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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. 2020 Feb 24; 25(4)M

Abstract

The aim of the present study was to evaluate the possible gut inhibitory role of the phosphodiesterase (PDE) inhibitor roflumilast. Increasing doses of roflumilast were tested against castor oil-induced diarrhea in mice, whereas the pharmacodynamics of the same effect was determined in isolated rabbit jejunum tissues. For in silico analysis, the identified PDE protein was docked with roflumilast and papaverine using the Autodock vina program from the PyRx virtual screening tool. Roflumilast protected against diarrhea significantly at 0.5 and 1.5 mg/kg doses, with 40% and 80% protection. Ex vivo findings from jejunum tissues show that roflumilast possesses an antispasmodic effect by inhibiting spontaneous contractions in a concentration-dependent manner. Roflumilast reversed carbachol (CCh, 1 µM)-mediated and potassium (K+, 80 mM)-mediated contractile responses with comparable efficacies but different potencies. The observed potency against K+ was significantly higher in comparison to CCh, similar to verapamil. Experiments were extended to further confirm the inhibitory effect on Ca++ channels. Interestingly, roflumilast deflected Ca++ concentration-response curves (CRCs) to the right with suppression of the maximum peak at both tested doses (0.001-0.003 mg/mL), similar to verapamil. The PDE-inhibitory effect was authenticated when pre-incubation of jejunum tissues with roflumilast (0.03-0.1 mg/mL) produced a leftward deflection of isoprenaline-mediated inhibitory CRCs and increased the tissue level of cAMP, similar to papaverine. This idea was further strengthened by molecular docking studies, where roflumilast exhibited a better binding affinity (-9.4 kcal/mol) with the PDE protein than the standard papaverine (-8.3 kcal/mol). In conclusion, inhibition of Ca++ channels and the PDE-4 enzyme explains the pharmacodynamics of the gut inhibitory effect of roflumilast.

Authors+Show Affiliations

Department of Pharmacology & Toxicology, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia.Department of Pharmacology & Toxicology, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia.Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tishk International University, Erbil 44001, Kurdistan, Iraq.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32102361

Citation

Rehman, Najeeb Ur, et al. "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 (Basel, Switzerland), vol. 25, no. 4, 2020.
Rehman NU, Ansari MN, Samad A. 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. 2020;25(4).
Rehman, N. U., Ansari, M. N., & 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 (Basel, Switzerland), 25(4). https://doi.org/10.3390/molecules25041008
Rehman NU, Ansari MN, Samad A. 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. 2020 Feb 24;25(4) PubMed PMID: 32102361.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Rehman,Najeeb Ur, AU - Ansari,Mohd Nazam, AU - Samad,Abdul, Y1 - 2020/02/24/ PY - 2020/01/14/received PY - 2020/02/21/revised PY - 2020/02/24/accepted PY - 2020/2/28/entrez PY - 2020/2/28/pubmed PY - 2020/2/28/medline KW - Ca++ channel blocker KW - PDE inhibitor KW - antispasmodic KW - autoDock vina KW - molecular docking KW - roflumilast JF - Molecules (Basel, Switzerland) JO - Molecules VL - 25 IS - 4 N2 - The aim of the present study was to evaluate the possible gut inhibitory role of the phosphodiesterase (PDE) inhibitor roflumilast. Increasing doses of roflumilast were tested against castor oil-induced diarrhea in mice, whereas the pharmacodynamics of the same effect was determined in isolated rabbit jejunum tissues. For in silico analysis, the identified PDE protein was docked with roflumilast and papaverine using the Autodock vina program from the PyRx virtual screening tool. Roflumilast protected against diarrhea significantly at 0.5 and 1.5 mg/kg doses, with 40% and 80% protection. Ex vivo findings from jejunum tissues show that roflumilast possesses an antispasmodic effect by inhibiting spontaneous contractions in a concentration-dependent manner. Roflumilast reversed carbachol (CCh, 1 µM)-mediated and potassium (K+, 80 mM)-mediated contractile responses with comparable efficacies but different potencies. The observed potency against K+ was significantly higher in comparison to CCh, similar to verapamil. Experiments were extended to further confirm the inhibitory effect on Ca++ channels. Interestingly, roflumilast deflected Ca++ concentration-response curves (CRCs) to the right with suppression of the maximum peak at both tested doses (0.001-0.003 mg/mL), similar to verapamil. The PDE-inhibitory effect was authenticated when pre-incubation of jejunum tissues with roflumilast (0.03-0.1 mg/mL) produced a leftward deflection of isoprenaline-mediated inhibitory CRCs and increased the tissue level of cAMP, similar to papaverine. This idea was further strengthened by molecular docking studies, where roflumilast exhibited a better binding affinity (-9.4 kcal/mol) with the PDE protein than the standard papaverine (-8.3 kcal/mol). In conclusion, inhibition of Ca++ channels and the PDE-4 enzyme explains the pharmacodynamics of the gut inhibitory effect of roflumilast. SN - 1420-3049 UR - https://www.unboundmedicine.com/medline/citation/32102361/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_ L2 - https://www.mdpi.com/resolver?pii=molecules25041008 DB - PRIME DP - Unbound Medicine ER -