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The resolution of inflammation is a biosynthetically active process controlled by the interplay between oxygenated polyunsaturated mediators and G-protein coupled receptor-signaling pathways. These enzymatically oxygenated polyunsaturated fatty acids belong to distinct families of specialized pro-resolving autacoids. The protectin family of mediators has attracted an interest because of their potent pro-resolving and anti-inflammatory actions verified in several in vivo disease models. Herein, we present the stereoselective synthesis and biological evaluations of 3-oxa-PD1n-3 DPA, a protectin D1 analog. Results from mouse models indicate that the mediators protectin D1, PD1n-3 DPA and the new analog 3-oxa-PD1n-3 DPA all relieved streptozotocin-induced diabetic neuropathic pain at doses of 90 and 300 pmol, equivalent to 30 and 100 ng, respectively, following intrathecal (I.T.) injection. Of interest, at a low dose of only 30 pmol (10 ng; I.T.) only 3-oxa PD1n-3 DPA was able to alleviate neuropathic pain, directly compared to vehicle controls. Moreover, using a chronic itch model of cutaneous T-cell lymphoma (CTCL), all three compounds at 300 pmol (100 ng) showed a significant reduction in itching for several hours. The biomolecular information on the structure-functions of the protectins and the new synthetic analog 3-oxa-PD1n-3 DPA is of interest towards developing new immunoresolvents.
Learn More >Pruritus, commonly known as itch, is a very common symptom in numerous dermatological disorders and systemic diseases. It can manifest as acute, or when lasting longer than 6 weeks, it is considered chronic and can lead to significant distress and reduced quality-of-life of those suffering. Current therapeutics are limited and are lacking in efficacy, and the development of more effective treatments is needed. The neurokinin 1 receptor (NK1R) antagonists are a novel class of drugs that possess several properties such as antidepressant, anxiolytic and antiemetic activities. Recently, several studies have described the antipruritic activity of NK1R antagonists for treating chronic pruritus. In this review we outline the pathogenesis of chronic pruritus, the mechanism by which the neuropeptide substance P (SP) and its receptor NK1R may be targeted to inhibit pruritic activity, and the efficacy and tolerability of NK1R antagonists, which have been, or are currently being investigated for treating conditions where chronic pruritus is a major symptom. Increasing evidence from ongoing and completed studies demonstrates the importance of SP and NK1R signalling in mediating pruritic activity. Several NK1R antagonists have shown significant antipruritic activity and thus targeting the SP-NK1R pathway may provide a therapeutic option for treating chronic pruritus of certain origin/s in the foreseeable future.
Learn More >Patients with atopic dermatitis experience increased nocturnal pruritus which leads to scratching and sleep disturbances that significantly contribute to poor quality of life. Objective measurements of nighttime scratching and sleep quantity can help assess the efficacy of an intervention. Wearable sensors can provide novel, objective measures of nighttime scratching and sleep; however, many current approaches were not designed for passive, unsupervised monitoring during daily life. In this work, we present the development and analytical validation of a method that sequentially processes epochs of sample-level accelerometer data from a wrist-worn device to provide continuous digital measures of nighttime scratching and sleep quantity. This approach uses heuristic and machine learning algorithms in a hierarchical paradigm by first determining when the patient intends to sleep, then detecting sleep-wake states along with scratching episodes, and lastly deriving objective measures of both sleep and scratch. Leveraging reference data collected in a sleep laboratory (NCT ID: NCT03490877), results show that sensor-derived measures of total sleep opportunity (TSO; time when patient intends to sleep) and total sleep time (TST) correlate well with reference polysomnography data (TSO: r = 0.72, p < 0.001; TST: r = 0.76, p < 0.001; N = 32). Log transformed sensor derived measures of total scratching duration achieve strong agreement with reference annotated video recordings (r = 0.82, p < 0.001; N = 25). These results support the use of wearable sensors for objective, continuous measurement of nighttime scratching and sleep during daily life.
