In vitro and in vivo effects of Peganum harmala L. seeds extract against influenza A virus

Document Type : Original Research Article

Authors

1 Students Research Committee, Medical Plants Research Center, Shahrekord University of Medical Science, Shahrekord, Iran

2 Medical Plants Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran

3 Department of Influenza and other Respiratory Viruses, Pasteur Institute of Iran, Tehran, Iran

4 Department of Epidemiology and Biostatistics, Shahrekord University of Medical Sciences, Shahrekord, Iran

Abstract

Objective: Influenza A virus infections are still a major health problem and the choices available for the control and treatment of the disease are limited. This research evaluated in vitro and in vivo antiviral effects of Peganum harmala L. seeds (PHS) extract against influenza A virus.
Materials and Methods: In this research, in vitro anti-influenza A virus activity of the extract was assessed in Madin-Darby canine kidney (MDCK) cells. In order to evaluate anti-influenza activity of PHS extract in vivo, BALB/c mice were infected with 5LD50 of mouse-adapted influenza virus (H1N1; PR8) and received 200 mg/kg/day of PHS extract or 20 mg/kg/day oseltamivir. Lungs of seven mice per group were removed on day 3 post-infection and lung virus titers were determined by qRT-PCR. Mice survival, body weights and general conditions were observed for up to 14 days post-infection.
Results: The results demonstrated that, the ethanolic extract of PHS possesses high activity against influenza virus with IC50 value of 15.7 (CI95%:11.7-21) μg/ml in MDCK cells. Our results also showed that, oral administration of PHS extract (200 mg/kg/day) or oseltamivir (20 mg/kg/day) to infected mice, increased the survival rate, reduced body weight loss, and decreased lung virus titer.
Conclusion: Based on our findings, P. harmala seeds extract can inhibit influenza A virus replication in vitro and in vivo. Therefore, isolation and characterization of the plant’s active compounds and investigation of the underlying mechanisms of its antiviral action are highly suggested.

