The Impact of Supplements on Recovery After Peripheral Nerve Injury: A Review of the Literature

Peripheral nerve injury (PNI) can result from trauma, surgical resection, iatrogenic injury, and/or local anesthetic toxicity. Damage to peripheral nerves may result in debilitating weakness, numbness, paresthesia, pain, and/or autonomic instability. As PNI is associated with inflammation and nerve degeneration, means to mitigate this response could result in improved outcomes. Numerous nutrients have been investigated to prevent the negative sequelae of PNI. Alpha-lipoic acid, cytidine diphosphate-choline (CDP Choline), curcumin, melatonin, vitamin B12, and vitamin E have demonstrated notable success in improving recovery following PNI within animal models. While animal studies show ample evidence that various supplements may improve recovery after PNI, similar evidence in human patients is limited. The goal of this review is to analyze supplements that have been used successfully in animal models of PNI to serve as a reference for future studies on human patients. By analyzing supplements that have shown efficacy in animal studies, healthcare providers will have a resource from which to guide decision-making regarding future human studies investigating the role that supplements could play in PNI recovery. Ultimately, establishing a comprehensive understanding of these supplements in human patients following PNI may significantly improve post-surgical outcomes, quality of life, and peripheral nerve regeneration.


Introduction And Background
The peripheral nervous system relays information between the CNS and the remainder of the nervous system outside of the brain and spinal cord [1]. The majority of peripheral nerve injuries (PNI) are secondary to trauma, surgical resection, or toxicity from local anesthetics. Regardless of the cause, severe neuropathic pain is one of the morbidities that can occur due to PNI. Either remove severe neuropathic pain or list the different morbidities that may be associated with PNI [2][3][4][5].
Following PNI, a cascade of inflammatory and ischemic molecular events occur in the proximal and distal nerve and can contribute to subsequent neuropathy [6]. PNI results in the formation of free radicals and the release of cytokines. Free radicals increase the permeability of cellular membranes and allow for the intracellular influx of calcium. This influx can lead to the destruction of neurofilaments and microtubules by activating proteolytic pathways [7]. If the free radical damage is allowed to proceed unmitigated, successful nerve regeneration will not occur, resulting in functional or sensory deficit or painful neuropathic pain. If there were means to decrease the inflammatory cascade and quell the free radical production, the extent of injury might not be as great, and recovery could be augmented. Interventions that prevent oxidative stress, neuroinflammation, and cellular injury could be utilized to achieve this. While alternative mechanisms of PNI secondary to surgical trauma may exist, free radical generation and oxidative stress are the most widely understood mechanisms that contribute to PNI at this time.
There is a paucity of human studies investigating nutrients and supplements that may aid peripheral nerve regeneration and recovery. However, animal studies show ample evidence that various supplements may improve recovery after PNI. A review published in 2018 discussed nutrients that may play a role in preserving nerve function and in augmenting recovery after PNI. Nutrients of interest included omega-3 and omega-6 fatty acids, B vitamins, antioxidants, minerals, phenolic compounds, and alpha-lipoic acid [3]. However, numerous supplements which were not previously reviewed in this publication have also demonstrated success in animal models post PNI. The goal of this review is to analyze supplements that have been used successfully in animal models of PNI to serve as a reference for future studies on human patients. By analyzing supplements that have shown efficacy in animal studies, healthcare providers will have a resource from which to guide decision-making regarding future human studies investigating the role that supplements could play in PNI recovery.
EGCG was able to improve the axonal and myelin regeneration, enhance functional recovery [54] and neuronal survival time after transection [55], reduce markers of oxidation [56], alleviate motor and sensory impairment, and improve neuronal regeneration [57].

Melatonin
Melatonin is secreted by the pineal gland at the base of the brain and it plays numerous roles in the human body, including regulating circadian rhythms, sleep physiology, mental status, reproduction, tumor development, and aging [58][59][60]. In addition, it acts as an antioxidant via a direct influence on toxic radicals and through the induction of enzymes that detoxify free radicals [7].
Three studies addressed the role of quercetin after PNI; two were performed in mouse models [75,76], and one each was performed in both mouse and rat models [77].
Quercetin enhanced axon remyelination, motor nerve conduction velocity, plantar muscle function [76], and nerve regeneration [77]. It was also found to be superior to gabapentin and morphine in alleviating mechanical and thermal hypersensitivity [75].

