Coenzyme Q10 (CoQ10) plays a crucial role in generating ATP through the electron transport chain within mitochondria, and ATP is essential for maintaining cellular functions. CoQ10 acts as a potent antioxidant, helping to scavenge ROS within cells. This reduces cellular damage and oxidative stress, prevents lipid peroxidation and DNA damage, and protects cell and mitochondrial membranes from damage. CoQ10 also possesses anti-inflammatory properties that can reduce inflammatory responses and prevent additional inflammation-induced damage following nerve injury, thereby promoting nerve regeneration and accelerating nerve function recovery. After PNI, CoQ10 was shown to promote nerve regeneration and reduce oxidative stress and inflammation (Vachirarojpisan et al., 2024). Wistar rats administered CoQ10 following sciatic nerve injury exhibited faster nerve regeneration, with increased numbers and diameters of regenerated nerve fibers (Moradi et al., 2014). Following compression-induced FNI, CoQ10 administration increased myelin thickness, reduced secondary nerve damage due to oxidative stress, and improved both functional and histological recovery of the injured facial nerve (Yildirim et al., 2015). These results suggest that CoQ10 administration can improve peripheral facial nerve damage by suppressing oxidative stress and reducing inflammation.

Lipoic acid (LA) and alpha-lipoic acid (ALA) are potent antioxidants that help neutralize free radicals and reduce oxidative stress. These properties are crucial in managing nerve injuries, as oxidative stress can exacerbate nerve damage and impede recovery. LA has been shown to have neuroprotective effects, contributing to maintaining nerve function and promoting nerve regeneration. In diabetic neuropathy, LA administration improved neuropathic symptoms by reducing oxidative stress (Nagamatsu et al., 1995), LA and methylprednisolone (MP) play complementary roles in treating facial nerve injury (FNI), with combination treatment yielding better outcomes in terms of recovering nerve function and reducing inflammation (Tekdemir et al., 2018). Additionally, ALA prevents further damage following peripheral facial nerve transection injury by reducing oxidative stress through the removal of excessive ROS (Yoo et al., 2022). However, conflicting evidence exists regarding the efficacy of ALA. A Cochrane review concluded that ALA treatment in diabetic peripheral neuropathy (DPN) patients has little or no effect on neuropathy symptoms and functional impairment compared to placebo after 6 months of treatment (Baicus et al., 2024). This finding suggests that while ALA has shown potential benefits in some studies, its overall effectiveness in DPN may be limited. The conflicting results highlight the complexity of ALA’s action and suggest that its efficacy may vary depending on factors such as dosage, duration of treatment, and patient population. These inconsistencies indicate the need for further research to determine the optimal use of ALA and LA in nerve injury management and to clarify their roles as therapeutic agents in conditions associated with oxidative stress.

Methylprednisolone (MP) is a potent corticosteroid known for its ability to reduce inflammation and edema around damaged nerves, thereby promoting nerve healing. By decreasing inflammation, MP can reduce axonal degeneration and promote axonal regeneration, facilitating the overall recovery of nerve function. It is particularly effective in treating various nerve injuries, such as facial nerve palsy, and is widely used in clinical settings (Tekdemir et al., 2018). However, the use of MP is not without controversy. Some studies suggest that MP might have negative effects on nerve regeneration, potentially due to its interference with other physiological processes necessary for nerve recovery (Karlidag et al., 2012). For instance, in a traumatic peripheral facial nerve injury model, MP inhibited the enhancement of collagen fiber without enhancing Schwann cell proliferation or overall nerve function (Yanilmaz et al., 2015). Despite these concerns, MP administration significantly reduces edema and inflammation at the nerve injury site, relieving pressure on the nerve and promoting recovery. MP has shown effectiveness in promoting recovery from facial nerve compression injuries, contributing to functional and structural recovery through its neuroprotective and antioxidant effects (Şeneldir et al., 2024). It significantly improves axonal degeneration, vascular congestion caused by facial nerve palsy, and enhances electrophysiological recovery (Dincer et al., 2025). MP can thus be a useful therapeutic agent in managing nerve injuries by effectively promoting nerve recovery and contributing to functional and structural recovery through its neuroprotective and antioxidant effects (Gölcük and Şeneldir, 2025). MP can thus be a useful therapeutic agent in managing nerve injuries by effectively promoting nerve recovery and contributing to functional and structural recovery through its neuroprotective and antioxidant effects. The Second National Spinal Cord Injury Study (NASCIS-II) study on methylprednisolone for acute spinal cord injury was that methylprednisolone therapy, when administered within 8 h of injury, did not improve motor score recovery in patients with acute cervical or thoracic traumatic spinal cord injury and was associated with a higher rate of complications (Evaniew et al., 2015). Thus, while MP can be a useful therapeutic agent in managing nerve injuries by promoting nerve recovery and contributing to functional and structural recovery, its application should be carefully considered, taking into account the potential for complications and the mixed evidence regarding its efficacy.

