Anti-itch Therapies Research Articles

Neuroinflammation evoked mechanisms for neuropathic itch in the spared nerve injury mouse model of neuropathic pain

A large portion of neuropathic pain suffering patients may also concurrently experience neuropathic itch, with a negative impact on the quality of life. The limited understanding of neuropathic itch and the low efficacy of current anti-itch therapies dictate the urgent need of a better comprehension of molecular mechanisms involved and development of relevant animal models. This study was aimed to characterize the itching phenotype in a model of trauma-induced peripheral neuropathy, the spared nerve injury (SNI), and the molecular events underlying the overlap with the nociceptive behavior. SNI mice developed hyperknesis and spontaneous itch 7–14 days after surgery that was prevented by gabapentin treatment. Itch was associated with pain hypersensitivity, loss of intraepidermal nerve fiber (IENF) density and increased epidermal thickness. In coincidence with the peak of scratching behavior, SNI mice showed a spinal overexpression of IBA1 and GFAP, microglia and astrocyte markers respectively. An increase of the itch neuropeptide B-type natriuretic peptide (BNP) in NeuN+ cells, of its downstream effector interleukin 17 (IL17) along with increased pERK1/2 levels occurred in the spinal cord dorsal horn and DRG. A raise in BNP and IL17 was also detected at skin level. Stimulation of HaCat cells with conditioned medium from BV2-stimulated SH-SY5Y cells produced a dramatic reduction of HaCat cell viability. This study showed that SNI mice might represent a model for neuropathic itch and pain. Collectively, our finding suggest that neuropathic itch might initiate at spinal level, then affecting skin epidermis events, through a glia-mediated neuroinflammation-evoked BNP/IL17 mechanism.

Long-term use of lokivetmab in dogs with atopic dermatitis.

Lokivetmab, a caninised monoclonal antibody against interleukin (IL)-31, is an effective treatment for the pruritus associated with canine atopic dermatitis (cAD). To investigate the efficacy and safety of lokivetmab during long-term treatment defined as at least three consecutive lokivetmab injections in atopic dogs under field conditions. To assess individual factors influencing treatment outcome and adverse events. 150 dogs with cAD. Medical records of dogs treated with lokivetmab were reviewed, and owners and/or veterinarians were contacted as needed for follow-up. A decrease of the pruritus Visual Analog Scale (PVAS) score by ≥2 or a PVAS score ≤2 after treatment was considered as treatment success. Logistic regression was used to investigate the influence of a variety of factors on outcome: type of cAD (food versus environment), age at first lokivetmab administration, disease chronicity, dosage and/or secondary infection. Any adverse event that occurred during the study period was recorded. Lokivetmab reduced the PVAS score with long-term use (p < 0.01); the success rate was 53 of 69 total dogs (77%). The probability of treatment failure decreased with increasing treatment duration. None of the factors investigated influenced the treatment outcome. Twelve dogs of 150 (8%) showed adverse events such as gastrointestinal signs or lethargy. Lokivetmab appears to be an effective and safe long-term anti-itch therapy for dogs with cAD.

The Role of Transient Receptor Potential A1 and G Protein-Coupled Receptor 39 in Zinc-Mediated Acute and Chronic Itch in Mice.

