Journal of Experimental Pharmacology最新文献

{"title":"Viloxazine Increases Extracellular Concentrations of Norepinephrine, Dopamine, and Serotonin in the Rat Prefrontal Cortex at Doses Relevant for the Treatment of Attention-Deficit/Hyperactivity Disorder.","authors":"Jennie Garcia-Olivares, Brittney Yegla, Frank P Bymaster, Jami Earnest, Jennifer Koch, Chungping Yu, Jonathan Rubin","doi":"10.2147/JEP.S433524","DOIUrl":"10.2147/JEP.S433524","url":null,"abstract":"<p><strong>Background: </strong>Viloxazine ER (viloxazine extended-release capsules; Qelbree^®), a nonstimulant attention-deficit/hyperactivity disorder (ADHD) treatment, has known activity as a norepinephrine (NE) transporter (NET) inhibitor. In vitro studies have also shown direct pharmacological effects on specific serotonin (5-HT) receptors, but not on the serotonin transporter (SERT). An in vivo microdialysis study in rats showed viloxazine (50 mg/kg i.p.) increased extracellular 5-HT, NE, and dopamine (DA) in the prefrontal cortex (PFC), a key brain region in ADHD pathology. This study evaluated whether these effects occur at clinically relevant concentrations.</p><p><strong>Methods: </strong>Microdialysis experiments were conducted in freely-moving, Sprague-Dawley rats (males, 8 weeks). Viloxazine (1, 3, 10, 30 mg/kg) was administered intraperitoneally to establish the dose range in rats at which viloxazine plasma concentrations aligned with those of individuals with ADHD administered therapeutic doses of viloxazine ER. Concentrations of unbound viloxazine, NE, 5-HT, DA, and NE and 5-HT metabolites (3,5-dihydroxyphenylglycol [DHPG] and 5-hydroxyindoleacetic acid [5-HIAA]) were measured in PFC interstitial fluid. After identifying a therapeutically relevant dose (30 mg/kg), the experiment was repeated using 30 and 50 mg/kg viloxazine (as 50 mg/kg increased NE, 5-HT, and DA in prior studies).</p><p><strong>Results: </strong>Viloxazine unbound (free drug) plasma concentrations in rats at 30 mg/kg were comparable to free drug concentrations in individuals with ADHD taking clinically effective doses (based on validated population PK models). Viloxazine 30 mg/kg significantly increased extracellular NE, 5-HT, and DA PFC levels compared to vehicle. Concomitant decreases in DHPG, but not 5-HIAA, support the inhibitory effect of viloxazine on NET but not SERT.</p><p><strong>Conclusion: </strong>At clinically relevant concentrations, viloxazine increases PFC NE, DA, and 5-HT. Prefrontal augmentation of 5-HT does not appear to result from 5-HT reuptake inhibition but may be related to activation of 5-HT neurons. The potential therapeutic role of serotonergic effects in ADHD treatment merits further exploration.</p>","PeriodicalId":15846,"journal":{"name":"Journal of Experimental Pharmacology","volume":"16 ","pages":"13-24"},"PeriodicalIF":0.0,"publicationDate":"2024-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10799649/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139512648","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Methanol Crude Peel Extract of P. granatum Prevents Oxidative Damage in Kidneys of Rats Exposed to Highly Active Antiretroviral Therapy","authors":"Eliah Kwizera, Kenneth Ssekatawa, Patrick Aja, Conrad Miruka, Allan Wandera, J. Mpumbya, Robert Siida, Dayyabu Shehu, Tijjani Salihu","doi":"10.2147/jep.s438368","DOIUrl":"https://doi.org/10.2147/jep.s438368","url":null,"abstract":"","PeriodicalId":15846,"journal":{"name":"Journal of Experimental Pharmacology","volume":" 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139392543","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular Docking Study of Phytosterols in Lygodium microphyllum Towards SIRT1 and AMPK, the in vitro Brine Shrimp Toxicity Test, and the Phenols and Sterols Levels in the Extract","authors":"Putri Anggreini, Hadi Kuncoro, S. Sumiwi, J. Levita","doi":"10.2147/jep.s438435","DOIUrl":"https://doi.org/10.2147/jep.s438435","url":null,"abstract":"","PeriodicalId":15846,"journal":{"name":"Journal of Experimental Pharmacology","volume":"82 11","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139017336","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gastroprotective Activities of Aqueous and 80% Methanol Leaf Extracts of <i>Stephania abyssinica</i> (Quart.-Dill. and A. Rich.) Walp. (Menispermaceae) in Rats.","authors":"Banchayehu Firehun, Teshome Nedi","doi":"10.2147/JEP.S437707","DOIUrl":"10.2147/JEP.S437707","url":null,"abstract":"<p><strong>Background: </strong>An ethnobotanical study showed that the leaf of <i>Stephania abyssinica</i> (<i>S. abyssinica</i>) is used for the treatment of gastritis, but there is no scientific investigation.