{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,20]],"date-time":"2026-06-20T04:52:12Z","timestamp":1781931132595,"version":"3.54.5"},"reference-count":47,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2022,4,27]],"date-time":"2022-04-27T00:00:00Z","timestamp":1651017600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Deputyship for Research &amp; Innovation, Ministry of Education in Saudi Arabia","award":["IF-PSAU-2021\/03\/18673"],"award-info":[{"award-number":["IF-PSAU-2021\/03\/18673"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Plants"],"abstract":"<jats:p>The present study attempted to evaluate and rationalize the medicinal use of the methanolic extract of the fruits of Balanites aegyptiaca (B. aegyptiaca) in the treatment of hyperactive gut disorders. The in vivo, castor oil-induced diarrhea model in mice was followed to test its antidiarrheal effect. To test the antispasmodic effect and to explore its pharmacodynamic details, isolated small intestines (ileum) obtained from rats were selected to provide physiological conditions for the ex vivo assays. In the in vivo assays, the orally administered extract of B. aegyptiaca protected mice from diarrheal drops with resultant percent inhibitions of 40% and 80% at the respective doses of 200 mg\/kg and 400 mg\/kg, while the highest protection (100%) was observed with a positive control drug, loperamide, at 10 mg\/kg. In the ileum, B. aegyptiaca produced an antispasmodic effect in a concentration-dependent manner by inhibiting the carbachol (CCh; 1 \u00b5M) and high K+ (80 mM)-evoked spasms with resultant EC50 values of 1.44 mg\/mL (1.08\u20131.78) and 1.27 mg\/mL (0.98\u20131.66), respectively. Papaverine, a known phosphodiesterase enzyme (PDE) inhibitor and blocker of Ca++ channels (CCB), also inhibited both CCh and high K+ induced contractions at comparable EC50 values of 8.72 \u00b5M (7.92\u20139.24) and 8.14 \u00b5M (7.62\u20138.84), respectively. Contrary to the extract and papaverine, verapamil showed distinctly higher potency in regard to inhibiting high K+, compared to CCh-evoked spasms that had EC50 values of 0.16 \u00b5M (0.13\u20130.261) and 2.54 \u00b5M (2.28\u20132.92), respectively. The inhibitory effects of B. aegyptiaca on PDE were further confirmed when the pre-incubated extract shifted the isoprenaline-mediated relaxation curves (CRCs) towards the left, similar to papaverine, whereas the CCB-like effect was confirmed when the pre-incubated tissues with B. aegyptiaca caused deflection in the Ca++ CRCs towards the right, constructed in Ca++ free medium with suppression of the maximum response. Thus, this study provides detailed, mechanistic support for the medicinal use of B. aegyptiaca in the treatment of hyperactive gut disorders.<\/jats:p>","DOI":"10.3390\/plants11091183","type":"journal-article","created":{"date-parts":[[2022,4,27]],"date-time":"2022-04-27T22:20:20Z","timestamp":1651098020000},"page":"1183","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Dual Inhibition of Phosphodiesterase and Ca++ Channels Explains the Medicinal Use of Balanites aegyptiaca (L.) in Hyperactive Gut Disorders"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6925-7697","authenticated-orcid":false,"given":"Najeeb Ur","family":"Rehman","sequence":"first","affiliation":[{"name":"Department of Pharmacology & Toxicology, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8580-3002","authenticated-orcid":false,"given":"Mohd Nazam","family":"Ansari","sequence":"additional","affiliation":[{"name":"Department of Pharmacology & Toxicology, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2639-9200","authenticated-orcid":false,"given":"Wasim","family":"Ahmad","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Mohammed Al-Mana College for Medical Sciences, Dammam 34222, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Syed Rizwan","family":"Ahamad","sequence":"additional","affiliation":[{"name":"Central Laboratory, Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,4,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"340215","DOI":"10.1155\/2013\/340215","article-title":"Bidens pilosa L. (Asteraceae): Botanical Properties, Traditional Uses, Phytochemistry, and Pharmacology","volume":"2013","author":"Bartolome","year":"2013","journal-title":"Evid.