Itching is a common symptom of many skin or systemic diseases and has a negative impact on the quality of life. Zinc, one of the most important trace elements in an organism, plays an important role in the regulation of pain. Whether and how zinc regulates itching is largely unclear. Herein, we explored the role of Zn2+ in the regulation of acute and chronic itch in mice. It is found that intradermal injection (i.d.) of Zn2+ dose-dependently induced acute itch and transient receptor potential A1 (TRPA1) participated in Zn2+-induced acute itch in mice. Moreover, the pharmacological analysis showed the involvement of histamine, mast cells, opioid receptors, and capsaicin-sensitive C-fibers in Zn2+-induced acute itch in mice. Systemic administration of Zn2+ chelators, such as N,N,N′,N′-Tetrakis(2-pyridylmethyl)ethylenediamine (TPEN), pyrithione, and clioquinol were able to attenuate both acute itch and dry skin-induced chronic itch in mice. Quantitative polymerase chain reaction (Q-PCR) analysis showed that the messenger RNA (mRNA) expression levels of zinc transporters (ZIPs and ZnTs) significantly changed in the dorsal root ganglia (DRG) under dry skin-induced chronic itch condition in mice. Activation of extracellular signal-regulated kinase (ERK) pathway was induced in the DRG and skin by the administration of zinc or under dry skin condition, which was inhibited by systemic administration of Zn2+ chelators. Finally, we found that the expression of GPR39 (a zinc-sensing GPCR) was significantly upregulated in the dry skin mice model and involved in the pathogenesis of chronic itch. Together, these results indicated that the TRPA1/GPR39/ERK axis mediated the zinc-induced itch and, thus, targeting zinc signaling may be a promising strategy for anti-itch therapy.

Особливості патогенезу свербежу та протисвербіжної терапії в дітей з алергодерматозами (огляд літератури)

Allergic dermatoses are allergic skin diseases, the most common of which are: simple and allergic contact dermatitis, atopic dermatitis, various forms of eczema, acute and chronic allergic urticaria, Quincke's edema, toxicodermias, multiforme exudative erythema (Stevens–Johnson syndrome), acute epidermal necrolysis (Lyell's syndrome). The clinical course of all allergic dermatoses is accompanied by itch, although its severity varies depending on the nosology. An important focus of treatment of allergic dermatoses is to control of skin itch, as it is the leading symptom. According to the international program documents EAACI (European Academy of Allergy and Clinical Immunology), AAAAI (American Academy of Allergy, Asthma &amp; Immunology), PRACТALL (Practical Allergology Consensus Report) in treatment of allergic dermatoses the leading place takes anti-itch therapy, which requires an individual approach and daily care of skin. Systemic anti-itch therapy includes using of the following drugs: antihistamines, glucocorticosteroids, membrane's stabilizators (kromons), leukotriene receptor antagonists, anti-IgE. External anti-itch therapy consists of local application of emollients, topical glucocorticosteroids, topical calcineurin inhibitors, topical anti-histamines, reparants and epithelializing medications. Purpose — to increase knowledge about features of etiopathogenetically-based anti-itch therapy of allergic dermatoses in children. Conclusions. Treatment of itch of allergic dermatoses is diverse, complex and multi-stage, requires an individual approach to each patient, and includes: environmental control to eliminate allergenic and non-allergenic factors, systemic and local pharmacotherapy, skin care. Modern anti-itch therapy of allergic dermatoses should be etiopathogenetic and affect on local and system mechanisms of allergic inflammation with itch, it should be differentiated according to the stage of the disease, the phase of inflammation and the severity of skin manifestations and to be based on the rational use of drugs. No conflict of interest was declared by the author. Key words: children, allergy, allergic dermatoses, itch, anti-itch therapy.

Cutaneous mechanisms of itch signaling

Itch is defined as an unpleasant sensation that stimulates the scratch reflex. While acute itch, such as from an insect bite, is protective and serves as a warning signal for potential tissue damage, chronic itch significantly impairs quality of life. This condition is still poorly understood and lacks universally effective treatments. Uncovering the cellular and molecular mechanisms of chronic itch is crucial for the development of anti-itch therapies. Skin is the largest sensory organ in which itch sensation is initiated. Currently, knowledge of itch signaling pathways in the skin has focused on (1) neuroimmune crosstalk in itch and inflammation in the skin; (2) skin-expressed ion channels that regulate itch signaling; and (3) skin-derived antimicrobial peptides that act as endogenous pruritogens.

