Oxidative stress has been shown to play a significant role in a variety of both cutaneous and systemic diseases, including atopic dermatitis, psoriasis, diabetes, chronic kidney disease, and cholestasis1–5. Interestingly, chronic pruritus is a common feature of many of these diseases. Recently, it has also been shown that mitochondrial reactive oxygen species (mROS) may play a role in pain processing and that mitochondrial dysfunction can contribute to painful peripheral neuropathies6.
Reactive oxygen species (ROS) are molecules that play a role in normal physiological reactions. The body has different enzymatic [eg, superoxide dismutase (SOD), glutathione peroxidase, catalase] and nonenzymatic (eg, vitamins A, C, E; glutathione) antioxidant systems in place that combat oxidant effects. However, imbalances in the production of ROS and degradation by antioxidants can cause oxidative stress, which damages cells in the body and can lead to pathologic processes7. Mitochondria are one of the major sources of endogenous ROS6. However, environmental pollutants also drive the production of ROS which can lead to oxidative stress in the skin1.
Chronic pruritus and chronic pain are both debilitating conditions that can severely impact patients’ quality of life. Antioxidants have been successfully used to treat a variety of oxidative stress-driven diseases8. In this review, we aim to explore the role of ROS in the pathophysiology of pain and pruritus, as well as discuss the role of antioxidants as a potential therapeutic option for chronic itch and pruritic conditions.
Oxidative stress and the pathophysiology of pain
ROS have been suggested to play a role in both peripheral and central pain mechanisms. Mitochondria are found abundantly in peripheral sensory nerve fibers, and nociceptive receptors in these fibers such as TRPV1 and TRPA1 are known to be activated by mROS9,10. ROS generated by mitochondrial dysfunction have been shown to cause nociceptor hyperexcitability10, thus demonstrating that these mROS may play a role in peripheral pain signaling. Secondary hyperalgesia is defined as increased pain sensitivity in a region surrounding (but not including) the zone of injury and is known to occur due to central sensitization in the spinal cord dorsal horn. Schwartz et al found that treatment with antioxidant phenyl-N-tert-butylnitrone reduced secondary hyperalgesia in mice, indicating that ROS in the spinal cord may play a role in this pain mechanism11. They also found that spinal ROS, particularly mitochondrial superoxide, are critical players in controlling central pain sensitization, which has been supported in other studies12,13. ROS have been shown to affect pain signaling pathways involving nuclear factor kappa-B and mitogen-activated protein kinase second messenger systems, further suggesting that oxidative stress can exacerbate chronic pain14.
Antioxidants and chronic pain
Studies have shown that the removal of ROS by antioxidants can lead to significant pain reduction in both neuropathic and inflammatory pain14. Administration of a combination of antioxidants vitamin C and E inhibited neuropathic pain processing in the spinal cord in mice and alleviated the allodynia induced by a ROS donor15. Interestingly, this antioxidant combination did not inhibit inflammatory pain. Flavonoids are polyphenolic compounds that have both antioxidant and anti-inflammatory properties. Quercetin is a type of flavonoid that has been shown to reduce both inflammatory and neuropathic pain through its inhibition of oxidative stress16–18. This flavonoid’s analgesic properties are partly due to the activation of the Nrf2/HO-1 pathway, which protects cells from oxidative stress16. Administration of quercetin has also been shown to decrease TRPV1 protein expression in dorsal root ganglion (DRG) neurons of paclitaxel-treated mice, indicating that it can help reduce chemotherapy-induced peripheral neuropathy19. The flavonoid vitexin has been shown to alleviate inflammatory pain by a variety of mechanisms, including the reduction of oxidative stress20. Rutin, along with several other flavonoids, reduces free radical-mediated oxidative stress and increases levels of antioxidant enzymes in the nerve tissue of diabetic animals, thus helping alleviate diabetic neuropathy19. Epigallocatechin-3-gallate (EGCG), a flavonoid found in green tea, was found to be effective at reducing thermal hyperalgesia in neuropathic pain models18. Wei et al21 also showed that by reducing the expression of oxidative stress pathways, this compound may enhance neuronal survival after peripheral nerve injury.