</p><p><strong>Objective: </strong>The aim of this study was to evaluate the gastroprotective activities of both aqueous and 80% methanol leaf extracts of <i>S. abyssinica</i> in experimental rats.</p><p><strong>Methods: </strong>Decoction and maceration techniques were used to prepare aqueous and 80% methanol leaf extracts, respectively. The extracts were evaluated against pyloric ligation, indomethacin, and ethanol-induced gastric ulcer models at doses of 100, 200, and 400 mg/kg. Negative control received 2% tween 80, while positive controls received 20 mg/kg of omeprazole and 100 µg/kg of misoprostol. Parameters, such as ulcer index, gastric mucin content, gastric juice volume, pH, and free and total acidity were measured.</p><p><strong>Results: </strong>In the pyloric ligation induced gastric ulcer model, all doses of both extracts significantly reduced the ulcer index and gastric juice volume, while doses of 200 and 400 mg/kg exhibited a significant increment in mucus content and gastric juice pH as well as decrease in free and total acidity as compared to negative control. In indomethacin and ethanol induced gastric ulcer models, pretreatment with both extracts significantly reduced the ulcer index and enhanced gastric mucin content in a dose-dependent manner. Phytochemical screening of both extracts showed the existence of flavonoids, phenols, tannins, saponins, alkaloids, and coumarins with high contents of phenols, flavonoids, and alkaloids in 80% methanol extract.</p><p><strong>Conclusion: </strong>This study revealed that aqueous and 80% methanol leaf extracts of <i>S. abyssinica</i> possessed remarkable gastroprotective activities against experimentally induced gastric ulcer models, and this possibly justify the traditional use of <i>S. abyssinica</i> leaves to treat gastritis.</p>","PeriodicalId":15846,"journal":{"name":"Journal of Experimental Pharmacology","volume":"15 ","pages":"497-512"},"PeriodicalIF":0.0,"publicationDate":"2023-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10683649/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138460229","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antidiarrheal Activities of the Methanol Leaf Extracts of <i>Olinia rochetiana</i> (Oliniaceae) Against Castor Oil-Induced Diarrhea in Mice.","authors":"Lidet Terefe, Aschalew Nardos, Asfaw Debella, Beyene Dereje, Melese Arega, Abiy Gelagle Abebe, Worku Gemechu, Samuel Woldekidan","doi":"10.2147/JEP.S441555","DOIUrl":"https://doi.org/10.2147/JEP.S441555","url":null,"abstract":"<p><strong>Background: </strong><i>Olinia rochetiana</i> has been used traditionally to cure diarrheal disease. Therefore, this study aimed to investigate the acute toxicity and antidiarrheal effect of <i>O. rochetiana</i> leaf extracts.</p><p><strong>Methods: </strong>Cold maceration was used to extract plant leaf powder with 80% methanol. The extract's antidiarrheal action was tested against a castor oil-induced diarrheal model, a charcoal meal test, and enteropooling tests at doses of 100, 200, and 400 mg/kg. Negative controls received the vehicle at 10 mL/kg, while positive controls received loperamide at 3 mg/kg.</p><p><strong>Results: </strong>From the study, no apparent toxicity was observed when a single dose of 2000 mg/kg was administered. In the castor oil-induced model, the extract delayed the onset of diarrhea, reduced stool frequency, and decreased wet feces weight and number in a dose-dependent manner at 200 mg/kg (p < 0.05) and 400 mg/kg (p < 0.01). The percent reduction in moist feces at 100, 200, and 400 mg/kg was 54.2, 23.97, and 18.26%, respectively, indicating a significant dose-dependent decrease. In a charcoal meal test, the extracts at 200 and 400 mg/kg revealed a peristaltic index of 65 and 46%, respectively, with considerable inhibition of charcoal transport at 23 and 39%. The weight and volume of intestinal contents dropped significantly at a dose of 400 mg/kg (p < 0.01), which is 0.43 mg/kg, in the enteropooling test when compared with the tested dose. The computed in vivo antidiarrheal index revealed diarrheal inhibition values of 46.06 and 71.06% at 200 and 400 mg/kg, respectively.</p><p><strong>Conclusion: </strong>In the current investigation, <i>O. rochetiana</i> showed significant antidiarrheal activity with no symptoms of toxicity in mice.