MRGPRX4 is a bile acid receptor for human cholestatic itch

Patients with liver diseases often suffer from chronic itch, yet the pruritogen(s) and receptor(s) remain largely elusive. Here, we identify bile acids as natural ligands for MRGPRX4. MRGPRX4 is expressed in human dorsal root ganglion (hDRG) neurons and co-expresses with itch receptor HRH1. Bile acids elicited Ca2+ responses in cultured hDRG neurons, and bile acids or a MRGPRX4 specific agonist induced itch in human subjects. However, a specific agonist for another bile acid receptor TGR5 failed to induce itch in human subjects and we find that human TGR5 is not expressed in hDRG neurons. Finally, we show positive correlation between cholestatic itch and plasma bile acids level in itchy patients and the elevated bile acids is sufficient to activate MRGPRX4. Taken together, our data strongly suggest that MRGPRX4 is a novel bile acid receptor that likely underlies cholestatic itch in human, providing a promising new drug target for anti-itch therapies.

Relief of intractable pruritus with romidepsin in patients with cutaneous T ‐ cell lymphoma: A series of four cases

Cutaneous T‐cell lymphomas (CTCL) are a relatively rare and heterogeneous group of non‐Hodgkin lymphomas that typically present in the skin. The majority of patients with CTCL experience pruritus, which can interfere with daily activities, significantly impact quality of life, and is typically uncontrolled by standard anti‐itch therapies. Several lymphoma treatments have reported anti‐pruritic effects including romidepsin, a potent class 1 selective histone deacetylase inhibitor approved for the treatment of patients with CTCL who have had at least one prior systemic therapy. Here, we describe the cases of four patients with debilitating and refractory pruritus that were resolved with romidepsin. Resolution of pruritus was observed in both clinical responders and nonresponders, and dose modification was used successfully to manage adverse events and for maintenance treatment. The potential for pruritus relief with romidepsin should be considered when treating patients with CTCL.

TRP Channels as Drug Targets to Relieve Itch.

Although acute itch has a protective role by removing irritants to avoid further damage, chronic itch is debilitating, significantly impacting quality of life. Over the past two decades, a considerable amount of stimulating research has been carried out to delineate mechanisms of itch at the molecular, cellular, and circuit levels. There is growing evidence that transient receptor potential (TRP) channels play important roles in itch signaling. The purpose of this review is to summarize our current knowledge about the role of TRP channels in the generation of itch under both physiological and pathological conditions, thereby identifying them as potential drug targets for effective anti-itch therapies.

Epigallocatechin-3-gallate attenuates acute and chronic psoriatic itch in mice: Involvement of antioxidant, anti-inflammatory effects and suppression of ERK and Akt signaling pathways

Chronic itch is a distressing symptom of many skin diseases and negatively impacts quality of life. However, there is no medication for most forms of chronic itch, although antihistamines are often used for anti-itch treatment. Epigallocatechin-3-gallate (EGCG), a major green tea polyphenol, exhibits anti-oxidative and anti-inflammatory properties. Our previous studies highlighted a key role of oxidative stress and proinflammatory cytokines in acute and chronic itch. Here, we evaluated the effects of green tea polyphenon 60 and EGCG on acute and chronic itch in mouse models and explored its potential mechanisms. The effects of EGCG were determined by behavioral tests in mouse models of acute and chronic itch, which were induced by compound 48/80, chloroquine (CQ), and 5% imiquimod cream treatment, respectively. We found that systemic or local administration of green tea polyphenon 60 or EGCG significantly alleviated compound 48/80- and chloroquine-induced acute itch in a dose-dependent manner in mice. Incubation of EGCG significantly decreased the accumulation of intracellular reactive oxygen species (ROS) directly induced by compound 48/80 and CQ in cultured ND7-23 cells, a dorsal root ganglia derived cell line. EGCG also attenuated imiquimod-induced chronic psoriatic itch behaviors and skin epidermal hyperplasia in mice. In addition, EGCG inhibited the expression of IL-23 mRNA in skin and TRPV1 mRNA in dorsal root ganglia (DRG). Finally, EGCG remarkably inhibited compound 48/80-induced phosphorylation of extracellular signal-regulated kinase (ERK) and imiquimod-induced p-AKT in the spinal cord of mice, respectively. Collectively, these results indicated EGCG could be a promising strategy for anti-itch therapy.