Dexamethasone is a glucocorticoid that reduces inflammation and suppresses the immune response by inhibiting the release of pro-inflammatory cytokines and mediators. This reduction in inflammation minimizes secondary damage to nerve tissue post-injury, thereby promoting healing and regeneration. By reducing inflammation, dexamethasone also decreases edema around the damaged nerve to improve the microenvironment and facilitate the supply of essential nutrients and oxygen, which are crucial for the nerve recovery process. Although dexamethasone is not primarily recognized as an antioxidant, its ability to control inflammation and stabilize the cellular environment provides effective neuroprotection following nerve injury. For instance, following sciatic nerve injury, dexamethasone has been shown to reduce tissue edema and demyelination, promote remyelination, and help improve gastrocnemius muscle atrophy (Feng and Yuan, 2015). Another study demonstrated that dexamethasone administration after facial nerve compression injury improved functional recovery, as evidenced by increased amplitude values in EMG. In FNI caused by transection, dexamethasone exhibited anti-inflammatory effects, reducing edema and inflammation (Edizer et al., 2019). The safety of low-dose, preservative-free perineural dexamethasone suggests potential neuroprotective effects when used as an adjuvant to local anesthetics. However, concerns are raised about potential neurotoxicity, especially when it is combined with local anesthetics at higher concentrations or when formulations contain sulfites. Additionally, the review highlights the need for caution in patients with preexisting neuropathies due to their increased susceptibility to ischemic damage (De Cassai et al., 2025). These findings collectively indicate that dexamethasone can promote regeneration and recovery after nerve injury through its anti-inflammatory and neuroprotective effects. Nonetheless, clinical use should be carefully considered, especially regarding dosage and patient population, to mitigate potential risks associated with its use.

Ebselen is a neuroprotective agent that protects cellular components from oxidative damage by modulating enzyme cofactors, metalloproteins, and gene expression, exhibiting antioxidant and anti-inflammatory effects, and regulating the immune system. Ebselen acts as an analogue of glutathione peroxidase, an enzyme that neutralizes ROS and reduces oxidative stress. These properties enable ebselen to protect nerve cells from oxidative damage, which is a common result of nerve injury. In animal models of spinal cord injury, ebselen administration reduced oxidative stress due to spinal cord injury and increased the levels of antioxidant enzymes, thereby protecting neurons (Kalayci et al., 2005). After ischemia/reperfusion injury, ebselen inhibited excessive glutamate release and enhanced the inhibitory effects of GABA to alleviate nerve damage (Seo et al., 2009). Additionally, following peripheral facial nerve compression injury, ebselen administration yielded recovery patterns (Şeneldir et al., 2024). These findings indicate that ebselen exhibits neuroprotective effects in various nerve injury models, aiding in the protection and regeneration of nerve cells by reducing oxidative stress and exerting anti-inflammatory and antioxidant actions.

Oxytocin is a hormone essential for social bonding, childbirth, and lactation; it is produced in the hypothalamus and secreted by the pituitary gland. Beyond its well-known role in enhancing social interactions and maternal behaviors, oxytocin also reduces oxidative stress through powerful antioxidant actions by increasing the activity of antioxidant enzymes such as SOD and glutathione peroxidase, which neutralize harmful ROS. Oxytocin also reduces lipid peroxidation to help maintain cell membrane integrity, lowers inflammation, and reduces oxidative stress to protect cells from oxidative damage. In a sciatic nerve transection injury model, oxytocin administration resulted in higher amplitudes and shorter latency times in EMG, with increased vascular diameter and thickness, suggesting that it promotes revascularization and improves functional recovery (Gümüs et al., 2015). Oxytocin administration can also promote nerve recovery by upregulating nerve growth factor (NGF), Nrf2, and irisin (Tosyalı et al., 2023). Following facial nerve compression injury, oxytocin administration effectively modulated apoptosis and promoted facial nerve regeneration to yield significant improvements in functional recovery (Tanyeri et al., 2015). These findings suggest that oxytocin has potential as a therapeutic agent that may promote nerve regeneration and recovery through its neuroprotective and anti-inflammatory actions following PNI.

