British Journal of Pharmacology最新文献

{"title":"Insulin-degrading enzyme inhibition increases the unfolded protein response and favours lipid accumulation in the liver","authors":"Marine Andres,&nbsp;Nathalie Hennuyer,&nbsp;Khamis Zibar,&nbsp;Marie Bicharel-Leconte,&nbsp;Isabelle Duplan,&nbsp;Emmanuelle Enée,&nbsp;Emmanuelle Vallez,&nbsp;Adrien Herledan,&nbsp;Anne Loyens,&nbsp;Bart Staels,&nbsp;Benoit Deprez,&nbsp;Peter van Endert,&nbsp;Rebecca Deprez-Poulain,&nbsp;Steve Lancel","doi":"10.1111/bph.16436","DOIUrl":"10.1111/bph.16436","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Nonalcoholic fatty liver disease refers to liver pathologies, ranging from steatosis to steatohepatitis, with fibrosis ultimately leading to cirrhosis and hepatocellular carcinoma. Although several mechanisms have been suggested, including insulin resistance, oxidative stress, and inflammation, its pathophysiology remains imperfectly understood. Over the last decade, a dysfunctional unfolded protein response (UPR) triggered by endoplasmic reticulum (ER) stress emerged as one of the multiple driving factors. In parallel, growing evidence suggests that insulin-degrading enzyme (IDE), a highly conserved and ubiquitously expressed metallo-endopeptidase originally discovered for its role in insulin decay, may regulate ER stress and UPR.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>We investigated, by genetic and pharmacological approaches, in vitro and in vivo, whether IDE modulates ER stress-induced UPR and lipid accumulation in the liver.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>We found that IDE-deficient mice display higher hepatic triglyceride content along with higher inositol-requiring enzyme 1 (IRE1) pathway activation. Upon induction of ER stress by tunicamycin or palmitate in vitro or in vivo, pharmacological inhibition of IDE, using its inhibitor BDM44768, mainly exacerbated ER stress-induced IRE1 activation and promoted lipid accumulation in hepatocytes, effects that were abolished by the IRE1 inhibitors 4μ8c and KIRA6. Finally, we identified that IDE knockout promotes lipolysis in adipose tissue and increases hepatic CD36 expression, which may contribute to steatosis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion and Implications</h3>\u0000 \u0000 <p>These results unravel a novel role for IDE in the regulation of ER stress and development of hepatic steatosis. These findings pave the way to innovative strategies modulating IDE to treat metabolic diseases.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141174512","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to ‘Sphingosine-1-phosphate/TGF-β axis drives epithelial mesenchymal transition in asthma-like disease’","authors":"","doi":"10.1111/bph.16430","DOIUrl":"10.1111/bph.16430","url":null,"abstract":"<p>\u0000 <span>Riemma, M. A.</span>, <span>Cerqua, I.</span>, <span>Romano, B.</span>, <span>Irollo, E.</span>, <span>Bertolino, A.</span>, <span>Camerlingo, R.</span>, <span>Granato, E.</span>, <span>Rea, G.</span>, <span>Scala, S.</span>, <span>Terlizzi, M.</span>, <span>Spaziano, G.</span>, <span>Sorrentino, R.</span>, <span>D'Agostino, B.</span>, <span>Roviezzo, F.</span>, &amp; <span>Cirino, G.</span> (<span>2022</span>). <span>Sphingosine-1-phosphate/TGF-β axis drives epithelial mesenchymal transition in asthma-like disease</span>. <i>British Journal of Pharmacology</i>, <span>179</span>(<span>8</span>), <span>1753</span>–<span>1768</span>. https://doi.org/10.1111/bph.15754</p><p>Due to a mixup during the figure presentation phase while drafting, the article Figure 1G (a micrograph image depicting A549 cells exposed to S1P) was erroneously uploaded, and the original image in Figure 1g was published in another article by mistake.</p><p>In Figure 4a, the reported image of vehicle (saline plus BSA 0.001%) was erroneously the same of that reported in Figure 8e (saline). Although the experimental conditions were different, there was no difference between the two vehicle groups in fibroblast activation. We have replaced the panel with the right one.</p><p>Figure 6d originally showed two serial sections of the same tissue region in the vehicle. A different representative vehicle image has been chosen, and scale bars have been added. The image was integrated by reporting the scale bar as per the instrument (microscope).</p><p>We apologize for this error.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.16430","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141157515","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of LRP5/6/GSK-3β/β-catenin in the differences in exenatide- and insulin-promoted T2D osteogenesis and osteomodulation","authors":"Zijun Chen,&nbsp;Yuxi Wang,&nbsp;Guanhua Zhang,&nbsp;Jian Zheng,&nbsp;Lei Tian,&nbsp;Yingliang Song,&nbsp;Xiangdong Liu","doi":"10.1111/bph.16421","DOIUrl":"10.1111/bph.16421","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Insulin and exenatide are two hypoglycaemic agents that exhibit different osteogenic effects. This study compared the differences between exenatide and insulin in osseointegration in a rat model of Type 2 diabetes (T2D) and explored the mechanisms promoting osteogenesis in this model of T2D.