-Based Complement. Altern. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1747","DOI":"10.1016\/S0140-6736(06)68770-9","article-title":"Global and regional burden of disease and risk factors, 2001: Systematic analysis of population health data","volume":"367","author":"Lopez","year":"2006","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1053\/j.gastro.2019.06.014","article-title":"AGA Technical Review on the Evaluation of Functional Diarrhea and Diarrhea-Predominant Irritable Bowel Syndrome in Adults (IBS-D)","volume":"157","author":"Lytvyn","year":"2019","journal-title":"Gastroenterology"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Tadesse, W.T., Hailu, A.E., Gurmu, A.E., and Mechesso, A.F. (2014). Experimental assessment of antidiarrheal and antisecretory activity of 80% methanolic leaf extract of Zehneria scabra in mice. BMC Complement. Altern. Med., 14.","DOI":"10.1186\/1472-6882-14-460"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1007\/s11894-017-0557-x","article-title":"Antidiarrheal Drug Therapy","volume":"19","author":"Schiller","year":"2017","journal-title":"Curr. Gastroenterol. Rep."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1016\/S0140-6736(18)31488-0","article-title":"50 years of oral rehydration therapy: The solution is still simple","volume":"392","author":"Nalin","year":"2018","journal-title":"Lancet"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2711","DOI":"10.3748\/wjg.v22.i9.2711","article-title":"Calcium-sensing receptor: A new target for therapy of diarrhea","volume":"22","author":"Cheng","year":"2016","journal-title":"World J. Gastroenterol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e13526","DOI":"10.1111\/nmo.13526","article-title":"Enkephalinase inhibitors, potential therapeutics for the future treatment of diarrhea predominant functional gastrointestinal disorders","volume":"31","author":"Szymaszkiewicz","year":"2019","journal-title":"Neurogastroenterol. Motil."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/j.annemergmed.2017.04.008","article-title":"Clinical Review: Loperamide Toxicity","volume":"70","author":"Wu","year":"2017","journal-title":"Ann. Emerg. Med."},{"key":"ref_10","first-page":"59","article-title":"Loperamide Dependency: A Case Report","volume":"9","author":"Zarghami","year":"2017","journal-title":"Addict. Health"},{"key":"ref_11","first-page":"86","article-title":"Herbal medicine\u2014a rational approach in health care system","volume":"1","author":"Pathak","year":"2013","journal-title":"Int. J. Herbal Med."},{"key":"ref_12","first-page":"66","article-title":"Pharmacological review on natural antidiarrhoel agents","volume":"2","author":"Kumar","year":"2010","journal-title":"Pharma Chemica"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3415","DOI":"10.5897\/JMPR11.1707","article-title":"Ethnobotanical survey of medicinal plants used in the treatment of gastrointestinal disorders in the Eastern Cape Province, South Africa","volume":"6","author":"Olajuyigbe","year":"2012","journal-title":"J. Med. Plants Res."},{"key":"ref_14","first-page":"31","article-title":"Herbal approaches for diarrhea: A review","volume":"4","author":"Komal","year":"2013","journal-title":"Int. Res. J. Pharm."},{"key":"ref_15","unstructured":"Orwa, C., Mutua, A., Kindt, R., Jamnadass, R., and Anthony, S. (2009). Agrofores Tree Database: A Tree Reference and Selection Guide, World Agroforestry Centre. Version 4.0."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"55","DOI":"10.4103\/0973-7847.79100","article-title":"A review on Balanites aegyptiaca Del (desert date): Phytochemical constituents, traditional uses and pharmacological activity","volume":"5","author":"Chothani","year":"2011","journal-title":"Pharmacognosy Rev."},{"key":"ref_17","first-page":"1","article-title":"Medicinal properties of desert date plants (Balanites aegyptica)\u2014An overview","volume":"12","year":"2018","journal-title":"Glob. J. Pharmacol."