British Journal of Pharmacology最新文献

{"title":"The mitochondrial calcium uniporter inhibitor Ru265 increases neuronal excitability and reduces neurotransmission via off-target effects","authors":"Peng Xu,&nbsp;Sarpras Swain,&nbsp;Robyn J. Novorolsky,&nbsp;Esperanza Garcia,&nbsp;Zhouyang Huang,&nbsp;Terrance P. Snutch,&nbsp;Justin J. Wilson,&nbsp;George S. Robertson,&nbsp;Robert B. Renden","doi":"10.1111/bph.16425","DOIUrl":"10.1111/bph.16425","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Excitotoxicity due to mitochondrial calcium (Ca²⁺) overloading can trigger neuronal cell death in a variety of pathologies. Inhibiting the mitochondrial calcium uniporter (MCU) has been proposed as a therapeutic avenue to prevent calcium overloading. Ru265 (ClRu(NH₃)₄(μ-N)Ru(NH₃)₄Cl]Cl₃) is a cell-permeable inhibitor of the mitochondrial calcium uniporter (MCU) with nanomolar affinity. Ru265 reduces sensorimotor deficits and neuronal death in models of ischemic stroke. However, the therapeutic use of Ru265 is limited by the induction of seizure-like behaviours.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>We examined the effect of Ru265 on synaptic and neuronal function in acute brain slices and hippocampal neuron cultures derived from mice, in control and where MCU expression was genetically abrogated.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>Ru265 decreased evoked responses from calyx terminals and induced spontaneous action potential firing of both the terminal and postsynaptic principal cell. Recordings of presynaptic Ca²⁺ currents suggested that Ru265 blocks the P/Q type channel, confirmed by the inhibition of currents in cells exogenously expressing the P/Q type channel. Measurements of presynaptic K⁺ currents further revealed that Ru265 blocked a KCNQ current, leading to increased membrane excitability, underlying spontaneous spiking. Ca²⁺ imaging of hippocampal neurons showed that Ru265 increased synchronized, high-amplitude events, recapitulating seizure-like activity seen <i>in vivo</i>. Importantly, MCU ablation did not suppress Ru265-induced increases in neuronal activity and seizures.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions and Implications</h3>\u0000 \u0000 <p>Our findings provide a mechanistic explanation for the pro-convulsant effects of Ru265 and suggest counter screening assays based on the measurement of P/Q and KCNQ channel currents to identify safe MCU inhibitors.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11309911/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141080655","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":"Sevoflurane acts as an antidepressant by suppression of GluN2D-containing NMDA receptors on interneurons","authors":"Fei Guo,&nbsp;Bing Zhang,&nbsp;Fuyi Shen,&nbsp;Qian Li,&nbsp;Yingcai Song,&nbsp;Tianyu Li,&nbsp;Yongmei Zhang,&nbsp;Weijia Du,&nbsp;Yuanxi Li,&nbsp;Wei Liu,&nbsp;Hang Cao,&nbsp;Xianjin Zhou,&nbsp;Yinli Zheng,&nbsp;Shujia Zhu,&nbsp;Yang Li,&nbsp;Zhiqiang Liu","doi":"10.1111/bph.16420","DOIUrl":"10.1111/bph.16420","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Sevoflurane, a commonly used inhaled anaesthetic known for its favourable safety profile and rapid onset and offset, has not been thoroughly investigated as a potential treatment for depression. In this study, we reveal the mechanism through which sevoflurane delivers enduring antidepressant effects.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>To assess the antidepressant effects of sevoflurane, behavioural tests were conducted, along with in vitro and ex vivo whole-cell patch-clamp recordings, to examine the effects on GluN1–GluN2 incorporated <i>N</i>-methyl-<span>d</span>-aspartate (NMDA) receptors (NMDARs) and neuronal circuitry in the medial prefrontal cortex (mPFC). Multiple-channel electrophysiology in freely moving mice was performed to evaluate sevoflurane's effects on neuronal activity, and GluN2D knockout (<i>grin2d</i>^−/−) mice were used to confirm the requirement of GluN2D for the antidepressant effects.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>Repeated exposure to subanaesthetic doses of sevoflurane produced sustained antidepressant effects lasting up to 2 weeks. Sevoflurane preferentially inhibited GluN2C- and GluN2D-containing NMDARs, causing a reduction in interneuron activity. In contrast, sevoflurane increased action potentials (AP) firing and decreased spontaneous inhibitory postsynaptic current (sIPSC) in mPFC pyramidal neurons, demonstrating a disinhibitory effect. These effects were absent in <i>grin2d</i>^−/− mice, and both pharmacological blockade and genetic knockout of GluN2D abolished sevoflurane's antidepressant actions, suggesting that GluN2D is essential for its antidepressant effect.