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Main Subjects


Aarons DH, Rossi GV , Orzechowski RF. 1977. Cardiovascular actions of three harmala alkaloids: harmine, harmaline, and harmalol. J Pharm Sci, 66:1244-1248.
Akbari F, Ansari-Samani R, Karimi A, Mortazaei S, Shahinfard N ,Rafieian-Kopaei M. 2013. Effect of turnip on glucose and lipid profiles of alloxan-induced diabetic rats. Iran J Endocrin Metabol, 14: 492-497
Aqel M ,Hadidi M. 1991. Direct Relaxant Effect of Peganum Harmala Seed Extract on Smooth Muscles of Rabbit and Guinea Pig. Int J Pharmacogn, 29:176-182.
Asgarpanah J , Ramezanloo F. 2012. Chemistry, pharmacology and medicinal properties of Peganum harmala L. Afr J pharm pharmacol, 6:1573-1580.
Astulla A, Zaima K, Matsuno Y, Hirasawa Y, Ekasari W, Widyawaruyanti A, Zaini NC ,Morita H. 2008. Alkaloids from the seeds of Peganum harmala showing antiplasmodial and vasorelaxant activities. J Nat Med, 62:470-472.
Berrougui H, Martin-Cordero C, Khalil A, Hmamouchi M, Ettaib A, Marhuenda E ,Herrera MD. 2006. Vasorelaxant effects of harmine and harmaline extracted from Peganum harmala L. seeds in isolated rat aorta. Pharmacol Res, 54:150-157.
Bukhari N, Choi J, Jeon C, Park H, Kim W, Khan MA ,Leet S. 2008. Phytochemical studies of the alkaloids from Peganum harmala. Applied Cham, 12:101-104.
Cannell JJ, Zasloff M, Garland CF, Scragg R ,Giovannucci E. 2008. On the epidemiology of influenza. Virol J, 5:422X-425.
Chiou WF, Chen CC , Wei BL. 2011. 8-Prenylkaempferol Suppresses Influenza A Virus-Induced RANTES Production in A549 Cells via Blocking PI3K-Mediated Transcriptional Activation of NF-kappaB and IRF3. Evid Based Complement Alternat Med, 2011:920828.
Cos P, Vlietinck AJ, Berghe DV ,Maes L. 2006. Anti-infective potential of natural products: how to develop a stronger in vitro 'proof-of-concept'. J Ethnopharmacol, 106:290-302.
Dang Z, Jung K, Zhu L, Lai W, Xie H, Lee KH, Huang L ,Chen CH. 2014. Identification and Synthesis of Quinolizidines with Anti-Influenza A Virus Activity. ACS Med Chem Lett, 5:942-946.
Dapat C, Kondo H, Dapat IC, Baranovich T, Suzuki Y, Shobugawa Y, Saito K, Saito R ,Suzuki H. 2013. Neuraminidase inhibitor susceptibility profile of pandemic and seasonal influenza viruses during the 2009-2010 and 2010-2011 influenza seasons in Japan. Antiviral Res, 99:261-269.
Dawood FS, Jain S, Finelli L, Shaw MW, Lindstrom S, Garten RJ, Gubareva LV, Xu X, Bridges CB ,Uyeki TM. 2009. Emergence of a novel swine-origin influenza A (H1N1) virus in humans. N Engl J Med, 360:2605-2615.
Fortunato JJ, Reus GZ, Kirsch TR, Stringari RB, Stertz L, Kapczinski F, Pinto JP, Hallak JE, Zuardi AW, Crippa JA ,Quevedo J. 2009. Acute harmine administration induces antidepressive-like effects and increases BDNF levels in the rat hippocampus. Prog Neuropsychopharmacol Biol Psychiatry, 33:1425-1430.
Ge H, Wang YF, Xu J, Gu Q, Liu HB, Xiao PG, Zhou J, Liu Y, Yang Z ,Su H. 2010. Anti-influenza agents from Traditional Chinese Medicine. Nat Prod Rep, 27:1758-1780.
Hamsa TP ,Kuttan G. 2010. Harmine inhibits tumour specific neo-vessel formation by regulating VEGF, MMP, TIMP and pro-inflammatory mediators both in vivo and in vitro. Eur J Pharmacol, 649:64-73.
Hamsa TP , Kuttan G. 2011. Harmine activates intrinsic and extrinsic pathways of apoptosis in B16F-10 melanoma. Chin Med, 6:11.
Hayden F. 2009. Developing new antiviral agents for influenza treatment: what does the future hold? Clin Infect Dis, 48 Suppl 1:S3-13.
He J, Qi WB, Wang L, Tian J, Jiao PR, Liu GQ, Ye WC , Liao M. 2013. Amaryllidaceae alkaloids inhibit nuclear-to-cytoplasmic export of ribonucleoprotein (RNP) complex of highly pathogenic avian influenza virus H5N1. Influenza Other Respir Viruses, 7:922-931.