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>In vivo, micro-CT was used to detect differences in the peri-implant bone microstructure in vivo. Histology, dual-fluorescent labelling, immunofluorescence and immunohistochemistry were used to detect differences in tissue, cell and protein expression around the implants. In vitro, RT-PCR and western blotting were used to measure the expression of osteogenesis- and Wnt signalling-related genes and proteins in bone marrow mesenchymal stromal cells (BMSCs) from rats with T2D (TBMSCs) after PBS, insulin and exenatide treatment. RT-PCR was used to detect the expression of Wnt bypass cascade reactions under Wnt inactivation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>Micro-CT and section staining showed exenatide extensively promoted peri-implant osseointegration. Both in vivo and in vitro experiments showed exenatide substantially increased the expression of osteogenesis-related and activated the LRP5/6/GSK-3β/β-catenin-related Wnt pathway. Furthermore, exenatide suppressed expression of <i>Bmpr1a</i> to inhibit lipogenesis and promoted expression of <i>Btrc</i> to suppress inflammation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion and Implications</h3>\u0000 \u0000 <p>Compared to insulin, exenatide significantly improved osteogenesis in T2D rats and TBMSCs. In addition to its dependence on LRP5/6/GSK-3β/β-catenin signalling for osteogenic differentiation, exenatide-mediated osteomodulation also involves inhibition of inflammation and adipogenesis by BMPR1A and β-TrCP, respectively.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141157519","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The TREK-1 potassium channel is a potential pharmacological target for vasorelaxation in pulmonary hypertension","authors":"Réka Csáki,&nbsp;Chandran Nagaraj,&nbsp;János Almássy,&nbsp;Mohammad Ali Khozeimeh,&nbsp;Dusan Jeremic,&nbsp;Horst Olschewski,&nbsp;Alice Dobolyi,&nbsp;Konrad Hoetzenecker,&nbsp;Andrea Olschewski,&nbsp;Péter Enyedi,&nbsp;Miklós Lengyel","doi":"10.1111/bph.16426","DOIUrl":"10.1111/bph.16426","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and purpose</h3>\u0000 \u0000 <p>Pulmonary arterial hypertension (PAH) is a progressive disease in which chronic membrane potential (E_m) depolarisation of the pulmonary arterial smooth muscle cells (PASMCs) causes calcium overload, a key pathological alteration. Under resting conditions, the negative E_m is mainly set by two pore domain potassium (K_2P) channels, of which the TASK-1 has been extensively investigated.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>Ion channel currents and membrane potential of primary cultured human(h) PASMCs were measured using the voltage- and current clamp methods. Intracellular [Ca²⁺] was monitored using fluorescent microscopy. Pulmonary BP and vascular tone measurements were also performed <i>ex vivo</i> using a rat PAH model.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>TREK-1 was the most abundantly expressed K_2P in hPASMCs of healthy donors and idiopathic(I) PAH patients. Background K⁺-current was similar in hPASMCs for both groups and significantly enhanced by the TREK activator ML-335. In donor hPASMCs, siRNA silencing or pharmacological inhibition of TREK-1 caused depolarisation, reminiscent of the electrophysiological phenotype of idiopathic PAH. ML-335 hyperpolarised donor hPASMCs and normalised the E_m of IPAH hPASMCs. A close link was found between TREK-1 activity and intracellular Ca²⁺-signalling using a channel activator, ML-335, and an inhibitor, spadin. In the rat, ML-335 relaxed isolated pre-constricted pulmonary arteries and significantly decreased pulmonary arterial pressure in the isolated perfused lung.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions and Implications</h3>\u0000 \u0000 <p>These data suggest that TREK-1is a key factor in E_m setting and Ca²⁺ homeostasis of hPASMC, and therefore, essential for maintenance of a low resting pulmonary vascular tone. Thus TREK-1 may represent a new therapeutic target for PAH.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.16426","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141160749","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single nucleotide polymorphisms in the cannabinoid CB2 receptor: Molecular pharmacology and disease associations","authors":"Tahira Foyzun,&nbsp;Maddie Whiting,&nbsp;Kate K. Velasco,&nbsp;Jessie C. Jacobsen,&nbsp;Mark Connor,&nbsp;Natasha L. Grimsey","doi":"10.1111/bph.16383","DOIUrl":"10.1111/bph.16383","url":null,"abstract":"<p>Preclinical evidence implicating cannabinoid receptor 2 (CB₂) in various diseases has led researchers to question whether CB₂ genetics influence aetiology or progression. Associations between conditions and genetic loci are often studied via single nucleotide polymorphism (SNP) prevalence in case versus control populations. In the <i>CNR2</i> coding exon, ~36 SNPs have high overall population prevalence (minor allele frequencies [MAF] ~37%), including non-synonymous SNP (ns-SNP) rs2501432 encoding CB₂ 63Q/R. Interspersed are ~27 lower frequency SNPs, four being ns-SNPs. <i>CNR2</i> introns also harbour numerous SNPs. This review summarises CB₂ ns-SNP molecular pharmacology and evaluates evidence from ~70 studies investigating CB₂ genetic variants with proposed linkage to disease. Although <i>CNR2</i> genetic variation has been associated with a wide variety of conditions, including osteoporosis, immune-related disorders, and mental illnesses, further work is required to robustly validate <i>CNR2</i> disease links and clarify specific mechanisms linking <i>CNR2</i> genetic variation to disease pathophysiology and potential drug responses.