LPS exacerbates TRPV4-mediated itch through the intracellular TLR4-PI3K signalling.

Pruritus is often accompanied with bacterial infections, but the underlying mechanism is not fully understood. Although previous studies revealed that lipopolysaccharides (LPS) could directly activate TRPV4 channel and TRPV4 is involved in the generation of both acute itch and chronic itch, whether and how LPS affects TRPV4-mediated itch sensation remains unclear. Here, we showed that LPS-mediated TRPV4 sensitization exacerbated GSK101-induced scratching behaviour in mice. Moreover, this effect was compromised in TLR4-knockout mice, suggesting LPS acted through a TLR4-dependent mechanism. Mechanistically, LPS enhanced GSK101-evoked calcium influx in mouse ear skin cells and HEK293T cells transfected with TRPV4. Further, LPS sensitized TRPV4 channel through the intracellular TLR4-PI3K-AKT signalling. In summary, our study found a modulatory role of LPS in TRPV4 function and highlighted the TLR4-TRPV4 interaction in itch signal amplification.

Anoctamin 1, a multi-modal player in pain and itch.

Anoctamin 1 (ANO1/TMEM16A) encodes a Ca2+-activated Cl- channel. Among ANO1's many physiological functions, it plays a significant role in mediating nociception and itch. ANO1 is activated by intracellular Ca2+ and depolarization. Additionally, ANO1 is activated by heat above 44 °C, suggesting heat as another activation stimulus. ANO1 is highly expressed in nociceptors, indicating a role in nociception. Conditional Ano1 ablation in dorsal root ganglion (DRG) neurons results in a reduction in acute thermal pain, as well as thermal and mechanical allodynia or hyperalgesia evoked by inflammation or nerve injury. Pharmacological interventions also lead to a reduction in nocifensive behaviors. ANO1 is functionally linked to the bradykinin receptor and TRPV1. Bradykinin stimulates ANO1 via IP3-mediated Ca2+ release from intracellular stores, whereas TRPV1 stimulates ANO1 via a combination of Ca2+ influx and release. Nerve injury causes upregulation of ANO1 expression in DRG neurons, which is blocked by ANO1 antagonists. Due to its role in nociception, strong and specific ANO1 antagonists have been developed. ANO1 is also expressed in pruritoceptors, mediating Mas-related G protein-coupled receptors (Mrgprs)-dependent itch. The activation of ANO1 leads to chloride efflux and depolarization due to high intracellular chloride concentrations, causing pain and itch. Thus, ANO1 could be a potential target for the development of new drugs treating pain and itch.

Treatment of patients with evidence of mast cell-mediated itch in the absence of hives with omalizumab.

PURPOSE: The presence of wheals or hives has been viewed as a hallmark symptom of urticaria, a highly debilitating disease. This study explores our experience with omalizumab in patients with apparent mast-cell mediated pruritus in the absence of hives. MATERIALS AND METHODS: This is a retrospective case series examining all patients with mast cell-mediated pruritus in the absence of hives from April 2022 to May 2024 at a tertiary referral clinic at Icahn School of Medicine at Mount Sinai in New York. Peak pruritus-numerical rating scale (PP-NRS) itch score changes over time were recorded and analyzed. RESULTS: Six patients (67% women; mean [SD] age, 47.67 [13.52] years) were included in the analysis. The median [IQR] pruritus PP-NRS itch score before omalizumab injection was 9 [6 - 10] and the final median [IQR] PP-NRS itch score was 2.5 [0 - 5]. The mean [SD] reduction in the PP-NRS itch score was 6 [3.16]. CONCLUSIONS: This study suggests that patients with evidence of mast cell-mediated pruritus can be identified based on clinical features and may benefit from omalizumab therapy.

Spinal histamine H4 receptor mediates chronic pruritus via p-ERK in acetone-ether-water (AEW)-induced dry skin mice.