Hudson JB, Graham EA, Fong R, Hudson LL ,Towers GH. 1986. Further studies on the antiviral activity of harmine, a photoactive beta-carboline alkaloid. Photochem Photobiol, 44:483-487.
Ishida J, Wang HK, Oyama M, Cosentino ML, Hu CQ ,Lee KH. 2001. Anti-AIDS agents. 46. Anti-HIV activity of harman, an anti-HIV principle from Symplocos setchuensis, and its derivatives. J Nat Prod, 64:958-960.
Jackson RJ, Cooper KL, Tappenden P, Rees A, Simpson EL, Read RC ,Nicholson KG. 2011. Oseltamivir, zanamivir and amantadine in the prevention of influenza: a systematic review. J Infect, 62:14-25.
Jadhav P, Kapoor N, Thomas B, Lal H ,Kshirsagar N. 2012. Antiviral potential of selected Indian medicinal (ayurvedic) plants against herpes simplex virus 1 and 2. N Am J Med Sci, 4:641-647.
Jang YJ, Achary R, Lee HW, Lee HJ, Lee CK, Han SB, Jung YS, Kang NS, Kim P ,Kim M. 2014. Synthesis and anti-influenza virus activity of 4-oxo- or thioxo-4,5-dihydrofuro[3,4-c]pyridin-3(1H)-ones. Antiviral Res, 107:66-75.
Jbilou R, Amri H, Bouayad N, Ghailani N, Ennabili A , Sayah F. 2008. Insecticidal effects of extracts of seven plant species on larval development, alpha-amylase activity and offspring production of Tribolium castaneum (Herbst) (Insecta: Coleoptera: Tenebrionidae). Bioresour Technol, 99:959-964.
Jefferson T, Di Pietrantonj C, Debalini MG, Rivetti A ,Demicheli V. 2009. Inactivated influenza vaccines: methods, policies, and politics. J Clin Epidemiol, 62:677-686.
Karimi A, Moradi MT, Alidadi S , Hashemi L. 2016. Anti-adenovirus activity, antioxidant potential, and phenolic content of black tea (Camellia sinensis Kuntze) extract. J Complement Integr Med, 13:357-363.
Kiani S, Shamsi Shahrabadi M, Ataei A ,Sajjadi N. 2008. Peganum harmala seed extract can prevent HSV-1 replication in vitro. Iran J Virol, 4:11-16.
Kim Y, Narayanan S, Chang KO. 2010. Inhibition of influenza virus replication by plant-derived isoquercetin. Antiviral Res, 88:227-235.
Kodama E, Shigeta S, Suzuki T, De Clercq E. 1996. Application of a gastric cancer cell line (MKN-28) for anti-adenovirus screening using the MTT method. Antiviral Res, 31:159-164.
Lackenby A, Thompson CI ,Democratis J. 2008. The potential impact of neuraminidase inhibitor resistant influenza. Curr Opin Infect Dis, 21:626-638.
Madihi Y, Merrikhi A, Baradaran A, Ghobadi S, Shahinfard N, Ansari R, Karimi A, Mesripour A ,Rafieian-Kopaei M. 2013. Bioactive components and the effect of hydroalcoholic extract of Vaccinium myrtillus on postprandial atherosclerosis risk factors in rabbits. Pak J Med Sci, 29:384-389.
Mahmoudian M, Jalipour H , Salehian Dardashti P. 2002. Toxicity of Peganum harmala: Review and a Case Report. Iran J Pharmacol Therapeut, 1:1-4.
Mehrbod P, Ideris A, Omar AR, Hair-Bejo M, Tan SW, Kheiri MT ,Tabatabaian M. 2012. Attenuation of influenza virus infectivity with herbal-marine compound (HESA-A): an in vitro study in MDCK cells. Virol J, 9:44.
Mina CN, Farzaei MH ,Gholamreza A. 2015. Medicinal properties of Peganum harmala L. in traditional Iranian medicine and modern phytotherapy: a review. J Tradit Chin Med, 35:104-109.
Mirhosseini M, Baradaran A , Rafieian-Kopaei M. 2014. Anethum graveolens and hyperlipidemia: A randomized clinical trial. J Res Med Sci, 19:758-761.
Moloudizargari M, Mikaili P, Aghajanshakeri S, Asghari MH ,Shayegh J. 2013. Pharmacological and therapeutic effects of Peganum harmala and its main alkaloids. Pharmacogn Rev, 7:199-212.
Moradi B, Heidari-Soureshjani S, Asadi-Samani M, Yang Q. 2017. A systematic review of phytochemical and phytotherapeutic characteristics of bitter almond. Int J Pharm Phytopharmacol Res, 7(2):1-9.
Moradi MT, Karimi A, Alidadi S. 2016. In vitro antiproliferative and apoptosis-inducing activities of crude ethyle alcohole extract of Quercus brantii L. acorn and subsequent fractions. Chin J Nat Med, 14:196-202.