Resveratrol is a well-known polyphenolic compound; it is found in various plants, especially grapes, red wine, berries, and peanuts, and has antioxidant, anti-inflammatory, and cardioprotective effects. In PNI, in particular, resveratrol contributes to reducing oxidative stress by neutralizing ROS. Resveratrol increases the activity of antioxidant enzymes in the body, reduces inflammation, and promotes mitochondrial function. In a sciatic nerve compression injury model, resveratrol administration increased the protein expression of vascular endothelial growth factor (VEGF) and the number of axons in the damaged nerve, and thus enhanced nerve regeneration (Ding et al., 2018). Resveratrol also promoted nerve recovery by accelerating myelin clearance through the autophagy of Schwann cells (Zhang et al., 2020). Following facial nerve compression injury, resveratrol administration significantly improved blink reflex recovery and functional recovery, as evidenced by increased amplitudes in EMG In particular, resveratrol modulated apoptosis and increased intercellular levels of connexins (connexin 32 and 43), which are important for cell communication and tissue integrity during the healing process, and thus aided nerve recovery (Tanyeri et al., 2015). These findings suggest that resveratrol can play an important role in promoting recovery after nerve injury.

Melatonin is a hormone that is primarily produced by the pineal gland in the brain. It is well known to regulate the sleep-wake cycle, but it also possesses powerful antioxidant, anti-inflammatory, and neuroprotective effects. Based on these properties, extensive research has examined melatonin’s potential therapeutic effects in various conditions, including nerve injury. Melatonin reduces oxidative stress by stimulating antioxidant enzymes, such as SOD, catalase (Ct), and peroxidase (Uyanikgil et al., 2017). Schwann cells express melatonin receptors to enable melatonin signaling. Melatonin promotes the reorganization, migration, dedifferentiation, and regeneration of Schwann cells (Klymenko and Lutz, 2022). In promoting peripheral nerve recovery, melatonin inhibits ROS generation through mitophagy, maintains autophagic flow, and suppresses mitochondrial apoptosis [48]. After FNI, intraperitoneal injection of melatonin yielded more extensive systemic effects and better preservation of nerve diameter and myelin thickness compared to controls or local administration. Melatonin also increased the activity of antioxidant enzymes, such as SOD and glutathione peroxidase, to further protect cells from oxidative damage (Edizer et al., 2019). Following traumatic peripheral FNI, melatonin administration reduced the collagen fiber increase and myelin degeneration seen in controls, and thus enhanced nerve regeneration (Yanilmaz et al., 2015). Melatonin shows potential as a neuroprotective agent that can promote recovery following PNI. However, structure–function translation has been inconsistent in severe injury settings. In an axotomy/anastomosis model, melatonin yielded superior histopathology but did not produce significant short-term electrophysiological gains (e.g., EMG amplitude/latency) over a 12-week window, underscoring model- and dose-contingent effects on function. Comparative data in transection contexts further suggest that while melatonin can outperform steroids on select structural or electrophysiological parameters, near-term functional improvements are not uniformly observed and may require longer follow-up to emerge. Taken together, melatonin shows promise as an experimental antioxidant/neuroprotective agent in FNI, with benefits influenced by injury severity, timing, and dose. Translation will require standardized functional endpoints (EMG, reflexes, conduction), formal dose–response evaluation, and extended follow-up to determine whether structural gains consistently convert into clinically meaningful functional recovery.