Dry skin is common to many pruritic diseases and is difficult to improve with oral traditional antihistamines. Recently, increasing evidence indicated that histamine H4 receptor (H4R) plays an important role in the occurrence and development of pruritus. Extracellular signal-regulated kinase (ERK) phosphorylation activation in the spinal cord mediates histamine-induced acute and choric itch. However, whether the histamine H4 receptor regulates ERK activation in the dry skin itch remains unclear. In the study, we explore the role of the histamine H4 receptor and p-ERK in the spinal cord in a dry skin mouse model induced by acetone-ether-water (AEW). q-PCR, Western blot, pharmacology and immunofluorescence  were applied in the study. We established a dry skin itch model by repeated application of AEW on the nape of neck in mice. The AEW mice showed typically dry skin histological change and persistent spontaneous scratching behaviour. Histamine H4 receptor, instead of histamine H1 receptor, mediated spontaneous scratching behaviour in AEW mice. Moreover, c-Fos and p-ERK expression in the spinal cord neurons were increased and co-labelled with GRPR-positive neurons in AEW mice. Furthermore, H4R agonist 4-methyhistamine dihydrochloride (4-MH)induced itch. Both 4-MH-induced itch and the spontaneous itch in AEW mice were blocked by p-ERK inhibitor U0126. Finally, intrathecal H4R receptor antagonist JNJ7777120 inhibited spinal p-ERK expression in AEW mice. Our results indicated that spinal H4R mediates itch via ERK activation in the AEW-induced dry skin mice.

Device-based physical therapies in chronic pruritus: a narrative review.

Chronic pruritus is a highly prevalent disease associated with high psychosocial and economic burdens. In addition to pharmacological treatments, device-based physical therapies also offer antipruritic effects. Phototherapy, laser treatment, electrical neurostimulation technologies, acupuncture, cryotherapy, and cold atmospheric plasma are, in part, still experimental but emerging treatment options that augment our repertoire to treat patients with chronic pruritus. In this narrative review, we provided an overview of these physical modalities and their role in itch management.

Managing Pruritus in Advanced Chronic Disease.

Even though pruritus affects a significant number of people with chronic disease, it is rarely adequately treated. Drug therapies often rely on antihistamines, which have not shown to be beneficial in systemic pruritus. Hydroxyzine is frequently used to treat pruritus associated with kidney failure. Since Canada's sole manufacturer of hydroxyzine is no longer making this product, this is an ideal time to review the mechanisms of itch in advanced organ failure and the specific therapies that give relief. Although there is literature describing itch in patients with cancer, this article is limited to pathogenesis and treatment of systemic itch secondary to chronic, noncancer diseases. We summarize recent systematic reviews, although the studies included in these reviews are often small, and mostly cohort studies.

Prevalence of pruritus in the elderly in an outpatient dermatologic clinic: a monocentric pilot study.

Few studies have examined pruritus in elderly patients, a common dermatological condition. The study examines pruritus prevalence and characteristics in elderly patients referred to the Dermatology Unit, at Genoa's Galliera Hospital. The demographic characteristics of all Outpatient Clinic patients with any skin condition were examined, focusing on pruritus patients over 65. Pruritus was present in 36/262 patients (14%; M:F =20:16; mean age: 59.55 years). About 14% of 140 patients aged ≥65 years had pruritus, with 20/262 (8%; M:F =14:6; mean age: 74.6 years) exhibiting it. Visual analog score pruritus did not differ between patients aged ≥65 years (20/36) and <65 years (16/36) statistically. In 89% of patients, itch was related to a dermatological condition, mainly psoriasis. Only extracutaneous diseases resulted more frequently in the patients aged >65. No anamnestic link was found between drug use and pruritus in these patients. We confirm that pruritus is a common skin problem that affects both sexes, young and old, and is almost always caused by an underlying skin condition (mainly psoriasis). It is rarely caused by a new drug.

"Niclosamide: A potential antipruritic agent by modulating serotonin pathway through metabotropic glutamate receptors (mGluRs)".

