Targeting TRP Channels: from Drug Development to Clinical Trials

A special issue of Medical Sciences (ISSN 2076-3271).

Deadline for manuscript submissions: closed (30 April 2019) | Viewed by 18095

Special Issue Editor

Department of Pathology and Experimental Cancer Research, Semmelweis University, 1085 Budapest, Hungary
Interests: the capsaicin receptor TRPV1; small molecule TRP inhibitors; TRP channels and cancer; neurogenic inflammation and cancer; cancer pain
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Special Issue Information

Dear Colleagues,

With over 300 reviews during the past 5 years, Transient Receptor Potential (TRP) channels are among the most discussed therapeutic targets, covering areas from the clinically relevant (such as pain and inflammation) to the more obscure (like sperm quality and antischistosomal activity). Indeed, the vanilloid (capsaicin) receptor TRPV1 alone, the founding member of the TRP family, has been subject to 2300 papers since 2013. So, why add to this growing mountain of literature? The main reason is the extremely rapid change in this field. For example, TRPV1 antagonists were ushered into clinical trials with record speed within ten years of the cloning of TRPV1, where most flamed out due to a combination of unforeseen side-effects, like hyperthermia and compromised heat pain sensation. However, new-generation TRPV1 antagonists that do not perceptibly change body temperature are already making a comeback, not only as potential analgesic drugs, but also for indications like diabetes.

In 2016, Pharmaceuticals, a sister journal of Medical Sciences, published a well-received, but admittedly incomplete collection of reviews on TRP channels as therapeutic targets (“old thoughts, new concepts”), which is now also available as an eBook. We wish to follow this up with a more clinically oriented collection of review and research articles on TRP channels.

We look forward to your contributions.

Dr. Arpad Szallasi
Guest Editor

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Keywords

  • Transient receptor potential channels
  • TRPs
  • drugs
  • therapeutic target
  • pain
  • inflammation
  • TRVP1
  • new generation TRVP1 antagonists

Published Papers (5 papers)

