Functional mechanism of tracheal relaxation, antiasthmatic, and toxicological studies of 6‐hydroxyflavone

• Published in: Drug development research Vol. 80; no. 2; pp. 218 - 229
• Main Authors: Flores‐Flores, Angélica, Estrada‐Soto, Samuel, Millán‐Pacheco, César, Bazán‐Perkins, Blanca, Villalobos‐Molina, Rafael, Moreno‐Fierros, Leticia, Hernández‐Pando, Rogelio, García‐Jiménez, Sara, Rivera‐Leyva, Julio César
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01-03-2019; Wiley Subscription Services, Inc
• Subjects: 6‐hydroxyflavone; allergy; Asthma; Bioassays; Biocompatibility; Calcium; calcium channel blockade; Calcium channel blockers; Calcium channels (voltage-gated); Chemical compounds; Contraction; Cyclic GMP; Flavonoids; Guinea pigs; Medical treatment; Molecular docking; Muscle contraction; Muscles; Nitric oxide; Nitric-oxide synthase; Ovalbumin; Pharmacology; Respiratory diseases; Second messengers; Smooth muscle; Toxicity; Toxicity testing; toxicology; Trachea; tracheal relaxation; toxicology; calcium channel blockade; allergy; tracheal relaxation; asthma; 6-hydroxyflavone
• ISSN: 0272-4391; 1098-2299
• DOI: 10.1002/ddr.21484

Previously, we described tracheal rat rings relaxation by several flavonoids, being 6‐hydroxyflavone (6‐HOF) the most active derivative of the series. Thus, its mechanism of action was determined in an ex vivo tracheal rat ring bioassay. The anti‐asthmatic effect was assayed in in vivo OVAlbumin (OVA)‐sensitized guinea pigs. Finally, the toxicological profile of 6‐HOF was studied based on Organization of Economic Cooperation and Development guidelines with modifications. 6‐HOF–induced relaxation appears to be related with receptor‐operated calcium channel and voltage‐operated calcium channel blockade as the main mechanism of action, and also through the production of relaxant second messengers NO and cGMP. Molecular docking supports that 6‐HOF acts as calcium channel blocker and by activation of nitric oxide synthase. In addition, the in vivo anti‐asthmatic experiments demonstrate the dose‐dependent significant anti‐allergic effect of 6‐HOF induced by OVA, with best activity at 50 /kg. Finally, toxicological studies determined a LD50 > 2,000 mg/kg and, after 28 day of treatment with 6‐HOF (50 mg/kg) by intragastric route, mice did not exhibit evidence of any significant toxicity. In conclusion, experiments showed that 6‐HOF exerts significant relaxant activity through calcium channel blockade, and possibly, by NO/cGMP‐system stimulation on rat trachea, which interferes with the contraction mechanism of smooth muscle cells in the airways. In addition, the flavonoid shows potential anti‐asthmatic properties in an anti‐allergic pathway. Furthermore, because the pharmacological and safety evidence, we propose this flavonoid as lead for the development of a novel therapeutic agent for the treatment of asthma and related respiratory diseases.