Learn More >We have recently reported that the Cav3.2 T-type calcium channel which is well known for its key role in pain signalling, also mediates a critical function in the transmission of itch/pruritus. Here, we evaluated the effect of the clinically used anti-seizure medication ethosuximide, a well known inhibitor of T-type calcium channels, on male and female mice subjected to histaminergic- and non-histaminergic itch. When delivered intraperitoneally ethosuximide significantly reduced scratching behavior of mice of both sexes in response to subcutaneous injection of either histamine or chloroquine. When co-delivered subcutaneously together with either pruritogenic agent ethosuximide was also effective in inhibiting scratching responses in both male and female animals. Overall, our results are consistent with an important role of Cav3.2 T-type calcium channels in modulating histamine-dependent and histamine-independent itch transmission in the primary sensory pathway. Our findings also suggest that ethosuximide could be explored further as a possible therapeutic for the treatment of itch.
Learn More >The cytokine interleukin-31 has been implicated in the pathophysiology of multiple atopic disorderssuch asatopic dermatitis (AD), allergic rhinitisand airway hyperreactivity. In AD, IL-31 has been identified as one of the main 'drivers'of its cardinal symptom,pruritus. Here, we summarize the mechanisms by which IL-31 modulates inflammatory and allergic diseases. T 2 cells play a central role in AD and release high levels ofT 2-associated cytokines including IL-31,thereby mediating inflammatory responses, initiating immunoregulatory circuits, stimulating itch and neuronal outgrowth through activation ofthe heterodimeric receptor IL-31 receptor alpha (IL31RA)/Oncostatin M receptor (OSMRβ). IL31RA expression is found onhumanand murine dorsal root ganglia neurons, epithelial cells including keratinocytes as well asvarious innate immune cells. IL-31 is a critical cytokine involved in neuro-immune communication,which opens new avenues for cytokine modulation in neuroinflammatory diseases including AD/pruritus, as validated by recent clinical trials using an anti-IL-31 antibody. Accordingly, inhibition of IL-31-downstream signalingmay be a beneficial approach for various inflammatory diseases including prurigo.However, as to whether downstream JAK inhibitors directly block IL-31-mediated-signaling needs to be clarified. Targeting the IL-31/IL31RA/OSMRβ axis appears to be a promising approach for inflammatory, neuroinflammatory and pruritic disorders in the future.
Learn More >Pruritus is a common symptom of inflammatory skin conditions, including atopic dermatitis (AD). Although primary sensory neurons that transmit pruritic signals are well-cataloged, little is known about the neuronal alterations that occur as a result of skin disruption in AD. To address this question, we examined the molecular and behavioral consequences of challenging mice, which overexpress PAR2 in suprabasal keratinocytes, with serial topical application of the environmental allergen house dust mite (HDM). We monitored behavior and used RNA sequencing, qPCR, and in situ hybridization to evaluate gene expression in trigeminal ganglia (TG), before and after HDM. We found that neither nor wild-type (WT) mice exhibited spontaneous scratching, and pruritogen-induced acute scratching did not differ. In contrast, HDM exacerbated scratching in mice. Despite the absence of scratching in untreated mice, several TG genes in these mice were up-regulated compared to WT. HDM treatment of the mice enhanced up-regulation of this set of genes and induced additional genes, many within the subset of TG neurons that express TRPV1. The same set of genes was up-regulated in HDM-treated mice that did not scratch, but at lesser magnitude. Finally, we recorded comparable transcriptional changes in IL31Tg mice, demonstrating that a common genetic program is induced in two AD models. Taken together, we conclude that transcriptional changes that occur in primary sensory neurons in dermatitis-susceptible animals underlie a genetic priming that not only sensitizes the animal to chronic allergens but also contributes to pruritus in atopic skin disease.
Learn More >Mas gene-related G protein-coupled receptors (MRGPRs) are a GPCR family responsive to various exogenous and endogenous agonists, playing a fundamental role in pain and itch sensation. The primate-specific family member MRGPRX2 and its murine orthologue MRGPRB2 are expressed by mast cells, mediating IgE-independent signaling and pseudo-allergic drug reactions.
Learn More >Symptoms that resemble allergic reactions, such as pruritus, flushing, and hypotension, are common side effects of therapeutic drugs. In a true allergic reaction, Immunoglobulin E (IgE) antibodies recognize the drug and trigger mediator release from mast cells through cross-linking of IgE receptors. However, many drugs can bypass this pathway and can activate mast cells directly through MRGPRX2, a G protein-coupled receptor that responds to a wide range of small molecules, peptides, and proteins that have little in common except for a net positive charge. This review will provide an overview of MRGPRX2, including its expression pattern, studies of its pharmacology, and its orthologs. It also will review evidence for MRGPRX2 activation by many drugs closely associated with these reactions.
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