Vitamin B12
Vitamin B12 is a water-soluble vitamin obtained from dietary meat, eggs, dairy, and other animal-derived products [78]. The deficiency of vitamin B12 can result in neurotoxicity and contribute to the development of subacute combined degeneration, a disorder of the CNS characterized by sensory deficits, motor weakness, paresthesia, and gait ataxia [79]. In addition, within the peripheral nervous system, there is evidence suggesting that B vitamins play a role in peripheral nerve repair following insult [80].
Four studies investigated the role of vitamin B12 after PNI using rat models; two used vitamin B12 in combination with other vitamins [81,82], and two investigated the role of vitamin B12 alone [80,83].
Combined B-vitamin administration improved the toe-spreading reflex [81]. Compared to vitamin B1 and B6 alone, vitamin B12 was superior in augmenting peripheral nerve regeneration [80]. A combination of vitamin B12 and vitamin E acetate increased motor nerve conduction velocity and decreased the progression of thermal hyperalgesia following sciatic nerve crush injury [82]. At high doses, methylcobalamin, the active form of vitamin B12, accelerated nerve regeneration, increased myelination, and improved motor and functional recovery of injured nerves [80,83].

Vitamin E
Vitamin E is an essential lipid-soluble vitamin with potent antioxidant effects. In addition to preventing free-radical reactions, vitamin E can act as a chain-breaking antioxidant that prevents lipid peroxidation [84].
Five articles addressed the role of vitamin E following PNI, all of which were conducted in a rat model [82,85,86] except one mouse study [87] and one cat study [88].
Vitamin E administration improved sciatic nerve function, increased the number of functional motor neurons, suppressed cold and mechanical allodynia, and decreased Wallerian degeneration, nerve gliosis, muscle atrophy, blood malondialdehyde levels, and injury-induced 4-hydroxynonenal activity [85,86]. When combined with selenium, it decreased the degeneration of motor nerve terminals and preserved the function of the motor nerve terminals within the soleus muscle [88]. While topical vitamin E alone improved functional sciatic nerve recovery, combined vitamin E and pyrroloquinoline quinone demonstrated significantly stronger benefits to vitamin E alone in nerve conduction velocity, functional motor recovery, and nerve regeneration [87].
A summary of supplements with four or more citations is included below in Table 1.

Discussion
PNI can have devastating complications, ranging from functional or sensory deficits to painful neuroma formation. However, numerous supplements have demonstrated success in animal models of PNI to mitigate the inflammatory response and improve regeneration.
One consideration when translating animal study to human research is to assess the role of a single supplement versus combination therapy. While animal studies have investigated both single supplement and combination therapy, this is not as easily replicated in human research. As numerous supplements have demonstrated success in animal models of PNI, it might stand to reason that the most efficacious approach in humans would be to utilize numerous supplements simultaneously. While this may result in beneficial outcomes, it would remain uncertain which supplement was responsible for the observed results and if the supplements had an unexpected synergistic effect. Despite this uncertainty, the majority of the supplements aforementioned have a low side-effect profile and are generally well-tolerated by humans. Thus, while not clearly delineating the mechanism of action, combination trials in humans may still prove to be the most efficacious approach to optimize results.
Furthermore, the timing of the intervention was noted to augment healing after PNI. While many of the animal studies reviewed deliver the intervention prior to PNI, this is not always feasible in humans. However, interventions prior to injury are possible in certain scenarios, including amputation with nerve transection and surgeries that have the potential for nerve injury, such as parotidectomy with facial nerve preservation. In these instances, preoperative supplementation might play a synergistic role in a meticulous surgical technique in hastening nerve regeneration/ healing and preventing untoward outcomes. It was beyond the scope of this review to discuss supplementation to augment nerve recovery after nerve grafting and repair, but this is another area that requires investigation.
Also, rodents are metabolically very different from humans. They have a greater amount of metabolically active tissues, such as liver and kidney, and a lesser amount of metabolically inactive tissues, such as bones [134][135][136]. This could influence the rate of metabolism of supplements. In addition, rodents have different microbiomes than humans as they coevolved with different pathogens [137]. This would impact how rodents respond to various medications and how supplements are metabolized in the gut. Additionally, nerve gaps in rats are very small compared to most human gap lengths, and axotomies in rats can undergo complete recovery, unlike humans [138]. Thus, while animal models can certainly provide valuable information, they need to serve as a nidus for further, well-done human research.

Conclusions
In summary, numerous antioxidant supplements have demonstrated success in improving recovery after PNI. The mechanism of action is typically mitigation of inflammation and reactive oxygen species production. While these should serve as a nidus for future human trials, there are many important considerations when translating these studies to humans. However, the arena of supplementation to improve PNI in humans is relatively unexplored and requires well-structured prospective studies.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.