Tacrolimus for Enhancing Axonal Regeneration: Comparison
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Please note this is a comparison between Version 2 by Jessie Wu and Version 1 by Konstantin Feinberg.

Peripheral nerve injuries have far-reaching implications for individuals and society, leading to functional impairments, prolonged rehabilitation, and substantial socioeconomic burdens. Tacrolimus, a potent immunosuppressive drug known for its neuroregenerative properties, has emerged in experimental studies as a promising candidate to accelerate nerve fiber regeneration. 

  • tacrolimus
  • FK506
  • nerve regeneration
  • nerve injury
  • axon regeneration
  • clinical translation

1. Historical Perspective

Tacrolimus, also known as FK506, was initially isolated in 1984 from the fermentation broth of Streptomyces tsukubaensis [39][1], showing a potent inhibitory effect on T-cell-mediated immunity and surpassing cyclosporine’s potency by a factor of up to 100 [40][2]. Subsequent in vivo investigations demonstrated tacrolimus’ effectiveness in prolonging organ survival and reversing rejection across various allotransplanted organs, paving the way for its regular clinical use as an immunosuppressant to date.
The neuroregenerative properties of tacrolimus were first reported in 1994, demonstrating its capacity for promoting sensory neurite outgrowth in vitro, even at subnanomolar concentrations [41][3]. In the same year, Gold and colleagues observed an earlier return of muscle function and a 2.75-fold increase in the number of regenerating nerve fibers following nerve crush injuries in rats that received subcutaneous injections of tacrolimus daily (1.0 mg/kg) [42][4]. This woresearkch was later corroborated by a myriad of rodent nerve repair experiments, which collectively demonstrated that tacrolimus promotes axonal regeneration in vivo by 12% to 16% [43,44][5][6] and increases the number [44[6][7],45], diameter [44][6], and re-myelination state [44,45][6][7] of regenerating axons. These significant effects of tacrolimus translate into faster recovery of the motor function in experimental rat [42,45][4][7] and mouse [43][5] models.

2. Proposed Mechanisms of Action

While the precise mechanisms underlying the neurotrophic effects of tacrolimus are not fully elucidated, it is evident that the positive effects on the regrowth of regenerating nerve fibers are distinct from its immunosuppressive actions and primarily target the injured neuron. The neurotrophic effect is mediated through the FK506-binding protein (FKBP52) [46,47,48[8][9][10][11],49], which forms heterocomplexes with the 90 kDa heat shock protein (Hsp90) and its co-chaperone p23 within the neural nucleus [48][10]. FKBP52 plays a crucial role in guiding growth cones of regenerating neurites in response to both attractive and repulsive chemotactic signals [50][12], and following neuronal injury this complex undergoes redistribution to the growth cones of regenerating neurites upon exposure to tacrolimus in vitro, prompting their accelerated regeneration in vivo [48][10].

3. Clinical Experience

The clinical use of tacrolimus for peripheral nerve regeneration has been limited, even though it has growth-promoting effects on injured nerves. Nonetheless, there are specific clinical scenarios where its use has shown potential benefits.
After the systemic administration of tacrolimus in the context of upper-limb transplantation, remarkable rates of nerve regeneration, including the rapid progression of the Tinel sign by up to 3 mm/d and early reinnervation of intrinsic hand muscles [51,52[13][14][15],53], have been reported. These observations from multiple transplantation centers suggest that systemic tacrolimus administration contributes to the accelerated nerve regeneration observed in these cases. Similarly, notable functional outcomes have been observed in patients who underwent cadaveric nerve allografting for severe nerve gaps of up to 22 cm and received tacrolimus as a component of their treatment [54,55][16][17].
In a case report by Martin et al. [56][18], systemic tacrolimus was administered after transhumeral upper-extremity replantation in a 60-year-old woman with a poor prognosis for functional recovery. Surprisingly, the patient experienced rapid motor and sensory recovery with a 2-point discrimination of 9 mm on the thumb after 1 year and intrinsic motor reinnervation confirmed by electromyography after 19 months. In a prospective case series involving 4 patients, Phan et al. found that tacrolimus was well-tolerated [57][19]. However, they observed no significant improvements in sensory, motor, or functional recovery at the end of the 40-month follow-up period compared to the expected clinical outcome without treatment.
However, despite these encouraging reports, concerns over its narrow therapeutic window and systemic adverse effects associated with its systemic administration, mainly nephrotoxicity [58][20] and elevated levels of blood glucose [59][21] and liver enzymes [59][21], have limited its widespread application in peripheral nerve surgeries. To mitigate the systemic adverse effects of tacrolimus, researchers have directed their efforts towards developing biocompatible delivery systems that enable localized release directly at the site of nerve injury, while utilizing lower overall dosages.