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.16383","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141157522","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Non-coding RNAs and their potential exploitation in cancer therapy-related cardiotoxicity.","authors":"Riccardo Bernasconi, Gabriela M Kuster","doi":"10.1111/bph.16416","DOIUrl":"https://doi.org/10.1111/bph.16416","url":null,"abstract":"<p><p>Life expectancy in cancer patients has been extended in recent years, thanks to major breakthroughs in therapeutic developments. However, this also unmasked an increased incidence of cardiovascular diseases in cancer survivors, which is in part attributable to cancer therapy-related cardiovascular toxicity. Non-coding RNAs (ncRNAs) have received much appreciation due to their impact on gene expression. NcRNAs, which include microRNAs, long ncRNAs and circular RNAs, are non-protein-coding transcripts that are involved in the regulation of various biological processes, hence shaping cell identity and behaviour. They have also been implicated in disease development, including cardiovascular diseases, cancer and, more recently, cancer therapy-associated cardiotoxicity. This review outlines key features of cancer therapy-associated cardiotoxicity, what is known about the roles of ncRNAs in these processes and how ncRNAs could be exploited as therapeutic targets for cardioprotection.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141157518","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Treatment options for immune-related adverse events associated with immune checkpoint inhibitors.","authors":"Yu Hua Chen, Tamás Kovács, Péter Ferdinandy, Zoltán V Varga","doi":"10.1111/bph.16405","DOIUrl":"https://doi.org/10.1111/bph.16405","url":null,"abstract":"<p><p>The immunotherapy revolution with the use of immune checkpoint inhibitors (ICIs) started with the clinical use of the first ICI, ipilimumab, in 2011. Since then, the field of ICI therapy has rapidly expanded - with the FDA approval of 10 different ICI drugs so far and their incorporation into the therapeutic regimens of a range of malignancies. While ICIs have shown high anti-cancer efficacy, they also have characteristic side effects, termed immune-related adverse events (irAEs). These side effects hinder the therapeutic potential of ICIs and, therefore, finding ways to prevent and treat them is of paramount importance. The current protocols to manage irAEs follow an empirical route of steroid administration and, in more severe cases, ICI withdrawal. However, this approach is not optimal in many cases, as there are often steroid-refractory irAEs, and there is a potential for corticosteroid use to promote tumour progression. This review surveys the current alternative approaches to the treatments for irAEs, with the goal of summarizing and highlighting the best attempts to treat irAEs, without compromising anti-tumour immunity and allowing for rechallenge with ICIs after resolution of the irAEs.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141157526","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Highlights and hot topics in GPCR research from ‘Down Under’","authors":"Nicola J. Smith,&nbsp;Lauren T. May,&nbsp;Natasha L. Grimsey","doi":"10.1111/bph.16419","DOIUrl":"10.1111/bph.16419","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> LINKED ARTICLES</h3>\u0000 \u0000 <p>This article is part of a themed issue Therapeutic Targeting of G Protein-Coupled Receptors: hot topics from the Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists 2021 Virtual Annual Scientific Meeting. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.14/issuetoc</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.16419","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141154500","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Natural products: Call for hard evidence","authors":"Francesco Visioli","doi":"10.1111/bph.16437","DOIUrl":"10.1111/bph.16437","url":null,"abstract":"<p>Wild plants, algae, fungi etc. are an essential part of people's diet all over the world (Bacchetta et al., <span>2016</span>). According to the Food and Agriculture Organization of the United Nations more than 100 million people in the European Union, or about 20% of the world's population, consume wild plants as part of their diet and/or for medicinal purposes (Bacchetta et al., <span>2016</span>). A further &gt;65 million (14% of the world's population) occasionally