},{"key":"ref_18","first-page":"1736","article-title":"Phytochemical analysis of leaf extract of Balanites aegyptica L. by HPLC-MS analysis","volume":"7","author":"Satpute","year":"2018","journal-title":"J. Pharmacogn Phytochem."},{"key":"ref_19","first-page":"25","article-title":"Traditional oral health practices among Kanuri women of Borno State, Nigeria","volume":"107","author":"Bukar","year":"2004","journal-title":"Odontostomatol. Trop."},{"key":"ref_20","first-page":"755","article-title":"Protection of rats by extracts of some common Nigerian trees against acetaminophen-induced hepatotoxicity","volume":"5","author":"Ojo","year":"2006","journal-title":"Afr. J. Biotech."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1221","DOI":"10.1016\/j.biortech.2008.09.005","article-title":"Desert date (Balanites aegyptiaca) as an arid lands sustainable bioresource for biodiesel","volume":"100","author":"Chapagain","year":"2009","journal-title":"Bioresour Technol."},{"key":"ref_22","first-page":"564","article-title":"Anthelmintic activity of root bark of Balanites aegyptiaca (L.) Del","volume":"13","author":"Dwivedi","year":"2009","journal-title":"Ethnobot. Leafl."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1019","DOI":"10.1002\/1522-2675(200204)85:4<1019::AID-HLCA1019>3.0.CO;2-S","article-title":"New steroidal gylcosides from Balanites aegyptica","volume":"85","author":"Farid","year":"2002","journal-title":"Helv. Chim. Acta"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"14425","DOI":"10.3390\/molecules200814425","article-title":"Management of Hyperglycaemia by Ethyl Acetate Extract of Balanites aegyptiaca (Desert Date)","volume":"20","author":"Barbour","year":"2015","journal-title":"Molecules"},{"key":"ref_25","first-page":"8408326","article-title":"Antidiabetic and antioxidant impacts of desert Date (Balanites aegyptiaca) and Parsley (Petroselinum sativum) aqueous Extracts: Lessons from experimental rats","volume":"2016","author":"Wasfy","year":"2016","journal-title":"J. Diab. Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"87","DOI":"10.3923\/ajbkr.2020.87.96","article-title":"Effect of Balanites aegyptiaca Fruit-pericarp Extract on Fructose Induced Hyperglycemia and Hyperlipidemia in Rats","volume":"12","author":"Hassan","year":"2020","journal-title":"Asian J. Biotechnol."},{"key":"ref_27","first-page":"1","article-title":"Toxicity of Balanites aegyptiaca Seeds Oil in Wistar Albino Rats","volume":"18","author":"Ali","year":"2017","journal-title":"SUST J. Agric. Vet. Sci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1038\/sj.bjp.0701130","article-title":"Role of tachykinins in castor oil-induced diarrhoea in rats","volume":"121","author":"Croci","year":"1997","journal-title":"Br. J. Pharmacol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1211","DOI":"10.1002\/ptr.5367","article-title":"Antidiarrheal and Antispasmodic Activities of Buddleja polystachya are Mediated through Dual Inhibition of Ca(++) Influx and Phosphodiesterase Enzyme","volume":"29","author":"Rehman","year":"2015","journal-title":"Phytother. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1254\/jjp.12.137","article-title":"On the mechanism of diarrhea due to castor oil","volume":"12","author":"Iwao","year":"1962","journal-title":"Jpn. J. Pharmacol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"7974835","DOI":"10.1155\/2020\/7974835","article-title":"Multiple mechanisms of Flaxseed-effectiveness in Inflammatory Bowel disease","volume":"2020","author":"Palla","year":"2020","journal-title":"Evid.-Based Complement. Altern. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1086","DOI":"10.1002\/ptr.4819","article-title":"Species differences in the antidiarrheal and antispasmodic activities of Lepidium sativum and insight into underlying mechanisms","volume":"27","author":"Gilani","year":"2013","journal-title":"Phytother. Res."},{"key":"ref_33","first-page":"321","article-title":"Calcium antagonism and calcium entry blockade","volume":"38","author":"Godfraind","year":"1986","journal-title":"Pharmacol. Rev."