</p>","PeriodicalId":15846,"journal":{"name":"Journal of Experimental Pharmacology","volume":"15 ","pages":"485-495"},"PeriodicalIF":0.0,"publicationDate":"2023-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10676088/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138460228","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Acute and Sub-Acute Toxicity Evaluation of the Crude Methanolic Extract of <i>Justicia schimperiana</i> Leaf in Wistar Albino Rats.","authors":"Mihretu Jegnie, Teferra Abula, Samuel Woldekidan, Dinkenesh Chalchisa, Zemen Asmare, Mekbeb Afework","doi":"10.2147/JEP.S441273","DOIUrl":"https://doi.org/10.2147/JEP.S441273","url":null,"abstract":"<p><strong>Purpose: </strong>This study evaluates the acute and sub-acute toxicity of 80% methanolic extracts of the leaves of <i>Justicia schimperiana</i> in Wistar albino rat models.</p><p><strong>Methods: </strong>Dried powdered leaves of <i>Justicia schimperiana</i> were macerated in 80% methanol. The experiment was conducted in accordance with the Organization for Economic Co-operation and Development guideline 423 for acute and 407 for sub-acute toxicity testing. A single dose of 5000 mg/kg extract was orally administered to three female rats for the acute toxicity study. The plant extract was administered orally for 28 days in daily dosages of 250, 500, and 1000 mg/kg for the sub-acute study. Animals in a control group were given distilled water. A total of 40 rats (5 rats/group/sex) were used for the sub-acute toxicity testing. Daily food intake and weekly body weight measurements were done. The rats were sacrificed at the end of the 28-day treatment period for hematological, biochemical, and histopathological tests. One-way analysis of variance and Kruskal-Wallis tests were employed for the analysis.</p><p><strong>Results: </strong>The single-dose oral administration of the plant resulted in no deaths or serious morbidity. The median lethal dose was >5000 mg/kg. The 28-day oral treatment of the plant extract had no significant effect on general behavior, food intake, organ weight, biochemical parameters, or the majority of the hematological markers, with the exception of the decrease in hemoglobin and hematocrit in the 1000 mg/kg extract-treated groups compared to the controls. Both sexes experienced significant weight increases at all dosage levels. With the exception of minor alterations in a few of the organs, no significant histological change was identified.</p><p><strong>Conclusion: </strong>It is concluded that the single-dose and repeated-dose 28-day oral administration of the methanolic leaf extract of <i>Justicia schimperiana</i> is relatively safe.</p>","PeriodicalId":15846,"journal":{"name":"Journal of Experimental Pharmacology","volume":"15 ","pages":"467-483"},"PeriodicalIF":0.0,"publicationDate":"2023-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10664716/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138460278","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antidiabetic Activities of 80% Methanol Extract and Solvent Fractions of <i>Verbascum Sinaiticum</i> Benth (Scrophulariaceae) Leaves in Mice.","authors":"Beyene Dereje, Aschalew Nardos, Jemal Abdela, Lidet Terefe, Melese Arega, Terfo Mikre Yilma, Tilahun Tesfaye","doi":"10.2147/JEP.S437991","DOIUrl":"10.2147/JEP.S437991","url":null,"abstract":"<p><strong>Background: </strong>Because of the scarcity, high cost, and severe side effects of current medications, it is necessary to discover novel, safe, and affordable anti-diabetic drugs. The current study was conducted to evaluate the antidiabetic activities of <i>Verbascum sinaiticum</i> Benth leaves in mice.</p><p><strong>Methods: </strong>Leaf coarse powder was extracted with 80% methanol and then fractionated with n-hexane, ethyl acetate, and distilled water. The glucose-lowering effects of <i>V. sinaiticum</i> at 100, 200, and 400mg/kg were then studied. Glibenclamide was used as a positive control at a dose of 5 mg/kg. For oral glucose tolerance tests and hypoglycemia tests, Tween 2% was used as a negative control, while citrate buffer was used as a negative control for antihyperglycemic investigations. The results from the study were evaluated using one-way ANOVA, and then Tukey's post hoc multiple comparison test was performed.