NAC is a medication and dietary supplement derived from L-cysteine, known for its powerful antioxidant properties and its use as a mucolytic agent in respiratory diseases. NAC acts as a precursor for glutathione (GSH) in the body, playing a crucial role in regulating intracellular oxidative stress by increasing intracellular concentrations of GSH. Additionally, NAC inhibits the activation of nuclear factor kappa B (NF-κB), thereby reducing the levels of inflammatory cytokines such as TNF-α and interleukins (IL-6, IL-1β) (Tenório et al., 2021). Following sciatic nerve compression injury, NAC administration reduced perineurial thickness, axonal degeneration, axonal lysis, edema, inflammation, muscle atrophy, and myopathy through its antioxidant effects (Sarıtaş et al., 2024). In the context of facial nerve injuries, NAC has been shown to improve nerve regeneration and reduce nerve degeneration by increasing the proliferation of Schwann cells and modulating glial cell activity (Karlidag et al., 2012). NAC likely influences glial activation by reducing oxidative stress and inflammation, which can help prevent the overactivation of glial cells such as microglia and astrocytes. This modulation can decrease the release of neurotoxic mediators and promote a more supportive environment for nerve repair. In rats with compression-induced facial nerve injury (FNI), NAC administration resulted in better recovery in terms of eye blinking and vibrissae movement compared to controls at both 2 and 4 weeks post-injury. Electromyography (EMG) measurements indicated greater amplitude recovery, with eye-blink function recovering more rapidly by week 2 and vibrissae function by week 4 (Rivera et al., 2017). These results suggest that NAC can enhance the functional and electrical recovery of nerves following injury, in part by modulating glial cell responses to create a more favorable environment for nerve regeneration.

PEG is a highly biocompatible and soluble compound that is widely used in the medical field. In FNI, it functions by fusing damaged axonal membranes to restore axonal continuity, enhance nerve conduction and functional recovery, and restore action potentials at the injury site. PEG also helps maintain nerve function by preventing Wallerian degeneration, which is the degeneration of the axonal portion of a neuron upon its separation from the cell body (Smith et al., 2025). The application of PEG solution to the sciatic nerve at the cut axonal end was found to preserve neuromuscular junctions and prevent muscle atrophy, leading to the recovery of sensory and motor functions. This so-called “PEG fusion” provides a rapid and effective method for PNI repair, yielding significantly better functional outcomes compared to traditional nerve suturing techniques (Ghergherehchi et al., 2019). After sciatic nerve transection, PEG administration yielded functional recovery in EMG and inclined plane tests, increased levels of nerve growth factor (NGF), reduced fibrosis, and increased axonal density, indicating that it promotes neuroprotection and regeneration (Tunç et al., 2025). In a study involving transection of the mandibular branch of the facial nerve, the PEG fusion group exhibited larger axonal diameters compared to the control group, indicating that PEG fusion had a positive impact on preserving axonal structure (Salomone et al., 2018). These results suggest that PEG can promote functional and structural recovery following peripheral nerve injury.

Aminoguanidine (AG) is a compound known for its potent antioxidant effects and its ability to inhibit the formation of advanced glycation end-products (AGEs) and inducible nitric oxide synthase (iNOS). AG also demonstrated antioxidant activity against brain damage induced by doxorubicin (DOX), reducing levels of malondialdehyde (MDA) and glutathione peroxidase (GPx) while increasing the activity of glutathione S-transferase (GST) [54]. The increase in oxidative stress due to ischemia was mitigated by AG treatment, which increased the oxidized glutathione ratio (GSH/GSSG), activated GST, and reduced lipid peroxidation (Pasten et al., 2021). After ischemia was induced by occlusion of the right common iliac artery and femoral artery, AG administration was associated with functional recovery in hindlimb function tests, reduced endoneurial edema, and decreases in ROS and apoptosis (Alipour et al., 2011). Following traumatic peripheral FNI, AG administration reduced myelin degeneration and myelin debris accumulation, and EMG showed increases in nerve conduction velocity and amplitude over time, indicating improved nerve function (Yanilmaz et al., 2015). In PNI, AG decreases ROS and reduces the production of NO, which can form harmful peroxynitrite when combined with superoxide; thus, AG reduces oxidative stress in this context. Together, these results indicate that AG promotes nerve recovery and functional improvement by protecting nerve cells and maintaining structural integrity after injury.