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion and Implications</h3>\u0000 \u0000 <p>Sevoflurane directly targets GluN2D, leading to a specific decrease in interneuron activity and subsequent disinhibition of pyramidal neurons, which may underpin its antidepressant effects. Targeting the GluN2D subunit could hold promise as a potential therapeutic strategy for treating depression.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141080589","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":"A novel ryanodine receptor 2 inhibitor, M201-A, enhances natriuresis, renal function and lusi-inotropic actions: Preclinical and phase I study","authors":"Noboru Kaneko,&nbsp;Christopher M. Loughrey,&nbsp;Godfrey Smith,&nbsp;Ryuko Matsuda,&nbsp;Tomoko Hasunuma,&nbsp;Patric B. Mark,&nbsp;Masashi Toda,&nbsp;Makoto Shinozaki,&nbsp;Naoyuki Otani,&nbsp;Scott Kayley,&nbsp;Ana Da Silva Costa,&nbsp;Tamara P. Martin,&nbsp;Sara Dobi,&nbsp;Priyanka Saxena,&nbsp;Ken Shimamoto,&nbsp;Tetsuya Ishikawa,&nbsp;Ryuichi Kambayashi,&nbsp;Alexandra Riddell,&nbsp;Elspeth B. Elliott,&nbsp;Charlotte S. McCarroll,&nbsp;Toshiya Sakai,&nbsp;Yamano Mitsuhisa,&nbsp;Sayuri Hirano,&nbsp;Takeshi Kitai,&nbsp;Kengo Kusano,&nbsp;Yuko Inoue,&nbsp;Masahiko Nakamura,&nbsp;Migaku Kikuchi,&nbsp;Shigeru Toyoda,&nbsp;Isao Taguchi,&nbsp;Toshihiko Fujiwara,&nbsp;Atsushi Sugiyama,&nbsp;Yuji Kumagai,&nbsp;Kunio Iwata","doi":"10.1111/bph.16379","DOIUrl":"10.1111/bph.16379","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>The ryanodine receptor 2 (RyR2) is present in both the heart and kidneys, and plays a crucial role in maintaining intracellular Ca²⁺ homeostasis in cells in these organs. This study aimed to investigate the impact of M201-A on RyR2, as well as studying its effects on cardiac and renal functions in preclinical and clinical studies.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>Following the administration of M201-A (1,4-benzothiazepine-1-oxide derivative), we monitored diastolic Ca²⁺ leak via RyR2 and intracellular Ca²⁺ concentration in isolated rat cardiomyocytes and in cardiac and renal function in animals. In a clinical study, M201-A was administered intravenously at doses of 0.2 and 0.4 mg·kg⁻¹ once daily for 20 min for four consecutive days in healthy males, with the assessment of haemodynamic responses.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>In rat heart cells, M201-A effectively inhibited spontaneous diastolic Ca²⁺ leakage through RyR2 and exhibited positive lusi-inotropic effects on the rat heart. Additionally, it enhanced natriuresis and improved renal function in dogs. In human clinical studies, when administered intravenously, M201-A demonstrated an increase in natriuresis, glomerular filtration rate and creatinine clearance, while maintaining acceptable levels of drug safety and tolerability.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions and Implications</h3>\u0000 \u0000 <p>The novel drug M201-A inhibited diastolic Ca²⁺ leak via RyR2, improved cardiac lusi-inotropic effects in rats, and enhanced natriuresis and renal function in humans. These findings suggest that this drug may offer a potential new treatment option for chronic kidney disease and heart failure.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.16379","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141075215","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":"Extent of foetal exposure to maternal elexacaftor/tezacaftor/ivacaftor during pregnancy","authors":"Danni Li,&nbsp;Martin Donnelley,&nbsp;David Parsons,&nbsp;Mark D. Habgood,&nbsp;Elena K. Schneider-Futschik","doi":"10.1111/bph.16417","DOIUrl":"10.1111/bph.16417","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Cystic fibrosis (CF) patients are living longer and healthier due to improved treatments, e.g. cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy elexacaftor/tezacaftor/ivacaftor (ETI), with treatment possibly occurring in pregnancy. The risk of ETI to foetuses remain unknown. Thus the effect of maternally administered ETI on foetal genetic and structural development was investigated.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>Pregnant Sprague Dawley rats were orally treated with ETI (6.7 mg·kg⁻¹·day⁻¹ elexacaftor + 3.5 mg·kg⁻¹·day⁻¹ tezacaftor + 25 mg·kg⁻¹·day⁻¹ ivacaftor) for 7 days from E12 to E19. Tissue samples collected at E19 were analysed using histology and RNA sequencing. Histological changes and differentially expressed genes (DEG) were assessed.