</p><p><strong>Results: </strong>Blood glucose levels were significantly reduced by the <i>V. sinaiticum</i> 80% methanol extract at 400 mg/kg (p<0.05). The blood glucose levels were significantly lowered by the aqueous residue at 400 mg/kg (p<0.05) and the ethyl acetate fractions at 200 mg/kg (p<0.01) and 400 mg/kg (p<0.001); however, none of the fraction extracts resulted in hypoglycemic shock in healthy mice. Higher glucose tolerance was seen in orally glucose-loaded mice after exposure to 80% methanol extracts at 200 and 400 mg/kg (p<0.05), the aqueous residual fraction at 200 mg/kg (p<0.01), and the ethyl acetate fraction at 200 and 400 mg/kg (p<0.05). The ethyl acetate fraction at 200 and 400 mg/kg (p<0.01), the 80% methanol extract at 400 mg/kg (p<0.05) and the aqueous residue at 400 mg/kg (p 0.01) significantly lowered blood glucose levels in streptozotocin-induced diabetic mice.</p><p><strong>Conclusion: </strong>The results of this study revealed that the 80% methanol extract and solvent fractions of <i>V. sinaiticum</i> Benth leaves are endowed with antidiabetic activity.</p>","PeriodicalId":15846,"journal":{"name":"Journal of Experimental Pharmacology","volume":"15 ","pages":"423-436"},"PeriodicalIF":0.0,"publicationDate":"2023-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10642538/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"107591444","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synergistic Effects of Azithromycin and STING Agonist Promote IFN-I Production by Enhancing the Activation of STING-TBK1 Signaling.","authors":"Kanoktip Petcharat, Narongsuk Munkong, Rungthip Thongboontho, Widsanusan Chartarrayawadee, Arthid Thim-Uam","doi":"10.2147/JEP.S433181","DOIUrl":"https://doi.org/10.2147/JEP.S433181","url":null,"abstract":"<p><strong>Background: </strong>Azithromycin (AZM) is a macrolide antibiotic that exhibits anti-inflammatory and anti-viral infection properties by enhancing type-I interferon (IFN-I) responses. The stimulator of interferon genes (STING) can directly induce IFN-I production. However, elevated IFN-I induces auto-immune phenotypes such as systemic lupus erythematosus (SLE). The effects of AZM and STING on the production of IFN-I are unclear.</p><p><strong>Objective: </strong>Therefore, this study aims to evaluate the role of AZM and STING on IFN-I responses in macrophages.</p><p><strong>Methods: </strong>RAW 264.7 macrophages were treated with AZM with and without a STING-agonist (DMXAA), and the maturation of macrophages was determined using flow cytometry. Gene expression and pro-inflammatory cytokines were analyzed using qPCR and ELISA, respectively. Moreover, protein expression was investigated using Western blot assays and immunofluorescence.</p><p><strong>Results: </strong>Our results show that AZM significantly induced M1 phenotypes, promoting surface molecule expansion of CD80 and MHC-II and production of IL-6 and TNF-α cytokines on DMXAA-stimulated macrophages. Furthermore, we found that AZM-increased mRNA levels of interferon-stimulated genes (ISGs) could be due to the high expression of STNG-TBK1 signaling in the presence of DMXAA.</p><p><strong>Conclusion: </strong>Our data suggest that AZM enhancement of IFN-I responses was STING dependent in DMXAA-stimulated macrophages. These data underline a novel approach to AZM action-mediated STING-TBK1 signaling for regulating IFN-I responses and may further augment the scientific basis and potential use of AZM in clinical applications.</p>","PeriodicalId":15846,"journal":{"name":"Journal of Experimental Pharmacology","volume":"15 ","pages":"407-421"},"PeriodicalIF":0.0,"publicationDate":"2023-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10625772/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71482330","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluation of Anti-Inflammatory Activity of the Methanol Extracts of Premna schimperi Engl (Lamiaceae) Leaves in Rats","authors":"Melese Arega, Aschalew Nardos, Asfaw Debella, Beyene Dereje, Lidet Terefe, Abiy Abebe","doi":"10.2147/jep.s432615","DOIUrl":"https://doi.org/10.2147/jep.s432615","url":null,"abstract":"Background: Even though it is a protective reaction, inflammation continues to be one of the most challenging medical disorders. The current conventional anti-inflammatory drugs have many undesirable health effects and are in need of newer drugs. The purpose of this study was to evaluate the anti-inflammatory effects of an aqueous methanol crude extract of Premna schimperi leaves. Methods: Premna schimperi leaf was extracted with 80% methanol and concentrated; the concentrated extract was used to evaluate the acute