Oral analgesics, while effective, come with a battery of undesired side effects that range from stomach ulcers to physical dependence. Therefore, the use of antioxidants in pain management is of great clinical interest, for it proposes an alternative with fewer adverse effects. Natural products have been used for centuries for the treatment of pain, and many studies have attempted to evaluate their efficacy. Ginger, for example, attenuates pain through a variety of mechanisms, including its antioxidant properties. RTCs demonstrate that ginger shows promise in treating pain related to dysmenorrhea, osteoarthritis, and chronic lower back pain22. The pathogenesis of fibromyalgia, a chronic pain syndrome, has been linked to oxidative stress. Coenzyme Q10 has been shown to reduce pain in fibromyalgia patients due to its antioxidant and anti-inflammatory properties23. Cancer patients experience pain at high levels and are more likely than the general population to seek complementary and alternative therapies for pain management. In one study, up to 75% of cancer patients reported a reduction in pain severity after using a topical herbal medicine, and many said that this medication helped address unmet pain management needs24. Allicin, an antioxidant found in garlic, has been shown to inhibit the secretion of pain mediators and reduce pain in patients with oral squamous cell carcinoma25. Although these studies demonstrate the benefit of antioxidants in treating chronic pain, additional randomized clinical trials are needed to further evaluate their efficacy and safety.
Oxidative stress and the pathophysiology of pruritus
Animal studies have demonstrated that ROS and oxidative stress may play a role in the pathophysiology of both acute and chronic pruritus. Intradermal injection of hydrogen peroxide (H2O2) and tert-butylhydroperoxide—2 compounds commonly used to induce oxidative injury—led to robust scratching behavior in mice in a dose-dependent manner26. It was also determined that the transient receptor potential TRPA1 channel played a critical role in oxidant-induced pruritus26. This channel has previously been found to be activated by H2O2 and other substances that induce oxidative stress, such as byproducts of lipid peroxidation27. TRPA1 channels are known to be key components of non-histaminergic itch pathways that are involved in pruritic diseases such as atopic dermatitis28,29. Acrolein, a product and initiator of lipid peroxidation during oxidative stress, is an endogenous TRPA1 agonist and was found to induce scratching behavior in mice, suggesting its role as a novel endogenous pruritogen30. Recent studies show that TRPA1 might not be the only transient receptor potential channel involved in ROS-induced itch. TRPC3 is another ROS-sensitive channel that is expressed in small nerve fibers of DRG neurons and is activated by pruritogens6. Intradermal injection of actinomycin A, which allows for mROS overproduction through inhibition of the mitochondrial electron transport chain, was found to elicit robust scratching behavior in mice. This behavior was inhibited by administering a TRPC3-specific blocker, indicating that this channel played a role in inducing acute pruritus. Furthermore, this study also demonstrated that mROS overproduction from malfunctioning mitochondria elicited dry skin-induced chronic pruritus in mouse models via TRPC3. Repeated treatment with resveratrol, a known antioxidant, significantly attenuated scratching in these models compared to the vehicle6. Oxidative stress may also play a role in the pathogenesis of pruritus indirectly through mast cell activation. Compounds known to cause oxidative stress such as sodium sulfite and acrolein have been shown to induce mast cell degranulation31,32. Mast cells are important mediators of itch and play a role in pruritic conditions such as atopic dermatitis33. Mast cell activation is also accompanied by the generation of ROS such as superoxide and hydrogen peroxide, which could further contribute to pruritus34.
Role of ROS in pruritic diseases
Free radicals, ROS, and resultant oxidative stress have been shown to play a role in the pathogenesis of pruritic diseases such as atopic dermatitis and psoriasis.
Psoriasis is characterized by erythematous, pruritic papules and plaques with silvery scales located most commonly on the extensor surfaces. Pruritus has been shown to affect 60%–90% of patients with psoriasis and significantly affects the quality of life35. Although the severity of pruritus has been correlated with that of psoriasis, itch often persists even after the resolution of other symptoms and can be difficult to manage35. The pathogenesis of psoriasis is complex, and studies suggest that an imbalance between oxidants and antioxidants contributes to disease pathogenesis. A review of the role of oxidative stress in psoriasis by Dobrica et al36 found that oxidative stress markers are elevated in psoriasis and are associated with duration and disease severity. ROS are also believed to contribute to the pruritus associated with this disease, for antioxidants have been shown to improve psoriatic itch. The antioxidant EGCG, for example, was found to attenuate imiquimod-induced chronic psoriatic itch in mice models37.
