Journal of Pharmacology and Experimental Therapeutics最新文献

{"title":"Chronic activation of β-adrenergic receptors leads to tissue water and electrolyte retention.","authors":"Steeve Akumwami, Kento Kitada, Yoshihide Fujisawa, Netish Kumar Kundo, Md Moshiur Rahman, Asahiro Morishita, Hiroaki Kitamura, Asadur Rahman, Yuichi Ogino, Akira Nishiyama","doi":"10.1124/jpet.124.002185","DOIUrl":"10.1124/jpet.124.002185","url":null,"abstract":"<p><p>β-Adrenergic receptors (β-ARs) are expressed on the membranes of various cell types, and their activation affects body water balance by modulating renal sodium and water excretion, cardiovascular function, and metabolic processes. However, β-AR-associated body fluid imbalance has not been well characterized. In the present study, we hypothesized that chronic β-AR stimulation increases electrolyte and water content at the tissue level. We evaluated the effects of isoproterenol, a nonselective β-AR agonist, on electrolyte and water balance at the tissue level. Continuous isoproterenol administration for 14 days induced cardiac hypertrophy, associated with sodium-driven water retention in the heart; increased the total body sodium, potassium, and water contents at the tissue level; and increased the water intake and blood pressure of mice. There was greater urine output in response to the isoproterenol-induced body water retention. These isoproterenol-induced changes were reduced by propranolol, a nonselective β receptor inhibitor. Isoproterenol-treated mice, even without excessive water intake, had higher total body electrolyte and water contents, and this tissue water retention was associated with lower dry body mass, suggesting that β-AR stimulation in the absence of excess water intake induces catabolism and water retention. These findings suggest that β-AR activation induces tissue sodium and potassium retention, leading to body fluid retention, with or without excess water intake. This characterization of β-AR-induced electrolyte and fluid abnormalities improves our understanding of the pharmacological effects of β-AR inhibitors. SIGNIFICANCE STATEMENT: This study has shown that chronic β-adrenergic receptor (β-AR) stimulation causes cardiac hypertrophy associated with sodium-driven water retention in the heart and increases the accumulation of body sodium, potassium, and water at the tissue level. This characterization of the β-AR-induced abnormalities in electrolyte and water balance at the tissue level improves our understanding of the roles of β-AR in physiology and pathophysiology and the pharmacological effects of β-AR inhibitors.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 2","pages":"100017"},"PeriodicalIF":3.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143537334","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pan AMPK activation protects tubules in rat ischemic acute kidney injury.","authors":"Henriette Frikke-Schmidt, Kamal Albarazanji, Jenson Qi, David Frederick, Janos Steffen, Shanker Kalyana-Sundaram, Rong Meng, Zheng Huang Devine, Tao Chen, Qiu Li, Fuyong Du, George Ho, Jianying Liu, Roseann Riley, Romer A Gonzalez-Villalobos, Raul C Camacho, Andrea R Nawrocki, Meghan Pryor, Min Lee, Victoria Wong, Rosalie Matico, Elsie Diaz, Daniel Krosky, Mark Wall, Elise Gao, Akshay A Shah, James Leonard, Mark Erion, Alessandro Pocai, Mark R Player","doi":"10.1124/jpet.124.002120","DOIUrl":"10.1124/jpet.124.002120","url":null,"abstract":"<p><p>Acute kidney injury (AKI) is characterized by an abrupt decline in kidney function and has been associated with excess risks of death, kidney disease progression, and cardiovascular events. The kidney has a high energetic demand with mitochondrial health being essential to renal function, and damaged mitochondria have been reported across AKI subtypes. 