The Role of Topically Administered FK506 (Tacrolimus) at the Time of Facial Nerve Repair Using Entubulation Neurorrhaphy in a Rabbit Model

Abstract

Peripheral facial nerve palsy is a common sequela of traumatic craniofacial injury, often resulting in dramatic and sometimes permanent functional deficits. Exogenous agents and methods of repair that accelerate axonal regeneration would be of great benefit to the multitude of patients with facial nerve injuries. The objective of this study was to evaluate the effect of FK506 at the time of facial nerve repair using entubulation neurorrhaphy, and to compare entubulation neurorrhaphy versus interposition autograft in critical facial nerve gap defects. The study design was a prospective, randomized, blinded animal study with a control group. Twenty-five New Zealand White rabbits were assigned to 4 experimental groups and a control group. The buccal branch of the facial nerve was used in all procedures. Group 1 was the control group. Rabbits in group 2 underwent sham surgery. Group 3 was an interposition autograft group in which a 6-mm segment of nerve was transacted, flipped, and followed by epineural repair. Groups 4 and 5 underwent transection followed by entubulation neurorrhaphy with topical administration of either a carrier molecule (group 4) or an FK506 carrier molecule (group 5). Outcome measures included daily subjective assessment of upper lip movement; electromyographic studies at weeks 3, 5, and 8 postoperatively; and blinded quantitative histomorphometric evaluation after 8 weeks. All rabbits in all groups were noted to have spontaneous movement after 8 weeks, with 1 rabbit in group 5 obtaining the highest functional score among all study groups. Electrophysiologic studies showed polyphasic potentials, indicating reinnervation in 1 rabbit in group 5. Histomorphometric examination of group 5 rabbits revealed a similar cross-sectional area distal to transection and remyelination. Other groups showed decreased cross-sectional area and/or incomplete remyelination distal to the transection. FK506 applied topically at the time of facial nerve repair using entubulation neurorrhaphy demonstrated superior results in nerve regeneration versus entubulation neurorrhaphy carrier protein alone, and interposition autograft.

Effects of topically administered FK506 on sciatic nerve regeneration and reinnervation after vein graft repair of short nerve gaps

“…Entubulation neurorrhaphy is an excellent alternative to short interposition nerve grafts. 8 Vein graft technique is an effective repair method that allows axonal regeneration after short-gap nerve injuries.…”

“…8 Briefly, the original solution of FK506 (Prograf, Astellas Pharma) was 5 mg/ml, so 2 dilutions were performed to reduce the concentration to 10 ng/ml: carrier dilution (20 μl original FK506 into 10 ml sterile olive oil to give 10 μg/ml) and carrier-drug dilution (10 μl of first dilution into 10 ml olive oil to give 10 ng/ml). The natural viscosity of the oil maintained the carrier or carrier-drug combination within the vein graft.…”

“…18 Recently, studies have been focusing on its role as a neuroprotectant and neurotrophic agent that promotes functional recovery and reinnervation following peripheral nerve injury. 8,18 Systemic administration of FK506 in combination with graft therapy or tube repairing has been shown to enhance the rate of nerve regeneration and promote the degree of functional recovery. 5,21,28 Nephrotoxicity, hypertension, hyperesthesia, muscular weakness, and gastrointestinal symptoms are side effects of systemic administration of FK506 because of its nonselective mechanism of action.…”

Peripheral Nerve Regeneration using Silicone Rubber Chamber Combined by Local Administration of Cyclosporin a in Streptozotocin Induced Diabetic Rats

“…Entubulation neurorrhaphy is an excellent alternative to short interposition of nerve grafts [30]. In the present study we used silicone conduit as a conduit for keeping the delivered drug in situ.…”

Immunophilin ligands in peripheral nerve regeneration

“…FK506 treatment has been document in facial [16], sciatic [30,64,73], vagus [33] and obturator nerve models [79]. FK506 enhances collateral sprouting of peripheral nerve fibres [73].…”