Long-term anti-itch effect of botulinum neurotoxin A is associated with downregulation of TRPV1 and TRPA1 in the dorsal root ganglia in mice.

Itch is a common symptom in patients with skin and systemic diseases, but the effective treatment is limited. Here, we evaluated the anti-itch effects of the botulinum toxin type A (BoNT/A) using acute and chronic dry skin itch mouse models, which were induced by compound 48/80, chloroquine, and a mixture of acetone-diethylether-water treatment, respectively. Pretreatment of intradermal BoNT/A exerted long-term inhibitory effects on compound 48/80-induced and chloroquine-induced acute itch on days 1, 3, 7, and 14, but not on day 21, in mice. Furthermore, a single injection of BoNT/A reduced the expression of the transient receptor potential cation channel, subfamily V, member 1 (TRPV1), and the transient receptor potential cation channel, subfamily A, member 1 (TRPA1) at both transcriptional and translational levels in the dorsal root ganglia (DRG) in mice. Pretreatment of BoNT/A also attenuated chronic itch induced by acetone-diethylether-water treatment and abolished the upregulation of TRPA1 in the DRG. Thus, it was suggested that downregulation of the expression of TRPA1 and TRPV1 in the DRG may contribute toward the long-term anti-itch effects of a single injection of BoNT/A in mice and BoNT/A treatment may serve as an alternative strategy for anti-itch therapy.

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

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.

Improved pruritus correlates with lower levels of IL-31 in CTCL patients under different therapeutic modalities

Pruritus is one of the cardinal symptoms found in patients with leukemic cutaneous T cell lymphoma (CTCL). The nature of the pruritus experienced by CTCL patients is complex, involving different pathways and cell mediators, thus making it poorly responsive to conventional anti-itch therapies. Recent reports highlight the role of interleukin 31 (IL-31) as a novel cytokine involved in the pathogenesis of pruritus in atopic dermatitis and CTCL. Here we provide both in vivo and in vitro evidence suggesting that histone deacetylase (HDAC) inhibitors may mitigate itch through lowering of levels of IL-31-expressing T cells. Furthermore, we demonstrate that chemokine receptor type-4 (CCR4)-bearing T cells are a main source of IL-31 in CTCL, and that neutralizing the IL-31 pathway through targeting of the CCR4-expressing T cells may represent a promising therapeutic strategy for symptomatic relief in CTCL.

Itch mechanisms and circuits.

The itch-scratch reflex serves as a protective mechanism in everyday life. However, chronic persistent itching can be devastating. Despite the clinical importance of the itch sensation, its mechanism remains elusive. In the past decade, substantial progress has been made to uncover the mystery of itching. Here, we review the molecules, cells, and circuits known to mediate the itch sensation, which, coupled with advances in understanding the pathophysiology of chronic itching conditions, will hopefully contribute to the development of new anti-itch therapies.

Novel acoustic evaluation system for scratching behavior in itching dermatitis: Rapid and accurate analysis for nocturnal scratching of atopic dermatitis patients