5' Adenosine monophosphate-activated protein kinase (AMPK) activation preserves cellular energetics through improvement of mitochondrial function and biogenesis when ATP levels are low, such as under ischemia-induced AKI. We developed a selective potent small molecule pan AMPK activator, compound 1, and tested its ability to increase AMPK activity and preserve kidney function during ischemia/reperfusion injury in rats. A single administration of compound 1 caused sustained activation of AMPK for at least 24 hours, protected against acute tubular necrosis, and reduced clinical markers of tubular injury such as NephroCheck and fractional excretion of sodium. Reduction in plasma creatinine and increased glomerular filtration rate indicated preservation of kidney function. Surprisingly, we observed a strong diuretic effect of AMPK activation associated with natriuresis both with and without AKI. Our findings demonstrate that activation of AMPK leads to protection of tubular function under hypoxic/ischemic conditions which holds promise as a potential novel therapeutic approach for AKI. SIGNIFICANCE STATEMENT: No approved pharmacological therapies currently exist for acute kidney injury. We developed compound 1, which dose-dependently activated 5' adenosine monophosphate-activated protein kinase in the kidney and protected kidney function and tubules after ischemic renal injury in the rat. This was accompanied by natriuresis in injured as well as uninjured rats.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 2","pages":"100002"},"PeriodicalIF":3.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143536753","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PLK1 phosphorylates WRN at replication forks.","authors":"Lei Wang, Daheng He, Qianjin Li, David Orren, Chi Wang, Jinpeng Liu, Zhiguo Li, Xiaoqi Liu","doi":"10.1016/j.jpet.2024.100051","DOIUrl":"https://doi.org/10.1016/j.jpet.2024.100051","url":null,"abstract":"<p><p>Prostate cancer, particularly castration-resistant prostate cancer, remains a serious public health issue. Androgen signaling inhibitors have emerged as a major treatment approach but with limited success. Thus, identification of novel treatment targets is of high clinical relevance. Polo-like kinase 1 (PLK1) has documented roles in various aspects of prostate cancer, including resistance to androgen inhibitors. Radiotherapy is another major approach for treating prostate cancer, but how Plk1 might regulate the efficacy of radiotherapy is unknown. Nonhomologous end joining (NHEJ) and homologous recombination (HR) are 2 major DNA repair pathways, with cellular choices between NHEJ and HR being elegantly regulated by end-processing. However, how the long-range DNA end resection is regulated remains poorly understood. It has been documented that Werner syndrome protein (WRN) is actively involved in the long-range resection pathway. In this study, we demonstrate that PLK1-associated phosphorylation of WRN regulates end resection at double-strand breaks, thereby promoting HR and chromosome stability. Cells expressing the WRN nonphosphorylatable mutant show the phenotype similar to WRN null cells because they lack the ability for long-range resection and increase NHEJ. In summary, we reveal that PLK1-associated Mre11, Rad50 and Nbs1 phosphorylation promotes end resection, eventually affecting cellular choices for double-strand break repair pathways. SIGNIFICANCE STATEMENT: Both DNA damage repair and PLK1 play critical roles in the efficacy of radiotherapy of prostate cancer. The data presented here will provide guidance on how to manipulate PLK1 to improve the efficacy of radiotherapy in clinical settings.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 2","pages":"100051"},"PeriodicalIF":3.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143536783","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dipeptidyl peptidase-4 inhibitor linagliptin improves fibrosis, apoptosis, and cardiac function in a large animal model of chronic myocardial ischemia.","authors":"Dwight Douglas Harris, Christopher Stone, Mark Broadwin, Meghamsh Kanuparthy, Sharif A Sabe, Ju-Woo Nho, Jad Hamze, M Ruhul Abid, Frank W Sellke","doi":"10.1016/j.jpet.2024.100532","DOIUrl":"10.1016/j.jpet.2024.100532","url":null,"abstract":"<p><p>Interest is increasing in using novel diabetic medications, such as glucagon-like peptide 1 (GLP-1) receptor agonists, to manage coronary artery disease. Dipeptidyl peptidase-4 (DPP-4) inhibitors enhance GLP-1 activity through the same pathway as GLP-1 agonists; however, DPP-4 inhibitors have not been fully evaluated in the setting of ischemic heart disease. We chose