4. Localized Drug Delivery: Maintaining Efficacy and Reducing Off-Target Effects

The introduction of bioengineered local delivery devices for the controlled and sustained microdosing of tacrolimus at the nerve injury site have reinvigorated the interest in leveraging its potential for peripheral nerve surgery.
Osmotic pumps have been utilized to deliver tacrolimus both systemically and locally to rats following sciatic epineural nerve repair, resulting in improved motor function compared to untreated controls [60][22]. However, the clinical use of osmotic pumps is hampered by their non-biodegradable nature, which increases the risk of secondary complications, including inflammation and fibrosis, and necessitates surgical removal.
Therefore, the research has evolved towards designing devices that can maintain a controllable drug delivery rate while achieving biodegradability and biocompatibility. Lin, Wang, and colleagues developed a mixed thermosensitive hydrogel (poloxamer (PLX)-poly(l-alanine-lysine with pluronic F-127)) to enable the sustained release of tacrolimus and demonstrated improved functional recovery after a sciatic nerve cut and epineural repair in mice [61,62][23][24]. While hydrogels excel in sustained drug release, precise control over the release kinetics remains challenging, potentially leading to suboptimal dosing accuracy and fluctuations in therapeutic levels due to inherent variability in the hydrogel degradation rates [63][25]. Tajdaran and colleagues developed a polymeric drug delivery system using poly(lactic-co-glycolic) acid (PLGA) microspheres to encapsulate tacrolimus and tested their system in a rat peripheral nerve transection and immediate epineural repair model [64,65][26][27]. The microspheres have been added to FDA-approved fibrin glue and the repaired nerve has been embedded to create a local tacrolimus-enriched environment [65,66,67][27][28][29]. This system has demonstrated preclinical efficacy through accelerated axonal regeneration and minimal systemic exposure to other organs. However, the translation of this system into commercial and clinical settings is impeded by the laborious preparation process at the bedside.
To address the demand for a clinically feasible and efficient approach, the research has pivoted towards the development of an off-the-shelf delivery system. Inspired by nerve wraps, which are clinically used to create a gliding bed for entrapped nerves [68[30][31],69], bioengineered tacrolimus-releasing poly(L-lactide-ε-caprolactone) (PLC) microfilms have been innovated to be wrapped around the nerve repair site in a mouse sciatic nerve transection and direct epineural repair model [70][32]. Recently, tacrolimus-loaded electrospun polycarbonate urethane (PCNU) nanofibers have been introduced to combine sustained release characteristics in a mesh-structured nerve wrap enabling diffusion and cell migration though the construct, thereby potentially causing less interference with the Wallerian degeneration process [71][33].
Rodents that were treated with these biodegradable local delivery devices as an adjunct to the gold standard epineural nerve repair demonstrated more motor and sensory neurons that regenerated their axons distal to the nerve repair site [65,70,71][27][32][33] and an earlier return of motor function [71][33]. Even in the cornea, the local and sustained release of tacrolimus has been demonstrated to accelerate ocular surface reinnervation following ophthalmic nerve injury [72][34].
In concomitant biodistribution and toxicity analyses, high levels of tacrolimus were detected in the regenerating nerve and its supplying spinal cord segments, supporting the hypothesis of neuronal uptake [65,71][27][33]. Conversely, the off-target levels of tacrolimus in the kidney, brain, liver, and heart at 7 and 28 days following surgery were around 80% lower compared to systemic delivery (2 mg/kg/d; p < 0.05) [65,71][27][33]. Consistently, local delivery resulted in a significant reduction in the peak plasma concentration if tacrolimus, reaching only 3% of the levels observed with systemic delivery [71][33]. Collectively, this indicates that the local release of tacrolimus may avoid toxic off-target effects while maintaining effective levels locally.
In addition to their application in direct epineural nerve repair, these local drug delivery systems hold an intriguing potential to improve functional outcomes in nerve gap reconstruction using both autologous and allogenic nerve graft repair methods [67][29]. However, the ideal drug delivery regimen for those interposition grafts is the subject of ongoing studies. Moreover, developing synthetic nerve guidance channels with inherent tacrolimus delivery capabilities may help to overcome the need for autologous materials for nerve gap reconstruction and substantially advance the landscape of peripheral nerve surgery [73][35].

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