Quantitative analysis of itching in patients with itching dermatitis including atopic dermatitis (AD) is indispensable for the evaluation of disease activity and response to therapy. However, the objective evaluation system for itching is limited. We have developed a new objective and quantitative scratching behavior detection system using a wristwatch-type sound detector. The scratch sound detected on the wrist is recorded on a personal computer through a filtering, squaring and smoothing process by specific hardware. Subsequently, the data is automatically processed and judged for the scratching movement using specific software based on the periodicity and energy of the signal. Twenty-four measurements for healthy volunteers and those with AD by this system were evaluated by comparison with a simultaneously recorded video analysis system. The ratio of scratching time in sleeping time evaluated by these two systems was almost identical. The healthy subjects scratched their skin approximately 2 min during 6 h of sleeping time, while the mean scratching time of AD subjects was 24 min in their sleeping time. In contrast to the time-consuming video analysis system, this system takes only several minutes for evaluation of an overnight record. This scratch sound detection system is expected to serve as a new objective evaluation tool for itching dermatitis, namely, AD, and development of anti-itch therapies for dermatitis.

A unique therapeutic approach to emesis and itch with a proanthocyanidin-rich genonutrient

BackgroundWe examined the therapeutic potential of a proprietary Croton palanostigma extract (Zangrado®) in the management of emesis and itch.MethodsEmesis was induced in ferrets with morphine-6-glucuronide (0.05 mg/kg sc) in the presence of Zangrado (3 mg/kg, ip) and the cannabinoid receptor 1 antagonist, AM 251 (5 mg/kg, ip). Topical Zangrado (1%) was assessed for anti-pruretic actions in the 5-HT-induced scratching model in rats and evaluated in capsaicin-induced gastric hyperemia as measured by laser doppler flow. In the ApcMinmouse model of precancerous adenomatosis polyposis, mice received Zangrado (100 μg/ml in drinking water) from the age of 6 – 16 weeks for effects on polyp number. In RAW 264.7 cells Zangrado was examined for effects on lipopolysaccharide-induced nitrite production.ResultsZangrado was a highly effective anti-emetic, reducing morphine-induced vomiting and retching by 77%. These benefits were not associated with sedation or hypothermia and were not reversed by cannabinoid receptor antagonism. Itch responses were blocked in both the morphine and 5-HT models. Zangrado did not exacerbate the ApcMincondition rather health was improved. Capsaicin-induced hyperemia was blocked by Zangrado, which also attenuated the production of nitric oxide by activated macrophages.ConclusionZangrado is an effective anti-emetic and anti-itch therapy that is devoid of common side-effects, cannabinoid-independent and broadly suppresses sensory afferent nerve activation. This complementary medicine represents a promising new approach to the management of nausea, itch and irritable bowel syndrome.

Topical anti-itch therapy

Topical anti-itch therapy could be causative (antiviral, antimycotic, and/or antiparasitic preparations) or symptomatic. Symptomatic therapy includes substituting some other sensation by cooling, heating, and/or counterirritation, by anesthesia of sensory nerve endings with local anesthetics, blocking mediators of pruritus (to deplete substance P or to block acetylcholine release), and reducing inflammation of the skin with corticosteroids or topical immunomodulators (pimecrolimus and tacrolimus). In addition to drugs, the patient should be taught to use emollients and to avoid skin dryness and vasodilatation by contact with irritants. Topical anti-itch preparations can be recommended not only for treatment of localized pruritus, but also for therapy of generalized pruritus when general measures are not effective, systemic drugs are contraindicated, and/or as addition to causative or systemic therapy. Topical anti-itch preparations should be prescribed after the diagnosis is made and used as the first-choice treatment together with general measures.

The future: critical knowledge about anti-itch therapy

Itch is an extremely frequent and enervating symptom of many diseases. Current anti-itch therapy, which is based almost exclusively on an "immunocentric" viewpoint, is often unsatisfactory. Recent studies show that this symptom is in fact the result of a complex interplay among skin, nervous system, endocrine system, and immune system. This explains the frequent failure of therapeutic strategies focused only on a single factor and suggests the usefulness of a polypharmacologic symptomatic treatment, designed on a case-by-case basis as a result of a multidisciplinary approach. We discuss the perspectives of anti-itch therapy in light of the new pathogenetic and pharmacologic acquisitions.