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>No overt structural abnormalities were found in foetal pancreas, liver, lung and small intestine after 7-day ETI exposure. Very few non-functionally associated DEG in foetal liver, lung and small intestine were identified using RNA-seq. 29 DEG were identified in thymus (27 up-regulated and two down-regulated) and most were functionally linked to each other. Gene ontology enrichment analysis revealed that multiple muscle-related terms were significantly enriched. Many more DEG were identified in cortex (44 up-regulated and four down-regulated) and a group of these were involved in central nervous system and brain development.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion and Implication</h3>\u0000 \u0000 <p>Sub-chronic ETI treatment in late pregnancy does not appear to pose a significant risk to the genetic and structural development of many foetal tissues. However, significant gene changes in foetal thymic myoid cells and cortical neuronal development requires future follow-up studies to assess the risk to these organs.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.16417","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141070451","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":"Schwann cell TRPA1 elicits reserpine-induced fibromyalgia pain in mice","authors":"Evelyne Silva Brum,&nbsp;Maria Fernanda Pessano Fialho,&nbsp;Daniel Souza Monteiro de Araújo,&nbsp;Lorenzo Landini,&nbsp;Matilde Marini,&nbsp;Mustafa Titiz,&nbsp;Bruna Luiza Kuhn,&nbsp;Clarissa Piccinin Frizzo,&nbsp;Pedro Henrique Silva Araújo,&nbsp;Rafaela Mano Guimarães,&nbsp;Thiago Mattar Cunha,&nbsp;Cássia Regina Silva,&nbsp;Gabriela Trevisan,&nbsp;Pierangelo Geppetti,&nbsp;Romina Nassini,&nbsp;Francesco De Logu,&nbsp;Sara Marchesan Oliveira","doi":"10.1111/bph.16413","DOIUrl":"10.1111/bph.16413","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Fibromyalgia is a complex clinical disorder with an unknown aetiology, characterized by generalized pain and co-morbid symptoms such as anxiety and depression. An imbalance of oxidants and antioxidants is proposed to play a pivotal role in the pathogenesis of fibromyalgia symptoms. However, the precise mechanisms by which oxidative stress contributes to fibromyalgia-induced pain remain unclear. The transient receptor potential ankyrin 1 (TRPA1) channel, known as both a pain sensor and an oxidative stress sensor, has been implicated in various painful conditions.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>The feed-forward mechanism that implicates reactive oxygen species (ROS) driven by TRPA1 was investigated in a reserpine-induced fibromyalgia model in C57BL/6J mice employing pharmacological interventions and genetic approaches.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>Reserpine-treated mice developed pain-like behaviours (mechanical/cold hypersensitivity) and early anxiety-depressive-like disorders, accompanied by increased levels of oxidative stress markers in the sciatic nerve tissues. These effects were not observed upon pharmacological blockade or global genetic deletion of the TRPA1 channel and macrophage depletion. Furthermore, we demonstrated that selective silencing of TRPA1 in Schwann cells reduced reserpine-induced neuroinflammation (NADPH oxidase 1-dependent ROS generation and macrophage increase in the sciatic nerve) and attenuated fibromyalgia-like behaviours.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion and Implications</h3>\u0000 \u0000 <p>Activated Schwann cells expressing TRPA1 promote an intracellular pathway culminating in the release of ROS and recruitment of macrophages in the mouse sciatic nerve. These cellular and molecular events sustain mechanical and cold hypersensitivity in the reserpine-evoked fibromyalgia model. Targeting TRPA1 channels on Schwann cells could offer a novel therapeutic approach for managing fibromyalgia-related behaviours.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141075326","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":"Differing contributions of the gut microbiota to the blood pressure lowering effects induced by first-line antihypertensive drugs","authors":"Cristina González-Correa,&nbsp;Javier Moleón,&nbsp;Sofía Miñano,&nbsp;Iñaki Robles-Vera,&nbsp;Marta Toral,&nbsp;Antonio Manuel Barranco,&nbsp;Natividad Martín-Morales,&nbsp;Francisco O'Valle,&nbsp;Eduardo Guerra-Hernández,&nbsp;Manuel Sánchez,&nbsp;Manuel Gómez-Guzmán,&nbsp;Rosario Jiménez,&nbsp;Miguel Romero,&nbsp;Juan Duarte","doi":"10.1111/bph.16410","DOIUrl":"10.1111/bph.16410","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>This study analyses whether first-line antihypertensive drugs ameliorate the dysbiosis state in hypertension, and to test if this modification contributes to their blood pressure (BP) lowering properties in a genetic model of neurogenic hypertension.