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Research

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14 pages, 919 KiB  
Article
TRPV1 Antagonists as Novel Anti-Diabetic Agents: Regulation of Oral Glucose Tolerance and Insulin Secretion Through Reduction of Low-Grade Inflammation?
Med. Sci. 2019, 7(8), 82; https://doi.org/10.3390/medsci7080082 - 24 Jul 2019
Cited by 13 | Viewed by 4190
Abstract
With a global prevalence among adults over 18 years of age approaching 9%, Type 2 diabetes mellitus (T2DM) has reached pandemic proportions and represents a major unmet medical need. To date, no disease modifying treatment is available for T2DM patients. Accumulating evidence suggest [...] Read more.
With a global prevalence among adults over 18 years of age approaching 9%, Type 2 diabetes mellitus (T2DM) has reached pandemic proportions and represents a major unmet medical need. To date, no disease modifying treatment is available for T2DM patients. Accumulating evidence suggest that the sensory nervous system is involved in the progression of T2DM by maintaining low-grade inflammation via the vanilloid (capsaicin) receptor, Transient Receptor Potential Vanilloid-1 (TRPV1). In this study, we tested the hypothesis that TRPV1 is directly involved in glucose homeostasis in rodents. TRPV1 receptor knockout mice (Trpv1−/−) and their wild-type littermates were kept on high-fat diet for 15 weeks. Moreover, Zucker obese rats were given the small molecule TRPV1 antagonist, N-(4-Tertiarybutylphenyl)-4-(3-cholorphyridin-2-yl)tetrahydropyrazine-1(2H)-carbox-amide (BCTC), per os twice-a-day or vehicle for eight days. Oral glucose tolerance and glucose-stimulated insulin secretion was improved by both genetic inactivation (Trpv1−/− mice) and pharmacological blockade (BCTC) of TRPV1. In the obese rat, the improved glucose tolerance was accompanied by a reduction in inflammatory markers in the mesenteric fat, suggesting that blockade of low-grade inflammation contributes to the positive effect of TRPV1 antagonism on glucose metabolism. We propose that TRPV1 could be a promising therapeutic target in T2DM by improving glucose intolerance and correcting dysfunctional insulin secretion. Full article
(This article belongs to the Special Issue Targeting TRP Channels: from Drug Development to Clinical Trials)
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8 pages, 1486 KiB  
Article
TRPA1 Channel is Involved in SLIGRL-Evoked Thermal and Mechanical Hyperalgesia in Mice
Med. Sci. 2019, 7(4), 62; https://doi.org/10.3390/medsci7040062 - 18 Apr 2019
Cited by 6 | Viewed by 2825
Abstract
Persistent itch (pruritus) accompanying dermatologic and systemic diseases can significantly impair the quality of life. It is well known that itch is broadly categorized as histaminergic (sensitive to antihistamine medications) or non-histaminergic. Sensory neurons expressing Mas-related G-protein-coupled receptors (Mrgprs) mediate histamine-independent itch. These [...] Read more.
Persistent itch (pruritus) accompanying dermatologic and systemic diseases can significantly impair the quality of life. It is well known that itch is broadly categorized as histaminergic (sensitive to antihistamine medications) or non-histaminergic. Sensory neurons expressing Mas-related G-protein-coupled receptors (Mrgprs) mediate histamine-independent itch. These receptors have been shown to bind selective pruritogens in the periphery and mediate non-histaminergic itch. For example, mouse MrgprA3 responds to chloroquine (an anti-malarial drug), and are responsible for relaying chloroquine-induced scratching in mice. Mouse MrgprC11 responds to a different subset of pruritogens including bovine adrenal medulla peptide (BAM8–22) and the peptide Ser-Leu-Ile-Gly-Arg-Leu (SLIGRL). On the other hand, the possibility that itch mediators also influence pain is supported by recent findings that most non-histaminergic itch mediators require the transient receptor potential ankyrin 1 (TRPA1) channel. We have recently found a significant increase of thermal and mechanical hyperalgesia induced by non-histaminergic pruritogens chloroquine and BAM8–22, injected into mice hindpaw, for the first 30–45 min. Pretreatment with TRPA1 channel antagonist HC-030031 did significantly reduce the magnitude of this hyperalgesia, as well as significantly shortened the time-course of hyperalgesia induced by chloroquine and BAM8–22. Here, we report that MrgprC11-mediated itch by their agonist SLIGRL is accompanied by heat and mechanical hyperalgesia via the TRPA1 channel. We measured nociceptive thermal paw withdrawal latencies and mechanical thresholds bilaterally in mice at various time points following intra-plantar injection of SLIGRL producing hyperalgesia. When pretreated with the TRPA1 antagonist HC-030031, we found a significant reduction of thermal and mechanical hyperalgesia. Full article
(This article belongs to the Special Issue Targeting TRP Channels: from Drug Development to Clinical Trials)
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Review