Pruritus is an uncomfortable sensation induced by various pruritogens, including serotonin. Serotonin, acting as an inflammatory mediator, can activate a histamine-independent pathway. Consequently, many anti-pruritus medications, such as antihistamines, are not effective in adequately relieving patient symptoms. Niclosamide, an anthelmintic drug, has recently demonstrated an affinity for Metabotropic glutamate receptors (mGluRs). mGluRs are a group of receptors activated by glutamate, and they are involved in regulating neuronal excitability. In this study, we utilized mouse models of serotonergic itch and administered different doses of Niclosamide to examine the expression of mGluR1, mGluR5, and 5-HT2. The administration of 5 mg/kg Niclosamide successfully suppressed pruritus in the mice. Additionally, the levels of mGluR1, mGluR5, 5-HT2, and TRPV1 were significantly reduced. These findings suggest that Niclosamide holds promise as a potential antipruritic drug.

Mirogabalin inhibits scratching behavior of spontaneous model mouse of atopic dermatitis.

Introduction: Atopic dermatitis (AD) is one of the most prevalent intractable chronic itch diseases worldwide. In recent years, new molecular-targeted drugs have emerged, but side effects and economic challenges remain. Therefore, since it is important for AD patients to have a wider range of treatment options, it is important to explore new therapeutic agents. Gabapentinoids, gabapentin and pregabalin, have been shown to be effective for the clinical treatment of several chronic itch. Recently, mirogabalin (MGB) was developed as a novel gabapentinoid. MGB is a drug for neuropathic pain and has a margin of safety between its side effects and the analgesic effect for animal experiments. Herein, we showed that MGB exhibited an antipruritic effect in a mouse model of AD using NC/Nga mice. Methods and results: The oral administration of MGB (10 mg/kg) inhibited spontaneous scratching behavior in AD mice and its effect was dose dependently. Then, when MGB (10 mg/kg) was orally administrated to healthy mice, it did not affect motor function, including locomotor activity, wheel activity, and coordinated movement. Moreover, gabapentin (100 mg/kg) and pregabalin (30 mg/kg), inhibited spontaneous scratching behavior in AD mice and decreased motor function in healthy mice. Furthermore, intracisternal injection of MGB (10 µg/site) significantly suppressed spontaneous scratching behavior in AD mice. Discussion: In summary, our results suggest that MGB exerts an antipruritic effect via the spinal dorsal horn using NC/Nga mice. We hope that MGB is a candidate for a novel therapeutic agent for AD with relatively few side effects.

[Neuropathy in pruritus medicine : Recommended diagnostics and therapy]. / Neuropathie in der Pruritusmedizin : Empfohlene Diagnostik und Therapie.

Chronic itch is a frequent and debilitating condition that greatly affects the quality of life of those affected. In a subset of patients, damage to the peripheral or central nervous system constitutes the cause of the itch. Small-fiber neuropathy, nerve compression syndromes, post-herpetic neuralgia, scars and burns are possible conditions affecting the peripheral nervous system potentially causing itch, whereas space-occupying lesions affecting the spinal cord and stroke are examples of conditions that may induce central itch. Neuropathic itch starts on normal appearing skin, is often accompanied by pain sensations and other dysesthesias, and usually relieved by local cold application. Its distribution depends on the affected site of the somatosensory system. A comprehensive medical history is paramount to reach the diagnosis, while complementary diagnostics with skin biopsies for the investigation of cutaneous neuromorphological alterations or medical imaging to rule out nerve impingement may be advised in selected cases. Topical agents such as capsaicin or local anesthetics as well as systemic drugs such as gabapentinoids, antidepressants and opioid receptor modulators are used in the treatment of neuropathic itch. This review article provides an overview of the clinical features, underlying causes, diagnostic workup and therapeutic approach in neuropathic itch.

[Treatment of chronic prurigo: update and perspectives]. / Therapie der chronischen Prurigo: Update und Perspektive.

BACKGROUND: Despite the high burden in patients with chronic prurigo (CPG), the first and so far only approved systemic therapy for this disease, dupilumab, has only been available since 2022. Therefore, treatment is mostly based on expert recommendations for off-label therapies. We aim to provide an overview of current therapies and possible future therapeutic drugs for CPG patients, which are currently in clinical trials. MATERIALS AND METHODS: For this review, a systematic literature and clinical trial search was conducted via PubMed and Clinical Trials using the terms "chronic prurigo", "chronic nodular prurigo", "prurigo nodularis" and "therapy". CONCLUSION: Multiple new therapeutic agents are currently under investigation in clinical trials, providing promising results for future treatment options. Moreover, an annotated checklist was developed recently to improve therapeutic decision-making in daily clinical practice with CPG patients.