collect some form of wild plants (Bacchetta et al., <span>2016</span>). In the context of human evolution, wild plants are of particular importance as they are at the dynamic interface between food and pharmacology. Plants are not just a simple food but can also be a type of dietary supplement with hypothesized cardiopreventive and chemopreventive properties (Lu et al., <span>in press</span>; Visioli, <span>2022</span>). Among the proposed mechanisms of action of plants as dietary supplements, anti-inflammatory, hepatoprotective and neuroprotective effects are of major importance and are being actively investigated, although the intracellular signalling pathways responsible for these effects remain to be fully elucidated (Forman et al., <span>2014</span>). Moreover, some plants contain potentially antibacterial products that could theoretically be used in the current and urgent search for new antibiotics to overcome resistance (Bacchetta et al., <span>2016</span>; Wernli et al., <span>2023</span>). Indeed, the bioactive components of plants (hereafter referred to as natural products) are being actively researched by pharmacologists worldwide.</p><p>In addition to pharmaceutical preparations, health food stores in many countries offer products made from or enriched with natural products (Visioli, <span>2022</span>). Examples include coffee based on <i>Cichorium intybus</i>, syrup made from <i>Taraxacum</i> spp. and pasta, to which the powder of <i>Urtica</i> spp. has been added to take advantage of the alleged health benefits of natural products (Bacchetta et al., <span>2016</span>). However, the true nature and extent of the pharmacological activities of natural products are still largely unexplored (with some notable exceptions, e.g. atropine, digoxin, paclitaxel, quinine, quinidine, morphine and capsaicin, among others). Furthermore, the actual impact of regular consumption of these molecules on the prevention of chronic diseases is currently unclear. Scientists have shown that wild vegetables often contain high concentrations of minerals and phytochemicals, such as (poly)phenols, terpenoids or polysaccharides, and high levels of some vitamins, for example A and C. In fact, a plant-based diet is associated with a higher life expectancy (Fadnes et al., <span>in press</span>; Willett et al., <span>2019</span>). One of the proposed mechanisms of action is that various plants produce biologically active secondary metabolites, many of which are phenolic in nature and thought to be ","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.16437","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141086474","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Subcutaneous administration of a novel TRPM8 antagonist reverses cold hypersensitivity while attenuating the drop in core body temperature","authors":"Michael S. Gold,&nbsp;Jorge B. Pineda-Farias,&nbsp;David Close,&nbsp;Smith Patel,&nbsp;Paul A. Johnston,&nbsp;Sean D. Stocker,&nbsp;V. Blair Journigan","doi":"10.1111/bph.16429","DOIUrl":"10.1111/bph.16429","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>We extend the characterization of the TRPM8 antagonist VBJ103 with tests of selectivity, specificity and distribution, therapeutic efficacy of systemic administration against oxaliplatin-induced cold hyperalgesia and the impact of systemic administration on core body temperature (CBT).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>Selectivity at human TRPA1 and TRPV1 as well as in vitro safety profiling was determined. Effects of systemic administration of VBJ103 were evaluated in a model of oxaliplatin-induced cold hyperalgesia. Both peripheral and centrally mediated effects of VBJ103 on CBT were assessed with radiotelemetry.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>VBJ103 had no antagonist activity at TRPV1 and TRPA1, but low potency TRPA1 activation. The only safety liability detected was partial inhibition of the dopamine transporter (DAT). VBJ103 delivered subcutaneously dose-dependently attenuated cold hypersensitivity in oxaliplatin-treated mice at 3, 10 and 30 mg·kg⁻¹ (n = 7, <i>P</i> &lt; 0.05). VBJ103 (30 mg·kg⁻¹) antinociception was influenced by neither the TRPA1 antagonist HC-030031 nor the DAT antagonist GBR12909. Subcutaneous administration of VBJ103 (3, 10 and 30 mg·kg⁻¹, but not 100 or 300 mg·kg⁻¹, n = 7) decreased CBT (2°C). Intraperitoneal (i.p.) administration of VBJ103 (3, 10 and 30 mg·kg⁻¹) dose-dependently decreased CBT to an extent larger than that detected with subcutaneous administration. Intracerebroventricular (i.c.v.) administration (306 nmol/1 μL; n = 5) did not alter CBT.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions and Implications</h3>\u0000 \u0000 <p>We achieve therapeutic efficacy with subcutaneous administration of a novel TRPM8 antagonist that attenuates deleterious influences on CBT, a side effect that has largely prevented the translation of TRPM8 as a target.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.16429","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141092845","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}