Methylcobalamin (MeCbl), the active form of vitamin B12, is essential for nerve health and effective in promoting nerve regeneration after PNI. MeCbl enhances the body’s antioxidant defenses to neutralize harmful ROS and contribute to reducing oxidative stress. Following sciatic nerve compression, MeCbl administration resulted in recovery of motor and sensory functions, as evidenced by improvements in the sciatic function index (SFI) and von Frey filament tests. MeCbl enhanced nerve conduction velocity, promoted nerve regeneration, and increased myelination to aid in axonal repair (Suzuki et al., 2017). In a rat model of sciatic nerve injury, continuous MeCbl administration via an osmotic mini-pump increased the activities of Erk1/2 and Akt, which are key signaling proteins involved in axon growth and neuron survival, and thereby promoted recovery of motor and sensory functions (Okada et al., 2010). After facial nerve compression injury, MeCbl promoted nerve regeneration and further reduced oxidative stress; its effects were particularly pronounced when combined with silicone-based drugs (Koyama et al., 2022). These findings demonstrate that MeCbl is effective in managing oxidative stress and facilitating nerve repair.

Silicon-based agents react with water to produce hydrogen gas, which acts as a selective antioxidant by targeting and neutralizing nerve cell-damaging ROS, hydroxyl radicals, and peroxynitrite. These agents exert anti-inflammatory effects by reducing pro-inflammatory cytokines and factors, show anti-apoptotic effects by inhibiting pathways leading to cell death, and yield anti-fibrotic effects by decreasing fibrosis-related markers (Koyama et al., 2023). In the case of PNI, oxidative stress due to excessive ROS can hinder nerve regeneration. Silicon-based agents protect nerve cells and create a more favorable environment for nerve regeneration by reducing oxidative stress, making them effective in promoting recovery from nerve damage-related conditions such as facial paralysis. After compression-induced FNI, silicon-based agents improved nerve regeneration by promoting myelination and reducing oxidative stress (Koyama et al., 2022). Due to these properties, silicon-based agents are reported to contribute to the treatment of nerve injuries.

Ozone therapy involves the use of ozone gas to stimulate the body’s natural antioxidant defense system, inducing appropriate oxidative stress to exert anti-inflammatory effects, eradicate pathogenic microorganisms, and promote tissue regeneration. Due to its small molecular structure, ozone quickly penetrates cells and tissues to eliminate pathogens and generate oxygen, promoting cellular and tissue recovery. Ozone therapy is effective in alleviating neuropathic pain by promoting efferocytosis of macrophages and activating AMPK/Gas6-MerTK/SOCS3 signaling to reduce neuroinflammation. In a chronic constriction injury (CCI) model, ozone therapy alleviated pain through this mechanism (Ruan et al., 2024). Following sciatic nerve transection, ozone therapy improved function in the SFI and withdrawal reflex (WDR) by enhancing antioxidant enzyme activity, promoting nerve fiber myelination, and increasing functional recovery (Ogut et al., 2020). After compression-induced FNI, ozone therapy improved damage to myelinated axons and demonstrated beneficial effects on regeneration (Ozbay et al., 2017). These results suggest that ozone therapy is effective in reducing oxidative stress associated with PNI and promoting nerve regeneration.

Rosuvastatin is primarily used to lower cholesterol levels, but it also possesses antioxidant properties that may be beneficial in treating PNI. Additionally, rosuvastatin enhances the body’s natural antioxidant defenses, improves endothelial function, and reduces inflammation, thereby creating a favorable environment for nerve healing and regeneration. Following sciatic nerve compression injury, rosuvastatin administration increased motor function recovery in the SFI test, increased the amplitude of compound muscle action potentials (CMAP), and improved nerve conduction. It also increased the number and thickness of myelinated fibers and enhanced the expression levels of neurotrophic factors, such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), to promote nerve cell function and recovery (Abdolmaleki et al., 2020). In a peripheral facial paralysis animal model, rosuvastatin administration contributed to electrophysiological recovery and significantly improved axonal degeneration and vascular congestion, and thus had beneficial effects on facial nerve regeneration (Dincer et al., 2025). In sum, rosuvastatin has shown potential as a therapeutic agent in the treatment of PNI.

Ginkgo biloba extract (GBE) is derived from the leaves of the ginkgo biloba tree and is known for its medicinal properties. It contains flavonoids and terpenoids, which have potent antioxidant and anti-inflammatory effects and help protect vascular endothelial cells from oxidative damage by scavenging free radicals (Singh et al., 2019). GBE also promotes microcirculation, which is crucial for nerve health and recovery. The extensive antioxidant properties of GBE may be beneficial in the prevention and treatment of diseases associated with free radical-induced damage (Rong et al., 1996). In an animal model of compression-induced facial nerve injury, recovery of vibrissae function was faster in the GBE-treated group compared to controls, and there were significant improvements in muscle action potential thresholds and conduction velocity in the GBE group (Jang et al., 2012). This suggests that GBE treatment facilitates electrophysiological recovery of the injured facial nerve.