Exploring the interplay of atopic dermatitis severity with sleep and mental health: a case-control study in adult patients.

OBJECTIVES: Atopic dermatitis (AD) is a chronic inflammatory skin disease often associated with non-atopic comorbidities. Recently, a severity-dependent relationship between AD and sleep/mental health diseases has been proposed. However, few studies investigated these comorbidities and their association with AD severity through validated questionnaires. This study aimed to use a set of validated instruments to assess the impact of AD on sleep and psychological disorders and estimate the association of itch and AD severity with sleep disorders and psychological symptoms, distinguishing between clinical-oriented and patient-oriented measures. METHODS: We conducted a case-control study, recruiting 57 adult AD patients (mean age ± std. dev. 34.28 years ± 13.07; 27 males) matched for age and sex with 57 healthy adults (34.39 years ± 13.09; 27 males). To investigate the differences in sleep quality, insomnia, depression, and anxiety between the two groups, we performed independent sample t-Tests. Moreover, we conducted univariate linear regression analyses to examine the relationship between itch and objective/subjective severity of AD and sleep quality, insomnia, and psychological symptoms. RESULTS: AD patients reported lower sleep quality (p = 0.002), more severe insomnia (p = 0.006) and depression (p = 0.013), and higher stress levels than healthy adults (p = 0.049). Itch intensity was linked to sleep disturbances and psychological symptoms (R2range = 0.13-0.19, prange = 0.02-<0.001). Objective and subjective AD severity were similarly associated with worse sleep quality (R2 = 0.26, p < 0.001; R2 = 0.24, p < 0.001; respectively), anxiety (R2 = 0.15, p = 0.04; R2 = 0.17, p = 0.001; respectively), and self-perceived stress (R2 = 0.10, p = 0.02; R2 = 0.07, p = 0.049; respectively). However, subjective AD severity was more strongly associated with insomnia (R2 = 0.31, p < 0.001) and depression (R2 = 0.20, p < 0.001) than clinical-oriented AD severity (R2 = 0.19, p < 0.001; R2 = 0.05, p = 0.098; respectively). CONCLUSIONS: The study demonstrated poor sleep quality and high levels of insomnia, depression, and stress in AD patients, with an aggravated psychological status for adults with more severe skin disease. We suggest implementing a multidisciplinary approach to AD management/treatment that considers objective and subjective measures of disease severity.

[Recommended diagnostics for pruritus affecting primary non-lesional skin]. / Empfohlene Diagnostik bei Pruritus auf primär unveränderter Haut.

BACKGROUND: Chronic pruritus affecting primary non-lesional skin (CPNL) manifests as a common symptom across a spectrum of diseases spanning various medical specialties. Given the diverse etiological factors involved, diagnosing the underlying condition poses a significant challenge. OBJECTIVES: To provide a comprehensive overview of clinical, laboratory, and imaging diagnostics for CPNL. MATERIALS AND METHODS: A thorough literature search on the diagnostics of chronic pruritus was conducted using PubMed with specific keywords "chronic pruritus AND non-lesional skin", "chronic itch AND non-lesional skin", "chronic pruritus AND diagnostics", "chronic itch AND diagnostics", "CKD-aP", "hepatic pruritus", "cholestatic pruritus", and "myeloproliferative neoplasms AND pruritus". RESULTS: A systematic diagnostic approach is recommended for patients with CPNL, guided by the prevalence of pruritus-associated diseases. Initial basic diagnostics facilitate a cost-effective and focused evaluation during the initial medical assessment. Information pertaining to underlying diseases can be further refined through specialized diagnostic procedures. CONCLUSIONS: CPNL often presents a diagnostic dilemma. Adopting a stepwise diagnostic strategy facilitates the identification of underlying etiologies, which is crucial for recognizing diseases and administering pruritus-specific pharmacotherapy.