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23 pages, 369 KiB  
Review
Transient Receptor Potential Cation Channels in Cancer Therapy
Med. Sci. 2019, 7(12), 108; https://doi.org/10.3390/medsci7120108 - 30 Nov 2019
Cited by 27 | Viewed by 3514
Abstract
In mammals, the transient receptor potential (TRP) channels family consists of six different families, namely TRPC (canonical), TRPV (vanilloid), TRPM (melastatin), TRPML (mucolipin), TRPP (polycystin), and TRPA (ankyrin), that are strictly connected with cancer cell proliferation, differentiation, cell death, angiogenesis, migration, and invasion. [...] Read more.
In mammals, the transient receptor potential (TRP) channels family consists of six different families, namely TRPC (canonical), TRPV (vanilloid), TRPM (melastatin), TRPML (mucolipin), TRPP (polycystin), and TRPA (ankyrin), that are strictly connected with cancer cell proliferation, differentiation, cell death, angiogenesis, migration, and invasion. Changes in TRP channels’ expression and function have been found to regulate cell proliferation and resistance or sensitivity of cancer cells to apoptotic-induced cell death, resulting in cancer-promoting effects or resistance to chemotherapy treatments. This review summarizes the data reported so far on the effect of targeting TRP channels in different types of cancer by using multiple TRP-specific agonists, antagonists alone, or in combination with classic chemotherapeutic agents, microRNA specifically targeting the TRP channels, and so forth, and the in vitro and in vivo feasibility evaluated in experimental models and in cancer patients. Considerable efforts have been made to fight cancer cells, and therapies targeting TRP channels seem to be the most promising strategy. However, more in-depth investigations are required to completely understand the role of TRP channels in cancer in order to design new, more specific, and valuable pharmacological tools. Full article
(This article belongs to the Special Issue Targeting TRP Channels: from Drug Development to Clinical Trials)
12 pages, 242 KiB  
Review
Non-Analgesic Symptomatic or Disease—Modifying Potential of TRPA1
Med. Sci. 2019, 7(10), 99; https://doi.org/10.3390/medsci7100099 - 23 Sep 2019
Cited by 9 | Viewed by 3303
Abstract
TRPA1, a versatile ion channel of the Transient Receptor Potential (TRP) channel family, detects a large variety of chemicals and can contribute to signal processing of other stimuli, e.g., due to its sensitivity to cytosolic calcium elevation or phosphoinositolphosphate modulation. At first, TRPA1 [...] Read more.
TRPA1, a versatile ion channel of the Transient Receptor Potential (TRP) channel family, detects a large variety of chemicals and can contribute to signal processing of other stimuli, e.g., due to its sensitivity to cytosolic calcium elevation or phosphoinositolphosphate modulation. At first, TRPA1 was found on sensory neurons, where it can act as a sensor for potential or actual tissue damage that ultimately may elicit pain or itch as warning symptoms. This review provides an update regarding the analgesic and antipruritic potential of TRPA1 modulation and the respective clinical trials. Furthermore, TRPA1 has been found in an increasing amount of other cell types. Therefore, the main focus of the review is to discuss the non-analgesic and particularly the disease-modifying potential of TRPA1. This includes diseases of the respiratory system, cancer, ischemia, allergy, diabetes, and the gastrointestinal system. The involvement of TRPA1 in the respective pathophysiological cascades is so far mainly based on pre-clinical data. Full article
(This article belongs to the Special Issue Targeting TRP Channels: from Drug Development to Clinical Trials)
15 pages, 258 KiB  
Review
TRP Channels as Lower Urinary Tract Sensory Targets
Med. Sci. 2019, 7(5), 67; https://doi.org/10.3390/medsci7050067 - 22 May 2019
Cited by 27 | Viewed by 3520
Abstract
Several members of the transient receptor potential (TRP) superfamily, including TRPV1, TRPV2, TRPV4, TRM4, TRPM8 and TRPA1, are expressed in the lower urinary tract (LUT), not only in neuronal fibers innervating the bladder and urethra, but also in the urothelial and muscular layers [...] Read more.
Several members of the transient receptor potential (TRP) superfamily, including TRPV1, TRPV2, TRPV4, TRM4, TRPM8 and TRPA1, are expressed in the lower urinary tract (LUT), not only in neuronal fibers innervating the bladder and urethra, but also in the urothelial and muscular layers of the bladder and urethral walls. In the LUT, TRP channels are mainly involved in nociception and mechanosensory transduction. Animal studies have suggested the therapeutic potential of several TRP channels for the treatment of both bladder over- and underactivity and bladder pain disorders,; however translation of this finding to clinical application has been slow and the involvement of these channels in normal human bladder function, and in various pathologic states have not been established. The development of selective TRP channel agonists and antagonists is ongoing and the use of such agents can be expected to offer new and important information concerning both normal physiological functions and possible therapeutic applications. Full article
(This article belongs to the Special Issue Targeting TRP Channels: from Drug Development to Clinical Trials)
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