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>Twenty-week-old male Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) were untreated or treated with captopril, amlodipine or hydrochlorothiazide. A faecal microbiota transplantation (FMT) experiment was also performed by gavage of faecal content from donor SHR-treated groups to SHR recipients for 3 weeks.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key results</h3>\u0000 \u0000 <p>Faeces from SHR showed gut dysbiosis, characterized by lower acetate- and higher lactate-producing bacteria and lower strict anaerobic bacteria. All three drugs increased the anaerobic bacteria proportion, captopril and amlodipine restored the proportion of acetate-producing bacterial populations to WKY levels, whereas hydrochlorothiazide decreased butyrate-producing bacteria. Captopril and amlodipine decreased gut pathology and permeability and attenuated sympathetic drive in the gut. Both drugs decreased neuroinflammation and oxidative stress in the hypothalamic paraventricular nuclei. Hydrochlorothiazide was unable to reduce neuroinflammation, gut sympathetic tone and gut integrity. FMT from SHR-amlodipine to SHR decreased BP, ameliorated aortic endothelium-dependent relaxation to acetylcholine, lowered NADPH oxidase activity, aortic Th17 infiltration and reduced neuroinflammation, whereas FMT from SHR-hydrochlorothiazide did not have these effects.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions and Implications</h3>\u0000 \u0000 <p>First-line antihypertensive drugs induced different modifications of gut integrity and gut dysbiosis in SHR, which result in no contribution of microbiota in the BP lowering effects of hydrochlorothiazide, whereas the vasculo-protective effect induced by amlodipine involves gut microbiota reshaping and gut-immune system communication.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.16410","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141070379","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":"The neuropharmacological properties of α-pyrrolidinobutiothiophenone, a new synthetic cathinone, in rodents; role of the dopaminergic system","authors":"Oc-Hee Kim,&nbsp;Kyung Oh Jeon,&nbsp;Gihyeon Kim,&nbsp;Choon-Gon Jang,&nbsp;Seong Shoon Yoon,&nbsp;Eun Young Jang","doi":"10.1111/bph.16422","DOIUrl":"10.1111/bph.16422","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>α-Pyrrolidinobutiothiophenone (α-PBT) is a chemical derivative of cathinone, a structural analogue of amphetamine. Until now, there have been a few previous neurochemical or neurobehavioural studies on the abuse potential of α-PBT.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>We examined the abuse potential of α-PBT by measuring psychomotor, rewarding, and reinforcing properties and methamphetamine-like discriminative stimulus effects in rodents using locomotor activity, conditioned place preference, self-administration, and drug discrimination studies. To clarify the underlying neuropharmacological mechanisms, we measured dopamine levels and neuronal activation in the dorsal striatum. In addition, we investigated the role of the dopamine D₁ receptor or D₂ receptors in α-PBT-induced hyperlocomotor activity, conditioned place preference, and the methamphetamine-like discriminative stimulus effect of α-PBT in rodents.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>α-PBT promoted hyperlocomotor activity in mice. α-PBT induced drug-paired place preference in mice and supported self-administration in rats. In a drug discrimination experiment, α-PBT fully substituted for the discriminative stimulus effects of methamphetamine in rats. Furthermore, α-PBT increased dopamine levels and c-Fos expression in the dorsal striatum of mice, which was associated with these behaviours. Finally, pretreatment with the D₁ receptor antagonist SCH23390 or the D₂ receptors antagonist eticlopride significantly attenuated acute or repeated α-PBT-induced hyperlocomotor activity, place preference, and the methamphetamine-like discriminative stimulus effects in rodents.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions and Implications</h3>\u0000 \u0000 <p>These findings suggest that α-PBT has abuse potential at the highest dose tested via enhanced dopaminergic transmission in the dorsal striatum of rodents. The results provide scientific evidence for the legal restrictions of the recreational use of α-PBT.