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1146\/annurev.pa.17.040177.001053","article-title":"Specific pharmacology of Ca++ in myocardium, cardiac pacemakers and vascular smooth muscle","volume":"17","author":"Fleckenstein","year":"1977","journal-title":"Rev. Pharmacol. Toxicol."},{"key":"ref_35","first-page":"662","article-title":"Antimuscarinic and non-competitive antagonist properties of dicyclomine hydrochloride in isolated human and rabbit bladder muscle","volume":"201","author":"Downie","year":"1977","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_36","first-page":"S252","article-title":"Phosphodiesterase inhibitors","volume":"147","author":"Spina","year":"2006","journal-title":"Br. J. Pharmacol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1016\/0014-2999(78)90284-4","article-title":"Antagonism of cholinomimetics by troxypyrrolidinium in guinea-pig atria and longitudinal ileal muscle: Comparison with hemicholinium-3","volume":"52","author":"Choo","year":"1978","journal-title":"Eur. J. Pharmacol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1254\/jphs.FPJ05013X","article-title":"Inhibitory mechanism of papaverine on carbachol-induced contraction in bovine trachea","volume":"98","author":"Kaneda","year":"2005","journal-title":"J. Pharmacol. Sci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1111\/j.1476-5381.1986.tb09476.x","article-title":"Comparison of the effects of BRL 34915 and verapamil on electrical and mechanical activity in rat portal vein","volume":"88","author":"Hamilton","year":"1986","journal-title":"Br. J. Pharmacol."},{"key":"ref_40","unstructured":"National Research Council (1996). Guide for the Care and Use of Laboratory Animals, National Academy Press."},{"key":"ref_41","unstructured":"Organization for Economic Cooperation and Development (2001). The OECD 423 Guideline for Testing of Chemicals Acute Oral Toxicity, OECD."},{"key":"ref_42","first-page":"144","article-title":"Antidiarrheal activity of ethanolic bark extract of Mitragyna diversifolia","volume":"4","author":"Uddin","year":"2009","journal-title":"Bangl. J. Pharmacol."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Rehman, N.U., Ansari, M.N., and Samad, A. (2020). In Silico, Ex Vivo and In Vivo Studies of Roflumilast as a Potential Antidiarrheal and Antispasmodic agent: Inhibition of the PDE-4 Enzyme and Voltage-gated Ca++ ion Channels. Molecules, 25.","DOI":"10.3390\/molecules25041008"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Alam, A., Rehman, N.U., Ansari, M.N., and Palla, A.H. (2021). Effects of Essential Oils of Elettaria cardamomum Grown in India and Guatemala on Gram-Negative Bacteria and Gastrointestinal Disorders. Molecules, 26.","DOI":"10.20944\/preprints202101.0410.v1"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1111\/j.1472-8206.2005.00378.x","article-title":"Antispasmodic and bronchodilator activities of St. John\u2019s wort are putatively mediated through dual inhibition of calcium influx and phosphodiesterase","volume":"19","author":"Gilani","year":"2005","journal-title":"Fundam. Clin. Pharmacol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1275","DOI":"10.1016\/j.neuropharm.2011.07.030","article-title":"The PDE10A inhibitor, papaverine, differentially activates ERK in male and female rat striatal slices","volume":"61","author":"Hsu","year":"2011","journal-title":"Neuropharmacology"},{"key":"ref_47","unstructured":"Rang, H.P., Dale, M.M., and Ritter, J.M. (1999). Pharmacology, Churchill Livingstone. [4th ed.]."}],"container-title":["Plants"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2223-7747\/11\/9\/1183\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:02:15Z","timestamp":1760137335000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2223-7747\/11\/9\/1183"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,4,27]]},"references-count":47,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2022,5]]}},"alternative-id":["plants11091183"],"URL":"https:\/\/doi.org\/10.3390\/plants11091183","relation":{},"ISSN":["2223-7747"],"issn-type":[{"value":"2223-7747","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,4,27]]}}}