P < .05). Histomorphometric and immunohistochemical studies also showed earlier regeneration of axons in the ALLO/FK506 than in the ALLO group (P < .05).

Conclusions

Administration of FK506 could accelerate functional recovery of the sciatic nerve after nerve allografting. It could have clinical implications for the surgical management of patients after facial nerve transection.

Section snippets

Experimental Design

The study design was based on the authors' previous work.⁷ In brief, 30 male white Wistar rats weighing approximately 300 g were randomly divided into 3 experimental groups (n = 10): a normal control (NC) group, an allograft (ALLO) group, and an FK506-treated (ALLO/FK506) group. Two weeks before and during the entire experiments, the animals were housed in individual plastic cages with an ambient temperature of 23 ± 3°C, stable air humidity, and a natural day-and-night cycle. The rats had free

BBB Recovery

Figure 1 shows BBB scores compared with baseline. All animals in the experimental groups, except sham-operated animals, showed a functional deficit 1 week after the operation. The animals treated with FK506 showed significant improvement in locomotion of the injured nerve compared with the NC animals within the study time line (P < .05).

SFI Outcome

Figure 2 shows the SFI of animals in the different groups. Before injury of the nerve, SFI values in the ALLO and ALLO/FK506 animals were near 0. After the

Discussion

The use of nerve allografts has clear demand because it bears many of the benefits of conduits, including off-the-shelf convenience, avoidance of a donor defect, and unlimited supply; it also might offer greater axon support and potentially even some neurotrophic factors.¹³ Unfortunately, substantial immunogenicity in human nerve tissue has necessitated the concomitant administration of immunosuppressive agents.¹⁴

The results of the present study showed that treatment with FK506 hastened

Acknowledgments

The authors thank Mr Matin, Mr Valinezhad, and Mr Ansarinia for their technical expertise.

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The immunosuppressant FK506 is one of the up and coming peripheral nerve regeneration molecules because of its neurotrophic and neuroprotective [75] properties. It also has immunosuppressive characteristics to help prevent allograft rejection during axonal lengthening [76], axon demyelination, and nerve degeneration [77]. However, there are major side effects such as nephrotoxicity, neurotoxicity for the central nervous system and hyperglycemia.
Functionalized neurotube are a third-generation of conduits with chemical or architectural bioactivity developed for axonal proliferation. The goal of this review is to provide a synopsis of the functionalized nerve conduits described in the literature according to their chemical and architectural properties and answer two questions: what are their mechanisms of action? Has their efficacy been proven compared to the autologous nerve graft? Our literature review relates all kind of conduits corresponding to functionalized neurotubes in peripheral nerve regeneration found in Medline and PubMed Central. Studies developing nerve gaps, chemotactic or structural features promoting each conduit, results, efficiency were selected. Fifty-five studies were selected and classified in: (a) intraluminal neurotrophic factors; (b) cell-based therapy (combined-in-vein muscles, amniotic membrane, Schwann cells, stem cells); (c) extracellular matrix proteins; (d) tissue engineering; (e) bioimplants. Functionalized neurotubes showed significantly better functional results than after end-to-end nerve suture. No studies can be able to show that neurotube results were better than autologous nerve graft results. We included all studies regardless of effectives to evaluate quality of reinnervation with modern tubulization. Functionalized neurotubes promote basic conduits for peripheral nerve regeneration. Thanks to bioengineering and microsurgery improvement, further neurotubes could promote best level of regeneration and functional recovery to successfully bridge a critical nerve gap.
Les neurotubes fonctionnalisés sont une troisième génération de guides de repousse nerveuse avec une bioactivité chimique et architecturale développées afin de favoriser la prolifération et l’orientation axonale. L’objectif de cette revue est de réaliser une synthèse des dispositifs de neurotubes fonctionnalisés décrits dans la littérature selon leurs mécanismes d’action. Leur efficacité est-elle prouvée comparativement à la greffe nerveuse autologue ? Notre revue rapporte tous types de neurotube fonctionnalisé dans le traitement d'une perte de substance (PDS) nerveuse périphérique de Medline et PubMed central. Les articles rapportant la PDS nerveuse, les mécanismes d’action, les résultats et l’efficacité des neurotubes fonctionnalisés furent sélectionnés. Au total, 55 articles ont été inclus et classés en (a) facteurs de croissance neurotrophiques intraluminaux, (b) thérapie de régénération nerveuse à base de cellules : veines manchonnées par des fibres musculaires, membrane amniotique, cellules de Schwann, cellules souches somatiques, (c) protéines de la matrice extra cellulaire, (d) ingénierie tissulaire, (e) bioimplants. Certains neurotubes fonctionnalisés dans la littérature ont de meilleurs résultats fonctionnels que la suture nerveuse simple. Aucune étude n’a pu démontrer significativement la supériorité des neurotubes fonctionnalisés comparativement à la greffe nerveuse autologue. Les neurotubes fonctionnalisés potentialisent les chambres de régénération nerveuse périphérique. Grâce à la bio-ingénierie tissulaire et à la recherche dans le domaine de la régénération nerveuse, de futurs neurotubes fonctionnalisés avec de meilleurs résultats fonctionnels et morphométriques sont à venir dans le traitement des PDS nerveuses périphériques.
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Surgical oncology and reconstructionInfluence of Tacrolimus (FK506) on Nerve Regeneration Using Allografts: A Rat Sciatic Nerve Model

Purpose

Materials and Methods

Results

Conclusions

Section snippets

Experimental Design

BBB Recovery

SFI Outcome

Discussion

Acknowledgments

Ann Anat

Clin Plast Surg

Pain

J Neurosci Methods

Mayo Clin Proc

Exp Neurol

J Hand Surg

Trends Neurosci