An updated reappraisal of dupilumab in children and adolescents with moderate-severe atopic dermatitis.

Atopic dermatitis (AD) is still a demanding challenge in clinical practice. Type 2 inflammation is the most common inflammatory pathway in children and adolescents with AD. Anti-inflammatory drugs, mainly corticosteroids (CS) and immunomodulant agents are the primary therapeutic approach to dampening type 2 inflammation. However, AD patients may require long-term high CS doses or drug combinations with possibly significant adverse effects to achieve and maintain disease control. In this regard, the advent of biologics constituted a breakthrough in managing this condition. Dupilumab is a monoclonal antibody directed against the IL-4 receptor α-subunit (IL-4Rα), antagonizing both IL-4 and IL-13 and is approved for pediatric severe AD. This review presents and discusses the most recent published studies on dupilumab in children and adolescents with AD. There is convincing evidence that dupilumab is safe and effective in managing AD. It can reduce skin lesions and associated itching, reduce the need for additional medications, and improve disease control and quality of life. However, a thorough diagnostic pathway is mandatory, especially considering the different AD phenotypes. The ideal eligible candidate is a child or adolescent with AD requiring systemic treatment because of severe clinical manifestations and impaired quality of life.

Targeting Intracranial Tumours with a Combination of RNA and Chemotherapy.

Glioblastoma multiforme (GBM) is a fast-growing and aggressive brain tumour, which remains largely resistant to treatment; the prognosis for patients is poor, with a median survival time of about 12-18 months, post diagnosis. In an effort to bring more efficacious treatments to patients, we targeted the down regulation of ITCH, an E3 ligase that is overexpressed in a variety of cancers, and which inhibits P73, a tumour suppressor gene. 6-O-glycolchitosan (GC) was used to deliver siRNA ITCH (GC60-siRNA-ITCH) and gemcitabine via the nose to brain route in CD-1 nude mice which had previously been implanted intracranially with U87-MG-luc2 cells. Prior to this in vivo study, an in vitro study established the synergistic effect of siRNA-ITCH in combination with a chemotherapy drug-gemcitabine. A downregulation of ITCH, an upregulation of p73 and enhanced apoptosis were observed in vitro in U87-MG cells, using qPCR, Western blot analysis, confocal laser scanning microscopy, flow cytometry and cytotoxicity assays. When GC60-siRNA-ITCH was combined with gemcitabine, there was a resultant decrease in cell proliferation in vitro. In CD1 mice, the administration of siRNA-ITCH (7 doses of 0.081 mg/kg) alone did not significantly affect animal survival (increasing mean survival from 29 to 33 days when compared to untreated animals), whereas intranasal gemcitabine had a significant effect on survival (increasing survival from 29 to 45 days when compared to untreated animals, p < 0.01). The most significant effect was seen with combination therapy (GC60-siRNA-ITCH plus gemcitabine), where survival increased by 89%, increasing from 29 to 54 days (p < 0.01). Our data demonstrate that siRNA chemosensitises brain tumours to gemcitabine and that the nose-to-brain delivery route may be a viable route for the treatment of intracranial tumours.

An updated patent review of TRPA1 antagonists (2020 - present).

INTRODUCTION: TRPA1 is a nonselective calcium channel, a member of the transient receptor potential (TRP) superfamily, also referred to as the 'irritant' receptor, being activated by pungent and noxious exogenous chemicals as well as by endogenous algogenic stimuli, to elicit pain, itching, and inflammatory conditions. For this reason, it is considered an attractive therapeutic target to treat a wide range of diseases including acute and chronic pain, itching, and inflammatory airway diseases. AREAS COVERED: The present review covers patents on TRPA1 antagonists disclosed from 2020 to present, falling in the following main classes: i) novel therapeutic applications for known or already disclosed antagonists, ii) identification and characterization of TRPA1 antagonists from natural sources, and iii) synthesis and evaluation of novel compounds. EXPERT OPINION: Despite the limited number of TRPA1 antagonists in clinical trials, there is an ever-growing interest on this receptor-channel as therapeutic target, mainly due to the relevant outcomes from basic research, which unveiled novel physio-pathological mechanisms where TRPA1 is believed to play a pivotal role, for example the Alzheimer's disease or ocular diseases, expanding the panel of potential therapeutic applications for TRPA1 modulators.