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141075236","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":"Non-coding RNAs to treat vascular smooth muscle cell dysfunction.","authors":"Simon D Brown, Eftychia Klimi, Wilfried A M Bakker, Abdelaziz Beqqali, Andrew H Baker","doi":"10.1111/bph.16409","DOIUrl":"https://doi.org/10.1111/bph.16409","url":null,"abstract":"<p><p>Vascular smooth muscle cell (vSMC) dysfunction is a critical contributor to cardiovascular diseases, including atherosclerosis, restenosis and vein graft failure. Recent advances have unveiled a fascinating range of non-coding RNAs (ncRNAs) that play a pivotal role in regulating vSMC function. This review aims to provide an in-depth analysis of the mechanisms underlying vSMC dysfunction and the therapeutic potential of various ncRNAs in mitigating this dysfunction, either preventing or reversing it. We explore the intricate interplay of microRNAs, long-non-coding RNAs and circular RNAs, shedding light on their roles in regulating key signalling pathways associated with vSMC dysfunction. We also discuss the prospects and challenges associated with developing ncRNA-based therapies for this prevalent type of cardiovascular pathology.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141075228","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":"Identification and characterisation of functional Kir6.1-containing ATP-sensitive potassium channels in the cardiac ventricular sarcolemmal membrane","authors":"Sean Brennan,&nbsp;Shen Chen,&nbsp;Samir Makwana,&nbsp;Simona Esposito,&nbsp;Lauren R. McGuinness,&nbsp;Abrar I. M. Alnaimi,&nbsp;Mark W. Sims,&nbsp;Manish Patel,&nbsp;Qadeer Aziz,&nbsp;Leona Ojake,&nbsp;James A. Roberts,&nbsp;Parveen Sharma,&nbsp;David Lodwick,&nbsp;Andrew Tinker,&nbsp;Richard Barrett-Jolley,&nbsp;Caroline Dart,&nbsp;Richard D. Rainbow","doi":"10.1111/bph.16390","DOIUrl":"10.1111/bph.16390","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>The canonical K_ir6.2/SUR2A ventricular K_ATP channel is highly ATP-sensitive and remains closed under normal physiological conditions. These channels activate only when prolonged metabolic compromise causes significant ATP depletion and then shortens the action potential to reduce contractile activity. Pharmacological activation of K_ATP channels is cardioprotective, but physiologically, it is difficult to understand how these channels protect the heart if they only open under extreme metabolic stress. The presence of a second K_ATP channel population could help explain this. Here, we characterise the biophysical and pharmacological behaviours of a constitutively active K_ir6.1-containing K_ATP channel in ventricular cardiomyocytes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>Patch-clamp recordings from rat ventricular myocytes in combination with well-defined pharmacological modulators was used to characterise these newly identified K⁺ channels. Action potential recording, calcium (Fluo-4) fluorescence measurements and video edge detection of contractile function were used to assess functional consequences of channel modulation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>Our data show a ventricular K⁺ conductance whose biophysical characteristics and response to pharmacological modulation were consistent with K_ir6.1-containing channels. These K_ir6.1-containing channels lack the ATP-sensitivity of the canonical channels and are constitutively active.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion and Implications</h3>\u0000 \u0000 <p>We conclude there are two functionally distinct populations of ventricular K_ATP channels: constitutively active K_ir6.1-containing channels that play an important role in fine-tuning the action potential and K_ir6.2/SUR2A channels that activate with prolonged ischaemia to impart late-stage protection against catastrophic ATP depletion. Further research is required to determine whether K_ir6.1 is an overlooked target in Comprehensive in vitro Proarrhythmia Assay (CiPA) cardiac safety screens.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.16390","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141064977","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":"Discovery platforms for RNA therapeutics.","authors":"Giulio Ciucci, Luca Braga, Serena Zacchigna","doi":"10.1111/bph.16424","DOIUrl":"https://doi.org/10.1111/bph.16424","url":null,"abstract":"<p><p>RNA therapeutics are emerging as a unique opportunity to drug currently \"undruggable\" molecules and diseases. While their advantages over conventional, small molecule drugs, their therapeutic implications and the tools for their effective in vivo delivery have been extensively reviewed, little attention has been so far paid to the technological platforms exploited for the discovery of RNA therapeutics. Here, we provide an overview of the existing platforms and ex vivo assays for RNA discovery, their advantages and disadvantages, as well as their main fields of application, with specific focus on RNA therapies that have reached either phase 3 or market approval.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140956381","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}