Atopic dermatitis is characterized by pruritic eruptions and characteristic eczematous skin changes most commonly in flexural surfaces of the skin. Pruritus is present in most patients and is one of the most debilitating symptoms of AD. The pathogenesis of atopic dermatitis involves an interplay of genetics and environment, and studies increasingly support the notion that oxidative stress also plays a role in this disease2,38. One study showed that urine levels of 8-hydroxy-2’-deoxyguanosine, a marker of oxidative stress, were significantly increased in children with atopic dermatitis compared with controls. The study concluded that impaired homeostasis of oxygen/nitrogen radicals and increased oxidative stress are involved in the pathophysiology of atopic dermatitis in children. However, higher urinary 8-OHdG levels did not significantly increase the risk of nighttime pruritus in these patients39. Other studies have demonstrated an increase in oxidative stress and a decrease in antioxidant levels in children with atopic dermatitis40,41.
Antioxidants and pruritus
The effects of antioxidant administration on acute and chronic itch have also been investigated. Systemic administration of antioxidants N-acetyl-L-cysteine (NAC) and N-tert-butyl-α-phenylnitrone has been shown to attenuate both histamine-dependent and histamine-independent acute pruritus in mouse models30. Furthermore, this study showed that treatment with NAC reduced dry skin-induced chronic pruritus. The study hypothesized that these antipruritic effects could be due to the inhibition of oxidative stress in the periphery (skin and DRG neurons) and suppression of p-ERK pathway activation in the spinal cord. This pathway has been shown to play a role in mediating histamine-induced acute pruritus30. NAC has also been shown to interact with TRPA1, proposing a peripheral mechanism through which this antioxidant inhibits itch42. In a recent study, the polyphenol EGCG attenuated both histaminergic and nonhistaminergic pruritus through the reduction of ROS in DRG cells. This compound was also able to inhibit p-ERK activation in the spinal cord, further supporting its role in suppressing histaminergic itch37.
ROS are also known to play a role in the inflammatory response7. ROS activates nuclear factor kappa-B pathways, which leads to the upregulation of inflammatory cytokines such as IL-6, IL-8, and IL-3343. Some of these cytokines have been implicated in pruritic pathways44,45. Therefore, antioxidants may exert antipruritic effects by inhibiting the production of proinflammatory cytokines. One study evaluating the antioxidant effects of nicotinamide mononucleotide on atopic dermatitis mouse models found that treatment with nicotinamide mononucleotide inhibited the increased expression of inflammatory cytokines and decreased scratching behavior46.
Furthermore, antioxidants may reduce pruritus through the inhibition of mast cell degranulation. The flavonoids luteolin, quercetin, and isoliquiritigenin have been reported to inhibit mast cell activation mediated by the MAS-related G protein-coupled receptor-X2 (MRGPRX2) in mice models47–49. This receptor plays a role in nonhistaminergic itch and is implicated in numerous pruritic conditions including atopic dermatitis, chronic prurigo, and urticaria50,51.
To date, there are a variety of anti-pruritic agents available, each targeting different aspects of the itch pathway. However, many of these agents have associated side effects and limited efficacy, and therefore are not recommended for chronic pruritus52–54. A recent survey of 1500 AD patients using topical corticosteroids showed that an overwhelming majority (91.5%) of patients had a desire for an alternative treatment option55. Furthermore, many of the newer antipruritic agents can be very costly54. Therefore, the use of antioxidants for the treatment of itch would provide a great therapeutic option for patients, for these are natural compounds that are less costly and associated with a favorable safety profile.