Vitamin E is a fat-soluble vitamin primarily known for the antioxidant activity of its α-tocopherol form. It is particularly effective in inhibiting lipid peroxidation, thereby protecting cell membranes from oxidative stress. Vitamin E also reduces oxidative stress by scavenging ROS, preventing nerve cell degeneration. These protective actions lead to reduced inflammation and enhanced recovery, making this vitamin a potentially useful therapeutic agent for diseases related to nerve damage. Vitamin E has demonstrated beneficial effects on motor function, pain hypersensitivity, and histopathological changes after nerve injury, promoting neuroprotection and regeneration by inhibiting oxidative stress pathways (Tamaddonfard et al., 2014). In a model of transection-induced FNI, vitamin E significantly increased the survival rate of motor neurons in the facial nucleus of the CNS and demonstrated neuroprotective effects by reducing lipid peroxidation and oxidative stress (Hoshida et al., 2009). However, the effects of vitamin E are not universally positive. A study on the nematode Caenorhabditis elegans revealed that high concentrations of vitamin E (400 μg/mL) can adversely affect thermosensation and thermotaxis learning. The study showed that such high doses impaired presynaptic function and decreased the fluorescent intensities of key neurons involved in thermosensation and learning. These findings suggest that while vitamin E has significant neuroprotective properties, its administration at high concentrations can lead to adverse effects, particularly on neuronal development and function (Li et al., 2013). These protective actions of vitamin E, when administered at appropriate doses, may notably promote neuroprotection and regeneration by inhibiting pathways related to oxidative stress following nerve injury. Benefits are dose- and context-dependent. Moderate dosing has been associated with functional and histological improvements, whereas high exposures have produced paradoxical or adverse effects (e.g., increased gliosis or neuronal dysfunction in select models), underscoring the need for formal dose–response evaluation and safety monitoring. Accordingly, clinical translation will require standardized functional endpoints and careful dose-finding before recommendations can be made.

CAPE is a bioactive compound that is found in bee propolis and known for its anti-inflammatory, antioxidant, and neuroprotective properties. As an antioxidant, CAPE neutralizes free radicals, inhibits lipid peroxidation, enhances antioxidant enzyme activity, and reduces oxidative stress and inflammation by inhibiting the NF-κB pathway. After spinal cord injury, CAPE downregulated DRP1 while activating SIRT1 and PGC1α to alleviate mitochondrial dysfunction and reduce inflammation and oxidative stress (Zhang et al., 2024). CAPE activates the Nrf2 pathway to increase antioxidant enzyme expression, stabilize ROS, and protect nerve cells. CAPE also inhibits the NF-κB pathway, thereby reducing pro-inflammatory cytokine expression and preventing neuroinflammation (Pérez et al., 2023). In a facial nerve crush model, CAPE administration promoted nerve regeneration; when it was combined with MP functional recovery was faster, as measured in terms of corneal reflex. Histopathological evaluation of the CAPE + MP group showed lower levels of axonal degeneration and vascular congestion, with thicker myelin sheaths (Gölcük and Şeneldir, 2025). These findings suggest that CAPE, with its neuroprotective, antioxidant, and anti-inflammatory effects, could serve as a potential therapeutic alternative that could be used to reduce the dosage and mitigate the systemic side effects of MP.

SELENOT mimetic peptide (PSELT), which is a synthetic peptide derived from the selenoprotein, SELENOT, is known for its antioxidant and neuroprotective properties. PSELT effectively reduces oxidative stress in PNI by neutralizing ROS, enhancing endogenous antioxidant defenses, and preventing lipid peroxidation. Additionally, PSELT modulates protective signaling pathways and reduces inflammation to create a favorable environment for nerve regeneration and functional recovery. PSELT administration improved motor coordination and spontaneous motor activity in mice treated with MPTP by targeting oxidative stress and regulating gene expression to promote cell survival (Alsharif et al., 2021). Following facial nerve transection, PSELT administration enhanced motor recovery, with higher mean motor unit action potential amplitude and shorter duration, with increased axonal density and myelination, and thus improved nerve regeneration and functional recovery (Pothion et al., 2022). Through its antioxidant and neuroprotective actions, PSELT can regulate key signaling pathways and reduce oxidative stress and inflammation, thereby enhancing nerve regeneration and functional recovery.