to study the DPP-4 inhibitor linagliptin (LIN) in a porcine model of chronic coronary ischemia. Seventeen Yorkshire swine underwent left thoracotomy and ameroid constrictor placement over the left circumflex coronary artery at age 11 weeks. Two weeks thereafter, swine received either vehicle without drug (n = 9) or LIN 2.5 mg (n = 8). Following the elapse of 5 weeks of treatment, swine underwent terminal harvest. LIN significantly increased stroke volume, ejection fraction, cardiac output, and ischemic myocardial perfusion, while decreasing Tau (all P < .05). Trichrome staining showed a marked reduction in ischemic myocardial interstitial and perivascular fibrosis, accompanied by decreased levels of transforming growth factor-β (all P < .05). Apoptosis, measured by terminal deoxynucleotidyl transferase-mediated digoxigenin-deoxyuridine nick-end labeling staining, was significantly reduced, and accompanied by decreases in apoptosis-inducing factor, BCL2-associated agonist of cell death, caspase-9, and cleaved caspase-9 (all P < .05). Additionally, there were significant increases in phosphoinositide 3-kinase, phospho-protein kinase B, 5' adenosine monophosphate-activated protein kinase, phospho-5' adenosine monophosphate-activated protein kinase, and endothelial nitric oxide synthase, and significant reductions in collagen 18 and angiostatin (all P < .05). LIN significantly improved left ventricular function, cellular survival, and attenuated adverse remodeling, all likely secondary to augmented perfusion ischemic myocardial perfusion. Given that this increased perfusion occurred independently of changes in vascular density, treatment likely resulted in enhanced microvascular reactivity. These benefits warrant further investigation of LIN to fully understand its potential as a therapy for ischemic heart disease. SIGNIFICANCE STATEMENT: Linagliptin significantly improved cardiac cellular survival, left ventricular function, and attenuated adverse myocardial remodeling in a clinically relevant, large animal model of chronic ischemic cardiomyopathy. This warrants further investigation of linagliptin to fully understand its therapeutic potential.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 2","pages":"100532"},"PeriodicalIF":3.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143537337","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Estrogen replacement restores period 2-mediated inhibition of ferroptosis and mitigates cardiac dysfunction in estrogen-deficient rats.","authors":"Syed Anees Ahmed, Abdel A Abdel-Rahman","doi":"10.1016/j.jpet.2024.103385","DOIUrl":"https://doi.org/10.1016/j.jpet.2024.103385","url":null,"abstract":"<p><p>The ovarian hormone 17β-estradiol (E2) confers cardioprotection via upregulating cardiac circadian rhythm period 2 (Per2) and is associated cardioprotective microRNA (miRNAs). However, whether Per2-mediated downregulation of ferroptosis-induced oxidative stress and injury in noncardiac tissues extends to the heart remains unknown. Therefore, studying the interplay between E2 and cardiac ferroptosis will have important ramifications for female cardiovascular health. We hypothesized that Per2-mediated suppression of cardiac ferroptosis contributes to E2-dependent cardioprotection while E2 deficiency promotes ferroptosis and cardiac dysfunction in female rats. The study used Sprague-Dawley rats with sham operation (sham), bilateral ovariectomy (E2-deficient) followed by E2 or vehicle treatment for 8 weeks. Cardiovascular function was assessed via radiotelemetry and echocardiography, with ex vivo analyses of ferroptosis markers, Per2, and associated miRNAs in heart tissues. E2-replete (sham and ovariectomy + E2) rats showed lower body weight gain, heart weight/body weight ratio, fat mass, and blood pressure compared with E2-deficient rats. Echocardiography data revealed reduced contractility indices in E2-deficient rats, which were restored to sham levels with E2 treatment. Molecular analyses revealed that E2-treated E2-deficient rats had upregulated Per2, cardioprotective miRNAs (499, 192, 194, and 144), and improved redox balance, along with decreased cardiodetrimental miRNAs (652 and 208b) and reactive oxygen species. In E2-deficient