Yun-Li Zhao1, Jing Cao2, Jian-Hua Shang1, Ya-Ping Liu1, Afsar Khan3, Heng-Shan Wang4, Yi Qian2, Lu Liu1, Min Ye5, Xiao-Dong Luo6. 1. State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, China. 2. State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, 38 Xueyuan Road, Beijing 100191, China. 3. State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, China; Department of Chemistry, COMSATS Institute of Information Technology, Abbottabad, 22060, Pakistan. 4. Guangxi Normal University, Guangxi Province, Guilin, 541004, China. 5. State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, 38 Xueyuan Road, Beijing 100191, China. Electronic address: yemin@bjmu.edu.cn. 6. State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, China. Electronic address: xdluo@mail.kib.ac.cn.
Abstract
BACKGROUND: Alstonia scholaris (L.) R. Br. (Apocynaceae), an important herbal medicine, has been widely used to treat respiratory tract diseases, such as cough, asthma, phlegm, and chronic obstructive pulmonary disease. PURPOSE: To evaluate pharmacological effect of alkaloids from A. scholaris on ovalbumin induced airways allergic inflammatory model, and explore whether the dosing frequency is related to pharmacokinetics. STUDY DESIGN: After oral administration of total alkaloids, the pharmacokinetic study of it was investigated. In addition, anti-allergic studies were carried out on ovalbumin-sensitized airways allergic inflammatory model of mice. METHODS: The pharmacokinetics of total alkaloids (TA) was investigated in SD rat plasma by a fully-validated LC-MS/MS method. Then, an ovalbumin (OVA)-sensitized airways allergic inflammatory model was established, in which mice were intra-gastrically administrated by 3 times a day (8.3 and 16.7mg/kg) based on the pharmacokinetic behavior of TA) and single (25, 50mg/kg) treatment regimen. Dexamethasone was used as a positive control for corticosteroid drugs. Cellular infiltration was assessed in the broncho-alveolar lavage fluid (BALF). Expressions of interleukin-4 (IL-4) and interleukin-10 (IL-10) in the BALF were determined, levels of immunoglobulin E (IgE) and eotaxin in serum were measured, and superoxide dismutase (SOD) activities as well as malondialdehyde (MDA) content in the serum and BALF were examined. Finally, histopathological examination in the lung was assessed by H. E. staining. RESULTS: The time course of plasma concentration of 4 bioactive indole alkaloids fitted an open two-compartment model after oral administration of total alkaloids at doses of 10, 25, and 50mg/kg. The area under the curve and the maximum concentration values of four major alkaloids increased dose-dependently, and half-life suggested a short-lasting pharmacological effect. Then, an ovalbumin-provoked airways allergic inflammatory model indicated that the pharmacological effect of administration of total alkaloids 3 times a day was a little better than that of single dose daily. The percentage of eosinophils in BALF was reduced obviously and the pathological damage of lung was also attenuated. There was also a significant reduction in IL-4 and promotion in IL-10 in the BALF. Serum IgE and eotaxin expression also significantly decreased in treated animals. Furthermore, the activity of SOD elevated remarkably and lipid peroxidation product (MDA) decreased in the administrated mice. CONCLUSION: The pharmacological effects administrated for 3 times a day had precedence over single dose daily, which was related to the prolonged retention time and the maintained plasma concentration. Moreover, scholaricine and vallesamine might be responsible for the treatment of allergic asthma, mainly in total alkaloids.
BACKGROUND:Alstonia scholaris (L.) R. Br. (Apocynaceae), an important herbal medicine, has been widely used to treat respiratory tract diseases, such as cough, asthma, phlegm, and chronic obstructive pulmonary disease. PURPOSE: To evaluate pharmacological effect of alkaloids from A. scholaris on ovalbumin induced airways allergic inflammatory model, and explore whether the dosing frequency is related to pharmacokinetics. STUDY DESIGN: After oral administration of total alkaloids, the pharmacokinetic study of it was investigated. In addition, anti-allergic studies were carried out on ovalbumin-sensitized airways allergic inflammatory model of mice. METHODS: The pharmacokinetics of total alkaloids (TA) was investigated in SD rat plasma by a fully-validated LC-MS/MS method. Then, an ovalbumin (OVA)-sensitized airways allergic inflammatory model was established, in which mice were intra-gastrically administrated by 3 times a day (8.3 and 16.7mg/kg) based on the pharmacokinetic behavior of TA) and single (25, 50mg/kg) treatment regimen. Dexamethasone was used as a positive control for corticosteroid drugs. Cellular infiltration was assessed in the broncho-alveolar lavage fluid (BALF). Expressions of interleukin-4 (IL-4) and interleukin-10 (IL-10) in the BALF were determined, levels of immunoglobulin E (IgE) and eotaxin in serum were measured, and superoxide dismutase (SOD) activities as well as malondialdehyde (MDA) content in the serum and BALF were examined. Finally, histopathological examination in the lung was assessed by H. E. staining. RESULTS: The time course of plasma concentration of 4 bioactive indole alkaloids fitted an open two-compartment model after oral administration of total alkaloids at doses of 10, 25, and 50mg/kg. The area under the curve and the maximum concentration values of four major alkaloids increased dose-dependently, and half-life suggested a short-lasting pharmacological effect. Then, an ovalbumin-provoked airways allergic inflammatory model indicated that the pharmacological effect of administration of total alkaloids 3 times a day was a little better than that of single dose daily. The percentage of eosinophils in BALF was reduced obviously and the pathological damage of lung was also attenuated. There was also a significant reduction in IL-4 and promotion in IL-10 in the BALF. Serum IgE and eotaxin expression also significantly decreased in treated animals. Furthermore, the activity of SOD elevated remarkably and lipid peroxidation product (MDA) decreased in the administrated mice. CONCLUSION: The pharmacological effects administrated for 3 times a day had precedence over single dose daily, which was related to the prolonged retention time and the maintained plasma concentration. Moreover, scholaricine and vallesamine might be responsible for the treatment of allergic asthma, mainly in total alkaloids.
Authors: Divya Kanchibhotla; Saumya Subramanian; Reddy M Ravi Kumar; K R Venkatesh Hari; Monika Pathania Journal: J Ayurveda Integr Med Date: 2022-06-23
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