Edaravone is a potent antioxidant that acts as a FR scavenger, effectively neutralizing unstable molecules that cause oxidative stress and cellular damage. By removing ROS and other FR, edaravone protects nerve cells from oxidative damage, reduces inflammation, and promotes nerve recovery. Due to its antioxidant and anti-inflammatory effects, edaravone has been clinically used in treating acute cerebral ischemia and amyotrophic lateral sclerosis (ALS). In a placental ischemia model, it reduced brain inflammation and oxidative stress, and improved fetal survival, growth, and maternal organ function (Yamashita and Abe, 2024). Edaravone decreased oxidative stress markers such as malondialdehyde (MDA), increased the levels of antioxidants such as SOD and GSH/GSSG, and reduced neuroinflammation through decreased activation of hippocampal microglia (Iba1+ cells) (Ma et al., 2024). However, not all studies report positive outcomes with edaravone. Some research suggests that supraphysiologic doses may lead to delayed recovery or adverse effects. It is crucial to consider the dose–response relationship, as varying doses can significantly impact the therapeutic outcomes. Additionally, while edaravone’s ability to reduce oxidative stress is effective in treating nerve damage-related conditions, such as Bell’s palsy caused by HSV-1 infection, potential off-target effects, particularly at high doses, should be addressed (Hato et al., 2013). Given its strong antioxidant and anti-inflammatory properties, edaravone shows potential as an effective therapeutic agent for preventing damage to cell membranes and tissues in conditions such as ischemic nerve injury (Takeda et al., 2008). Nonetheless, further research is needed to fully understand the optimal dosing and potential risks associated with its use in different clinical scenarios (Table 3) (Figure 2).

In crush/compression models, several antioxidants improved functional readouts. Resveratrol, dexamethasone, and oxytocin shortened reflex recovery times and increased EMG amplitudes versus controls; ebselen achieved functional and histological recovery comparable to methylprednisolone, suggesting a potential steroid-sparing alternative. CoQ10 lowered stimulation thresholds and increased myelin thickness with favorable histology, and Ginkgo biloba extract accelerated vibrissae function recovery with improved conduction metrics. Given the intrinsically higher regenerative potential and substantial spontaneous recovery in crush injuries, these gains are interpreted with caution and not extrapolated to more severe models.

In transection/anastomosis settings, structural improvements often outpaced short-term functional gains. For example, melatonin yielded superior histopathology without significant EMG improvement within 12 weeks. N-acetylcysteine outperformed methylprednisolone after anastomosis, with better EMG and histology and less degeneration, underscoring the risk of extrapolating steroid benefits across models. SELENOT-mimetic peptides (PSELT) improved MUAP characteristics and axonal metrics, suggesting mechanistic promise that warrants longer functional follow-up. PEG-fusion mitigated demyelination and increased axonal diameter but provided limited functional enhancement over the study window. Comparator data further indicate advantages over steroids in select parameters: aminoguanidine and melatonin showed superior electrophysiological and structural profiles to methylprednisolone in transection settings, although short-term functional gains were not always consistent.

In ischemic/viral contexts, edaravone reduced oxidative stress markers and suggested clinical benefit; however, assessments often relied on clinical observation without standardized electrophysiology. Standardized head-to-head confirmation against both no-treatment and steroid comparators is needed to define its incremental effect size and dose window (Table 4).

Several antioxidants (e.g., resveratrol, dexamethasone, oxytocin, ebselen, coenzyme Q10, and Ginkgo biloba extract) were associated with earlier improvements in electrophysiological or behavioral readouts versus controls in crush/compression models. Given the intrinsically high spontaneous recovery in these injuries, such gains should be interpreted as supportive signals rather than definitive efficacy and should not be extrapolated to more severe injuries without confirmatory data. Coenzyme Q10 and Ginkgo biloba extract, for instance, improved conduction metrics and myelination in preclinical studies, suggesting potential as adjuncts pending standardized endpoints and human validation.

