Antioxidants Attenuate Acute and Chronic Itch: Peripheral and Central Mechanisms of Oxidative Stress in Pruritus

Abstract

Itch (pruritus) is one of the most disabling syndromes in patients suffering from skin, liver, or kidney diseases. Our previous study highlighted a key role of oxidative stress in acute itch. Here, we evaluated the effects of antioxidants in mouse models of acute and chronic itch and explored the potential mechanisms. The effects of systemic administration of the antioxidants N-acetyl-L-cysteine (NAC) and N-tert-butyl-α-phenylnitrone (PBN) were determined by behavioral tests in mouse models of acute itch induced by compound 48/80 or chloroquine, and chronic itch by treatment with a mixture of acetone-diethyl-ether-water. We found that systemic administration of NAC or PBN significantly alleviated compound 48/80- and chloroquine-induced acute itch in a dose-dependent manner, attenuated dry skin-induced chronic itch, and suppressed oxidative stress in the affected skin. Antioxidants significantly decreased the accumulation of intracellular reactive oxygen species directly induced by compound 48/80 and chloroquine in the cultured dorsal root ganglia-derived cell line ND7-23. Finally, the antioxidants remarkably inhibited the compound 48/80-induced phosphorylation of extracellular signal-regulated kinase in the spinal cord. These results indicated that oxidative stress plays a critical role in acute and chronic itch in the periphery and spinal cord and antioxidant treatment may be a promising strategy for anti-itch therapy.

Persistent Extracellular Signal-Regulated Kinase Activation by the Histamine H4 Receptor in Spinal Neurons Underlies Chronic Itch

“…Different durations of ERK activation have also been reported to induce different cell responses (Marshall, 1995). Transient ERK activation in the spinal cord has been shown to be involved in histamine-dependent itch (Zhang et al, 2014;Zhou et al, 2017). In the present study, persistent ERK activation was found in DNFB-induced chronic spontaneous itch.…”

Selected serum oxidative stress biomarkers in dogs with non‐food‐induced and food‐induced atopic dermatitis

“…Previous studies performed in human atopic asthmatic patients and in dogs with AD have suggested that vitamin E supplementation was able to decrease disease severity. Furthermore, the systemic administration of antioxidants attenuated pruritus in a mouse model . Our findings further support the idea that targeted therapies, such as antioxidant therapies, could help to reduce clinical severity in those dogs where oxidative stress could be demonstrated.…”

“…Moreover, there is evidence that increased NF‐κB activation triggers skin inflammation . Secondly, OS also has been reported to contribute to the pathogenesis of pruritus in a mouse model where it was suggested that OS is a key mechanism for pruritus via activation of transient receptor potential subtype A1 (TRPA1) channels on primary sensory neurons and neurons in dorsal root ganglia and activation of phosphorylation of extracellular signal‐regulated kinase in the spinal cord …”

Recent Progress in Understanding the Mechanisms of Pain and Itch: the Second Special Issue

“…In addition to GRP and GRPR mentioned above [27], Zhou et al reveal oxidative stress as an important mechanism of acute and chronic itch via both central and peripheral regulation. They also demonstrate that anti-oxidants are effective in treating pruritus [28]. TNF-a is one of the best-known cytokines and drives pathological pain.…”