rats, glutathione depletion led to reduced glutathione peroxidase-4, iron overload from heme oxygenase-1 upregulation, and increased lipid peroxidation. This study highlights possible contribution of Per2-mediated inhibition of ferroptosis to E2-mediated cardioprotection in females, offering new insights for women's heart health. SIGNIFICANCE STATEMENT: This study describes the contribution of estrogen-mediated upregulation of cardiac circadian clock protein Per2 to the inhibition of ferroptosis and the improvement of cardiac function. The findings offer new perspective for understanding the intersection between hormonal regulation, circadian clock protein, microRNA, and ferroptosis in cardiovascular health. The research adds new knowledge on female molecular cardiology, particularly those related to ferroptosis. This perspective broadens current understanding of the complex molecular underpinnings of female heart health in presence or absence of estrogen.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 2","pages":"103385"},"PeriodicalIF":3.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143537308","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Na_Vigating nociceptive neuron signaling pathways to arrive at pain relief.","authors":"Geoffrey W Abbott, Rían W Manville","doi":"10.1016/j.jpet.2024.100037","DOIUrl":"https://doi.org/10.1016/j.jpet.2024.100037","url":null,"abstract":"","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 2","pages":"100037"},"PeriodicalIF":3.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143536752","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Serotonin 3 receptor antagonism reduces angiotensin II-induced abdominal aortic aneurysms: Contribution of periaortic fat-derived serotonin.","authors":"Yasir AlSiraj, Charles M Ensor, Victoria English, Analia Loria, Heba Ali, Lisa A Cassis","doi":"10.1016/j.jpet.2024.100533","DOIUrl":"10.1016/j.jpet.2024.100533","url":null,"abstract":"<p><p>Serotonin (5-HT) has been implicated in cerebral aneurysm rupture, but it is unclear whether 5-HT plays a role in aortic aneurysm development and rupture, despite well known contractile effects of 5-HT through aortic 5-HT receptors. Abdominal aortic aneurysms (AAAs) induced by angiotensin II (AngII) infusion to mice exhibit periaortic inflammation and are prone to rupture. Periaortic fat (PAF), a potential source of 5-HT through tryptophan hydroxylase 1 (Tph1), has been implicated in AAA development. We quantified mRNA abundance of 5-HT receptors (Htr1b, Htr2a, Htr2b, Htr3a, and Htr7) and Tph1 in thoracic and abdominal aortas and surrounding PAF. Compared with other 5-HT receptors, we detected high levels of serotonin 3 receptor type a (Htr3a) mRNA in the abdominal aortas and abdominal PAF. Tph1 mRNA and 5-HT immunostaining were detected in aortas and PAF, with 5-HT levels higher in abdominal than thoracic PAF, and higher in epididymal white than interscapular brown fat. AngII infusion facilitated evoked [³H]5-HT release from thoracic PAF and modestly reduced 5-HT levels in thoracic PAF and brown fat. Based on a high level of Htr3a mRNA in abdominal aortas and PAF, we investigated the development of AngII-induced AAAs when serotonin 3 receptors were pharmacologically antagonized with tropisetron. Tropisetron abrogated abdominal aortic lumen diameters, aneurysm (distal thoracic aneurysm and AAA) incidence, maximal AAA diameters, and aortic weights of AngII-infused male mice. These findings indicate a novel role for serotonin 3 receptor in AAA development, with a potential clinically relevant contribution for PAF as a local source of 5-HT. SIGNIFICANCE STATEMENT: Aortic aneurysms are life-threatening vascular disorders with no effective therapeutics. This study identified antagonism of the serotonin 3 receptor as a potential therapeutic target to reduce the formation and severity of experimentally-induced aneurysms in the thoracic and abdominal aorta. Additionally, periaortic fat was identified as a potential site for serotonin production in the development of aortic aneurysms.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 2","pages":"100533"},"PeriodicalIF":3.