In transection/anastomosis settings, structural improvements (e.g., myelination, axonal caliber) frequently outpaced near-term functional recovery. In some comparisons, N-acetylcysteine showed advantages over steroids on EMG and histology; SELENOT-mimetic peptides (PSELT) and PEG-fusion improved axonal metrics and reduced demyelination, yet provided limited short-window functional enhancement—indicating the need for longer follow-up and standardized electrophysiological endpoints before clinical recommendations can be made. Melatonin yielded histopathologic benefits with inconsistent short-term EMG gains, underscoring model- and dose-contingent translation challenges.

In infectious/ischemic contexts, edaravone reduced oxidative stress markers with suggested clinical benefit; however, assessments often relied on clinical observation without standardized electrophysiology. Head-to-head confirmation against both no-treatment and steroid comparators is required to define incremental effect size and dosing windows.

Most included studies used young, otherwise healthy animals. Because nerve regenerative capacity declines with age and comorbidities elevate oxidative stress, treatment effects may attenuate in older or metabolically compromised patients; dose windows and safety margins may also differ. Translational studies should therefore prespecify age/comorbidity strata and oxidative-stress baselines when designing trials.

In acute crush or compressive injuries-particularly within the first 72 h when some residual conduction is expected and spontaneous recovery is common-adjunctive antioxidants may be considered alongside standard care to potentially accelerate electrophysiological recovery. Preclinical studies report earlier reflex recovery and higher EMG amplitudes with resveratrol, dexamethasone, and oxytocin; ebselen achieved functional and histological recovery comparable to methylprednisolone, suggesting a possible steroid-sparing role. Coenzyme Q10 lowered stimulation thresholds and increased myelin thickness with favorable histology, and Ginkgo biloba extract accelerated recovery of vibrissae function with improved conduction metrics. Because crush models have intrinsically high spontaneous recovery, any apparent gains should be confirmed with standardized ENoG/EMG, blink reflex, and clinical grading before being interpreted as drug effects. Safety requires attention to bleeding risk with Ginkgo in patients on antithrombotics, potential CYP-mediated interactions with resveratrol, and the hyperglycemia/infection risks of dexamethasone. These signals are supportive but should not be extrapolated to more severe injuries without confirmatory data.

Following transection and primary repair, structural improvements (myelination, axonal caliber) frequently precede measurable functional gains. In this context, N-acetylcysteine has shown advantages over methylprednisolone on EMG and histology with less degeneration, supporting consideration as an early adjunct after anastomosis rather than defaulting to steroids. Melatonin has yielded histopathologic benefits without consistent short-term EMG improvements, indicating that function may lag behind structure in the early window. SELENOT-mimetic peptides (PSELT) and PEG-fusion have improved axonal metrics and reduced demyelination, respectively, yet have provided limited functional enhancement over short follow-up intervals and remain investigational. Clinically, we suggest planning extended follow-up of at least 6–12 months with MUAP and CMAP analyses and, where available, high-resolution imaging to capture delayed functional convergence. For safety, clinicians should be aware of gastrointestinal intolerance to NAC and rare bronchospasm with intravenous formulations. Comparative signals favoring NAC and, in select parameters, aminoguanidine or melatonin over steroids underscore the need to avoid uncritical extrapolation of steroid benefits across models.

In ischemic or viral facial palsy, edaravone has reduced oxidative stress markers and, in animal models, decreased the incidence and severity of palsy; however, many assessments have relied on clinical observation rather than standardized electrophysiology. Accordingly, any adjunctive use should be embedded in protocols that include head-to-head comparisons against both no-treatment and steroid controls, with predefined electrophysiological endpoints to quantify incremental benefit, and with renal function monitoring for safety. Until such data are available, edaravone should be regarded as a hypothesis-generating adjunct rather than a routine therapy in these indications.

A practical approach begins by triaging patients by mechanism (traumatic/compressive, transection/anastomosis, infectious/ischemic) and timing (acute 0–72 h, subacute 3–14 d, chronic >3 mo). Standard care is applied per guidelines, followed by a screen for contraindications and drug–drug interactions. An antioxidant adjunct is considered when preclinical signals match the mechanism of injury and safety is acceptable, recognizing the high spontaneous recovery seen in crush models and the structural–functional lag typical of transection settings. Patients are monitored with ENoG/EMG, blink reflex, and standardized facial scoring over 2–12 weeks, and continuation or de-escalation is determined by predefined thresholds and longitudinal trends. This algorithm prioritizes standardized electrophysiology and longer follow-up in models where short-term functional gains are unlikely to capture the full effect size.