toxicity and anti-inflammatory effects. For the acute toxicity study, a single dose of Premna schimperi extract at a dose of 2000 mg/kg was administered and observed for 14 days. Acute, sub-acute, and chronic anti-inflammatory models were employed to evaluate the anti-inflammatory effect of the extract compared to the standard drug. Data were analyzed with SPSS V. 27, and the significance was established with a one-way ANOVA followed by a post hoc Tukey’s test. Results: Acute oral toxicity testing at a dose of 2000 mg/kg did not show any sign of toxicity. According to the phytochemical study, the plants contained flavonoids, terpenoids, tannins, cardiac glycosides, steroids, phenolics, and anthraquinones. The extract doses of 200 mg/kg, 400 mg/kg, and 800 mg/kg of extracts effectively (p< 0.001) reduced paw edema in the acute and sub-acute models of inflammation. When compared to the negative control group, all tested doses in the chronic model significantly (p< 0.05) decreased the production of exudates and the amount of granuloma tissue. Conclusion: Premna schimperi displayed significant anti-inflammatory activity. The tested doses inhibit the formation of edema, granulomas, and exudates. Keywords: anti-inflammation, carrageenan, indomethacin, paw edema, Premna schimperi","PeriodicalId":15846,"journal":{"name":"Journal of Experimental Pharmacology","volume":"16 5","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135763409","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of Fungus-Derived Nornidulin as a Novel TMEM16A Inhibitor: A Potential Therapy to Inhibit Mucus Secretion in Asthma","authors":"Pawin Pongkorpsakol, Chantapol Yimnual, Wilasinee Satianrapapong, Nichakorn Worakajit, Suchada Kaewin, Praphatsorn Saetang, Vatcharin Rukachaisirikul, Chatchai Muanprasat","doi":"10.2147/jep.s427594","DOIUrl":"https://doi.org/10.2147/jep.s427594","url":null,"abstract":"Introduction Inhibition of Ca2+-activated transmembrane protein 16A (TMEM16A) Cl− channels has been proposed to alleviate mucus secretion in asthma. In this study, we identified a novel class of TMEM16A inhibitors from natural sources in airway epithelial Calu-3 cells and determine anti-asthmatic efficacy of the most potent candidate in a mouse model of asthma. Methods For electrophysiological analyses, IL-4-primed Calu-3 cell monolayers were mounted in Ussing chamber and treated with various fungus-derived depsidones prior to the addition of UTP, ionomycin, thapsigargin, or Eact to stimulate TMEM16A Cl− current. Ca2+-induced mucus secretion in Calu-3 cell monolayers was assessed by determining MUC5AC protein remaining in the cells using immunofluorescence staining. OVA-induced female BALB/c mice was used as an animal model of asthma. After the course of induction, cellular and mucus components in bronchoalveolar lavage were analyzed. Lungs were fixed and undergone with H&E and PAS staining for the evaluation of airway inflammation and mucus production, respectively. Results The screening of fungus-derived depsidones revealed that nornidulin completely abolished the UTP-activated TMEM16A current in Calu-3 cell monolayers with the IC50 and a maximal effect being at ~0.8 µM and 10 µM, respectively. Neither cell viability nor barrier function was affected by nornidulin. Mechanistically, nornidulin (10 µM) suppressed Cl− currents induced by ionomycin (a Ca2+-specific ionophore), thapsigargin (an inhibitor of the endoplasmic reticulum Ca2+ ATPase), and Eact (a putative TMEM16A activator) without interfering with intracellular Ca2+ ([Ca2+]i) levels. These results suggest that nornidulin exerts its effect without changing [Ca2+]i, possibly through direct effect on TMEM16A. Interestingly, nornidulin (at 10 µM) reduced Ca2+-dependent mucus release in the Calu-3 cell monolayers. In addition, nornidulin (20 mg/kg) inhibited bronchoalveolar mucus secretion without impeding airway inflammation in ovalbumin-induced asthmatic mice. Discussion and Conclusion Our study revealed that nornidulin is a novel TMEM16A inhibitor that suppresses mucus secretion without compromising immunologic activity. Further development of nornidulin may provide a new remedy for asthma or other diseases associated with allergic mucus hypersecretion without causing opportunistic infections.","PeriodicalId":15846,"journal":{"name":"Journal of Experimental Pharmacology","volume":"10 6","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135765243","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}