NAC may be beneficial in treating patients with disorders of body-focused repetitive behavior such as trichotillomania, onychophagia, and excoriation disorder, some of which are accompanied by pruritus. Patients with excoriation disorder treated with NAC had significant improvements in skin picking severity, although the effects of NAC for the treatment of trichotillomania remain under debate56,57. NAC’s efficacy may be due to the modulation of glutaminergic activity and indirect regulation of dopamine release, as well as its antioxidant properties56. Reduction of oxidate stress is thought to block compulsive behaviors, and oxidative stress has been shown to be involved in the pathophysiology of these conditions56,58. Patients with chronic pruritus experience scratching as an automatic response to itch, which leads to a vicious itch-scratch cycle that is perceived as a loss of control59. Furthermore, this itch-scratch cycle may activate reward systems in the brain such as dopaminergic neurons and the cingulate cortex59,60. Therefore, NAC may provide a beneficial therapeutic effect for patients suffering from chronic pruritus.
Levels of SOD, a potent antioxidant, are decreased in the serum of patients with psoriasis61,62. SOD has been shown to exert antipruritic effects through a variety of mechanisms, including downregulation of SP, CGRP, and IL-2, all of which are thought to mediate psoriatic itch35,63. Therefore, decreased levels of this antioxidant could contribute to itch in these patients, and supplementation may provide an effective treatment. Furthermore, a study evaluating coenzyme Q10, vitamin E, and selenium supplementation in psoriatic patients showed that clinical symptoms such as pruritus improved much faster in the group receiving the supplement when compared with placebo64. This supports the idea that antioxidants may be effective in managing psoriatic itch.
A recent systematic review by Yang et al65 analyzing the use of antioxidants in treating atopic dermatitis found a statistically significant reduction in disease severity but not in itch score, suggesting that although antioxidants may be used as an effective and safe treatment for atopic dermatitis, their anti-pruritic effect remains in question. Animal studies evaluating the use of antioxidants for the treatment of AD show mixed results in their ability to reduce pruritus46,66. A cream containing antioxidant such as EGCG, quercetin, and the flavonoid kaempferol was shown to significantly reduce pruritus intensity after 28 days in patients with atopic dermatitis67. Another review analyzing the use of topical antioxidant furfuryl palmitate showed that it is useful in reducing pruritus in atopic dermatitis as well as other dermatologic conditions68. Vitamin E has also been shown to decrease pruritus in patients with AD69,70. Phospholipase A2 (PLA2) is an enzyme involved in oxidative damage in membrane phospholipids. Excessive PLA2 elevates cyclooxygenase 2 and prostanoids, which leads to an increase in oxygen radicals. It has been shown that histamine-induced itch via TRPV1 channels is partially mediated by PLA271. Furthermore, PLA2 expression is found to be positively correlated with itch intensity ratings in psoriasis and atopic dermatitis patients72. Topical acetaminophen, which acts on the arachidonic acid pathway and function as an antioxidant, has been shown to significantly decrease both histaminergic and nonhistaminergic pruritus53. This suggests that, by modulating PLA2 pathway activity, topical acetaminophen could be an effective agent for the treatment of itch in these patients. It is important to keep in mind that the literature evaluating the role of oxidative stress in AD has several limitations, including a small number of publications on the topic, small study populations that are not representative of all ethnicities and geographic areas, and differing methodologies which make comparing studies difficult38.
Conclusion
Oxidative stress plays a role in a variety of diseases, and increasing evidence shows that it contributes to the pathophysiology of pain and pruritus. Although antioxidants show great promise in the treatment of some chronic pain conditions, more controlled studies are required to establish their efficacy in treating chronic pruritus. This topic should be further explored to better understand the pathogenesis of pruritic conditions and enhance therapeutic approaches.
Sources of funding
G.Y. is supported by NIH Grant 5R21AR078940-02.
Conflict of interest disclosure
G.Y.: Consultant and Board member Sanofi, Regeneron, Pfizer, Galderma, Novartis, Eli Lilly, Abbvie, Kiniksa, Trevi, Pierre Gabre, LEo, Escient, Celldex, Bellus, Research support Pfizer, Sanofi, Regeneron, Leo, Eli Lilly, Kiniksa, Novartis, Escient, Bellus, Galderma, Celldex. The remaining authors declare that they have no financial conflict of interest with regard to the content of this report.
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