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143537038","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The ability of Ibutropin to blunt fentanyl-induced respiratory depression is independent of its activation of carotid body chemoafferents.","authors":"Paulina M Getsy, Walter J May, Gregory A Coffee, Santhosh M Baby, Yee-Hsee Hsieh, James N Bates, Stephen J Lewis","doi":"10.1016/j.jpet.2024.100060","DOIUrl":"https://doi.org/10.1016/j.jpet.2024.100060","url":null,"abstract":"<p><p>This study examined the effects of intravenous injection of isobutyric tropine ester (Ibutropin) on ventilation in freely-moving sham-operated (SHAM) male Sprague Dawley rats and those with bilateral carotid sinus nerve transection (CSNX). This study also examined the effects of a subsequent injection of fentanyl on ventilatory parameters in both groups of rats. Ibutropin (200 μmol/kg, i.v.) elicited rapid and pronounced increases in breathing frequency, tidal volume, minute ventilation, peak inspiratory and expiratory flows, and inspiratory and expiratory drives in SHAM rats, but substantially smaller responses in CSNX rats. The subsequent injection of fentanyl (75 μg/kg, i.v.) elicited similar ventilatory responses in Ibutropin-treated SHAM and CSNX rats with markedly different changes in end-inspiratory and end-expiratory pauses, expiratory delay, and apneic pause. Moreover, the fentanyl-induced responses in Ibutropin-treated SHAM and CSNX rats were substantially smaller than in rats that were pre-injected with vehicle (saline) rather than Ibutropin. These novel findings suggest that Ibutropin acts at the carotid body-chemoafferent complex to drive ventilation by mechanisms that may involve the rapid entry of this cell-permeant tropine ester into chemoafferent nerve terminals and/or primary glomus cells. A key finding was that the ability of Ibutropin to blunt the adverse effects of fentanyl on breathing does not require functional carotid body chemoreceptor afferent input to brainstem structures controlling breathing. As such, the ability of Ibutropin to greatly diminish the adverse effects of fentanyl on breathing may involve the actions of Ibutropin within central respiratory control centers and/or peripheral structures other than the carotid bodies. SIGNIFICANCE STATEMENT: This study revealed that the ability of Ibutropin to blunt the respiratory depressant effects of fentanyl may involve mechanisms present in central respiratory control centers and/or peripheral structures other than the carotid bodies.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 2","pages":"100060"},"PeriodicalIF":3.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143537221","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterization of the dual ITK/JAK3 small molecule covalent inhibitor ATI-2138.","authors":"Aparna Kaul, Heidi Hope, Canxin Xu, Rakesh Basavalingappa, Sara K Binz, Chad Boily, Zachary Bradley, David Burt, Catherine Emanuel, Jacob Fairchild, Sarah Egan, Anne Hildebrand, Victoria Howell, Huiyan Huang, Emma Huff, Abbygail Iken, Stephanie Knapik, Melissa Lawrence, Huawen Lin, Jessea Wenjie Lu, Jonathan Mattingly, Dean McGraw, Nancy McGraw, Stephen Mnich, William Morton, Robert Ortmann, Tyler Piccinni-Ash, Rafael Saer, Cristiane Secca da Silva, Loreen Stillwell, William Taylor, Elizabeth Warner, Ann Wrightstone, E Jon Jacobsen, David R Anderson, Joseph Monahan","doi":"10.1016/j.jpet.2024.100054","DOIUrl":"https://doi.org/10.1016/j.jpet.2024.100054","url":null,"abstract":"<p><p>Aclaris Therapeutics Inc (ATI)-2138 is a novel investigational covalent inhibitor of interleukin-2-inducible T cell kinase (ITK), resting lymphocyte kinase, and Janus kinase 3 (JAK3) in development for the treatment of autoimmune and inflammatory diseases. In this study, we evaluated the inhibitory effects of ATI-2138 on ITK and JAK3 signaling in cells and preclinical animal models and assessed the safety, tolerability, pharmacokinetics, and pharmacodynamics of ATI-2138 in healthy human participants. ATI-2138 potently, selectively, and irreversibly inhibited ITK, resting lymphocyte kinase, and JAK3 kinases with similar potency observed against ITK and JAK3 in biochemical and immune cell signaling assays. Translation from cellular and whole blood studies to in vivo models was