Cocculus hirsutus-Derived Phytopharmaceutical Drug Has Potent Anti-dengue Activity.

Rahul Shukla,Ajai Prakash Gupta,Shivam Chaturvedi,Harish Madan,Ankur Poddar,Rinku Kalra,D Srinivasa Reddy,Upasana Arora,Navin Khanna,Ram A Vishwakarma,Prasoon Gupta,Richa Ahuja,Ruchi Sood,Sumeet Gairola,Rajgokul K Shanmugam,Hemalatha Beesetti,Ravindra Patil,Bhupendra Vashishta,Sumit Madan,Tapesh Jain,Kaushal Nayyar,Deepika Singh,Venugopal Singamaneni,Pankaj Kumar,Ravi Kant Rajpoot,Altaf A Lal,Yashbir S Bedi

doi:10.3389/fmicb.2021.746110

Abstract

Dengue is a serious public health concern worldwide, with ∼3 billion people at risk of contracting dengue virus (DENV) infections, with some suffering severe consequences of disease and leading to death. Currently, there is no broad use vaccine or drug available for the prevention or treatment of dengue, which leaves only anti-mosquito strategies to combat the dengue menace. The present study is an extension of our earlier study aimed at determining the in vitro and in vivo protective effects of a plant-derived phytopharmaceutical drug for the treatment of dengue. In our previous report, we had identified a methanolic extract of aerial parts of Cissampelos pareira to exhibit in vitro and in vivo anti-dengue activity against all the four DENV serotypes. The dried aerial parts of C. pareira supplied by local vendors were often found to be mixed with aerial parts of another plant of the same Menispermaceae family, Cocculus hirsutus, which shares common homology with C. pareira. In the current study, we have found C. hirsutus to have more potent anti-dengue activity as compared with C. pareira. The stem part of C. hirsutus was found to be more potent (∼25 times) than the aerial part (stem and leaf) irrespective of the extraction solvent used, viz., denatured spirit, hydro-alcohol (50:50), and aqueous. Moreover, the anti-dengue activity of stem extract in all the solvents was comparable. Hence, an aqueous extract of the stem of C. hirsutus (AQCH) was selected due to greater regulatory compliance. Five chemical markers, viz., Sinococuline, 20-Hydroxyecdysone, Makisterone-A, Magnoflorine, and Coniferyl alcohol, were identified in fingerprinting analysis. In a test of primary dengue infection in the AG129 mice model, AQCH extract at 25 mg/kg body weight exhibited protection when administered four and three times a day. The AQCH was also protective in the secondary DENV-infected AG129 mice model at 25 mg/kg/dose when administered four and three times a day. Additionally, the AQCH extract reduced serum viremia and small intestinal pathologies, viz., viral load, pro-inflammatory cytokines, and vascular leakage. Based on these findings, we have undertaken the potential preclinical development of C. hirsutus-based phytopharmaceutical, which could be studied further for its clinical development for treating dengue.

Highlights

Dengue is a mosquito-borne disease caused by infection of one or more of the four antigenically distinct dengue virus (DENV) serotypes
This study involved experiments on AG129 mice, which were performed at the International Centre for Genetic Engineering and Biotechnology, New Delhi (ICGEB/Institutional Animal Ethics Committee (IAEC)/08/2016/RGP-15), in compliance with the Committee for the Purpose of Control and Supervision of Experiments on Animals guidelines issued by the Government of India
In our previous study (Sood et al, 2015), a total of 19 plants were evaluated for their anti-dengue activity, two of which C. pareira and Tinospora cordifolia belonged to the family Menispermaceae, and both of them were found to possess anti-dengue activity

Summary

Introduction

Dengue is a mosquito-borne disease caused by infection of one or more of the four antigenically distinct dengue virus (DENV) serotypes. Population growth, increased international travel, rapid urbanization, and ineffectual vector control strategies have led to an expansion of the dengue disease footprint worldwide. At this time, dengue is endemic in more than 100 countries in South-East Asia, Eastern Mediterranean, Western Pacific, Americas, and Africa (Gubler, 2011; Struchiner et al, 2015; Wilder-Smith et al, 2019). According to a Global Burden of Disease study, dengue alone inflicts a total of ∼58 million symptomatic dengue virus infections worldwide, which estimates USD 8–9 billion annual economic burden for dengue illness globally as per 2013 prices (Shepard et al, 2016; Stanaway et al, 2016)

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