LEKTI domain 6 displays anti-inflammatory action in vitro and in a murine atopic dermatitis model.

BACKGROUND: Lympho-epithelial Kazal-type-related inhibitor (LEKTI) is a serine protease inhibitor consisting of multiple domains. A loss of function mutation is described in Netherton patients that show severe symptoms of atopic lesions and itch. OBJECTIVES: LEKTI domain 6 (LD6) has shown strong serine protease-inhibitory action in in vitro assays and thus it was tested in vitro and in vivo for potential anti-inflammatory action in models of atopic skin disease. METHODS: Human skin equivalents were treated with LD6 and an inflammatory reaction was challenged by kallikrein-related endopeptidase 5 (KLK5). Furthermore, LD6 was tested on dorsal root ganglia cells stimulated with KLK5, SLIGRL and histamine by calcium imaging. The effect of topically administered LD6 (0.4-0.8%) in lipoderm was compared to a topical formulation of betamethasone-diproprionate (0.1%) in a therapeutic setting on atopic dermatitis-like lesions in NC/Nga mice sensitized to house dust mite antigen. Endpoints were clinical scoring of the mice as well as determination of scratching behaviour. RESULTS: KLK5 induced an upregulation of CXCL-8, CCL20 and IL-6 in skin equivalents. This upregulation was reduced by pre-incubation with LD6. KLK5 as well as histamine induced calcium influx in a population of neurons. LD6 significantly reduced the calcium response to both stimuli. When administered onto lesional skin of NC/Nga mice, both LD6 and betamethasone-dipropionate significantly reduced the inflammatory reaction. The effect on itch behaviour was less pronounced. CONCLUSION: Topical administration of LD6 might be a new therapeutic option for treatment of lesional atopic skin.

[Quality of life and sleep quality in patients with chronic pruritus]. / Lebens- und Schlafqualität bei Patienten mit chronischem Pruritus.

Pruritus is defined as a symptom that leads to scratching. Clinically, a heterogeneous group of clinical pictures of different etiology must be considered. Pruritus is characterized by varying intensity and duration. Many patients and/or their social environment, which is influenced by this, cite the impact on sleep quality as an accompanying main symptom. The patient's quality of life is affected depending on the severity of the pruritus and often leads to comorbidity such as depressive disorders or sleep disorders as well as to an impact on psychosocial well-being if it becomes chronic. To date, in addition to the medical history, the established examination methods have been the determination of the disease burden by assessing disease activity, e.g., with validated disease-specific scores, plus the assessment of quality of life using a dermatological quality of life index (DLQI). The latest studies show that this is by no means sufficient to determine the severity of disease and, as a result, to identify adequate treatment options.

The fungal secretory peptide micasin induces itch by activating MRGPRX1/C11/A1 on peripheral neurons.

Pruritus is the leading symptom of dermatophytosis. Microsporium canis is one of the predominant dermatophytes causing dermatophytosis. However, the pruritogenic agents and the related molecular mechanisms of the dermatophyte M. canis remain poorly understood. Here, the secretion of the dermatophyte M. canis was found to dose-dependently evoke itch in mice. The fungal peptide micasin secreted from M. canis was then identified to elicit mouse significant scratching and itching responses. The peptide micasin was further revealed to directly activate mouse dorsal root ganglia (DRG) neurons to mediate the non-histaminergic itch. Knockout and antagonistic experiments demonstrated that MRGPRX1/C11/A1 rather than MRGPRX2/b2 activated by micasin contributed to pruritus. The chimera and mutation of MRGPRX1 showed that three domains (ECL3, TMH3 and TMH6) and four hydrophobic residues (Y99, F237, L240 and W241) of MRGPRX1 played the key role in micasin-triggered MRGPRX1 activation. Our study sheds light on the dermatophytosis-associated pruritus and may provide potential therapeutic targets and strategies against pruritus caused by dermatophytes.