observed, wherein ATI-2138 demonstrated disease-modifying activity in 2 rodent models of arthritis and an adoptive T cell model of colitis. In single and multiple ascending dose studies in healthy human participants, ATI-2138 had a favorable safety profile with linear pharmacokinetics. Biomarkers linked to both ITK and JAK3 activity were inhibited with ATI-2138 in an exposure-, dose-, and time-dependent manner and correlated with enzyme, cellular, whole blood, and rodent studies, thereby demonstrating predictive translational properties. As a potential first-in-class dual inhibitor of ITK and JAK3, ATI-2138 may be useful in the treatment of immunoinflammatory diseases. SIGNIFICANCE STATEMENT: Aclaris Therapeutics Inc (ATI)-2138 is a novel covalent inhibitor of interleukin-2-inducible T cell kinase (ITK)/resting lymphocyte kinase and Janus kinase 3 (JAK3). ATI-2138 inhibits JAK3 and ITK in enzyme and functional cellular assays, demonstrates disease-modifying activity in rodent models of arthritis and colitis, and inhibits biomarkers linked to both ITK and JAK3 activity in healthy human participants. With this dual kinase activity against components of these inflammatory signaling pathway, ATI-2138 has the potential for enhanced therapeutic efficacy in the treatment of autoimmune and chronic inflammatory disease.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 2","pages":"100054"},"PeriodicalIF":3.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143537288","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Brain distribution and muscarinic receptor occupancy of an active metabolite of fesoterodine in rats.","authors":"Mizuki Shiho, Shimako Tanaka, Eriko Nakatani, Toshiki Kurosawa, Yoshiyuki Kubo, Yoshiharu Deguchi, Takashi Okura","doi":"10.1016/j.jpet.2024.100058","DOIUrl":"https://doi.org/10.1016/j.jpet.2024.100058","url":null,"abstract":"<p><p>Several large-scale clinical trials have shown that long-term use of antimuscarinic agents for overactive bladder treatment increases the risk of dementia and that this risk varies between agents. Fesoterodine, an overactive bladder antimuscarinic, reportedly has no significant effect on cognitive function. Differences in the brain distribution of antimuscarinic agents and blockade of muscarinic receptors could be the reasons for the differences in central side effects among antimuscarinics. In this study, we assessed the brain distribution of antimuscarinic agents and muscarinic receptor occupancy using brain microdialysis and in vivo receptor-binding analysis in rats. The test drugs were 5-hydroxymethyl tolterodine (5-HMT), an active metabolite of fesoterodine, oxybutynin, and trihexyphenidyl, a central antimuscarinic agent. The brain/plasma unbound concentration ratio at steady state (K_puu) of 5-HMT was much lower than that of oxybutynin and trihexyphenidyl, indicating very low 5-HMT distribution in the brain. The muscarinic receptor occupancy in the rat brain at clinical plasma concentrations of 5-HMT was rarely observed, whereas the occupancy by oxybutynin and trihexyphenidyl was 20% and 67%, respectively. The brain muscarinic receptor occupancy, reconstituted using K_puu values and muscarinic receptor affinity retrieved from literature, revealed a significant correlation between the calculated and measured values. These results indicate that 5-HMT has low brain distribution and muscarinic receptor occupancy, which might be the reasons for the insignificant effect of fesoterodine on cognitive function. SIGNIFICANCE STATEMENT: This study reports that 5-hydroxymethyl tolterodine, the active metabolite of fesoterodine, has much lower brain distribution and muscarinic receptor occupancy compared with oxybutynin and trihexyphenidyl based on brain microdialysis and in vivo receptor-binding analysis with unlabeled muscarinic tracer in rats. The low brain distribution and muscarinic receptor occupancy of 5-hydroxymethyl tolterodine might be the reasons for the insignificant effect of fesoterodine on cognitive function.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 2","pages":"100058"},"PeriodicalIF":3.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143537287","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}