Moradi MT, Rafieian-Kopaei M, Karimi A. 2016. A review study on the effect of Iranian herbal medicines against in vitro replication of herpes simplex virus. Avicenna J Phytomed, 6:506-515.
Mosmann T. 1983. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods, 65:55-63.
Nasehi M, Piri M, Nouri M, Farzin D, Nayer-Nouri T , Zarrindast MR. 2010. Involvement of dopamine D1/D2 receptors on harmane-induced amnesia in the step-down passive avoidance test. Eur J Pharmacol, 634:77-83.
Nenaah G. 2010. Antibacterial and antifungal activities of (beta)-carboline alkaloids of Peganum harmala (L) seeds and their combination effects. Fitoterapia, 81:779-782.
Pan QM, Li YH, Hua J, Huang FP, Wang HS ,Liang D. 2015. Antiviral Matrine-Type Alkaloids from the Rhizomes of Sophora tonkinensis. J Nat Prod, 78:1683-1688.
Perrone LA, Plowden JK, Garcia-Sastre A, Katz JM , Tumpey TM. 2008. H5N1 and 1918 pandemic influenza virus infection results in early and excessive infiltration of macrophages and neutrophils in the lungs of mice. PLoS Pathog, 4:e1000115.
Reed LJ ,Muench H. 1938. A simple method of estimating fifty per cent endpoints. Am J Epid, 27:493-497.
Rharrabe K, Bakrim A, Ghailani N ,Sayah F. 2007. Bioinsecticidal effect of harmaline on Plodia interpunctella development (Lepidoptera: Pyralidae). Pestic Biochem Physiol, 89:137-145.
Rouhi-Boroujeni H, Heidarian E, Rouhi-Boroujeni H, Deris F ,Rafieian-Kopaei M. 2017. Medicinal plants with multiple effects on cardiovascular diseases: A systematic review. Curr Pharm Des, 23:999-1015.
Sarrafchi A, Bahmani M, Shirzad H ,Rafieian-Kopaei M. 2016. Oxidative stress and Parkinson's disease: New hopes in treatment with herbal antioxidants. Curr Pharm Des, 22:238-246.
Sathiyamoorthy P, Lugasi-Evgi H, Schlesinger P, Kedar I, Gopas J, Pollack Y ,Golan-Goldhirsh A. 1999. Screening for cytotoxic and antimalarial activities in desert plants of the negev and bedouin market plant products. Pharmaceut Biol, 37:188-195.
Schmittgen TD ,Livak KJ. 2008. Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc, 3:1101-1108.
Sewell RDE , Rafieian-Kopaei M. 2014. The history and ups and downs of herbal medicines usage. J Herbmed Pharmacol, 3:1-3.
Shahrani M, Rafieian M, Shirzad H, Hashemzadeh M, Yousefi H, Khadivi R, Amini SA, Dehghan M, Khayri S, Moradi M, Rahimian G ,Gheitasi I. 2007. Effect of Allium sativum L. extract on acid and pepsin secretion in basal condition and stimulated with vag stimulate in rat. J Med Plant, 6:28-37.
Shahverdi AR, Ostad SN, Khodaee S, Bitarafan L, Monsef-Esfahani HR, Jamalifar H, Nikavar B ,Mohseni M. 2008. PHCOG MAG.: Research Article Antimicrobial and cytotoxicity potential of Peganum harmala smoke. Phcog Mag, 4:236.
Shayganni E, Bahmani M, Asgary S ,Rafieian-Kopaei M. 2016. Inflammaging and cardiovascular disease: Management by medicinal plants. Phytomedicine, 23:1119-1126.
Splettstoesser F, Bonnet U, Wiemann M, Bingmann D ,Busselberg D. 2005. Modulation of voltage-gated channel currents by harmaline and harmane. Br J Pharmacol, 144:52-58.
van der Vries E, Schutten M, Fraaij P, Boucher C ,Osterhaus A. 2013. Influenza virus resistance to antiviral therapy. Adv Pharmacol, 67:217-246.
WHO . 2016. Avian and other zoonotic influenza: fact sheet.  http://www.who.int/mediacentre/factsheets/avian_influenza/en/
WHO . 2011. Manual for the Laboratory Diagnosis and Virological Surveillance of Influenza. Global Influenza Surveillance and Response System (GISRS),  p 151.
Yu J, Wang D, Jin J, Xu J, Li M, Wang H, Dou J ,Zhou C. 2016. Antiviral activity of SA-2 against influenza A virus in vitro/vivo and its inhibition of RNA polymerase. Antiviral Res, 127:68-78.
Zaker F, Oody A ,Arjmand A. 2007. A study on the antitumoral and differentiation effects of peganum harmala derivatives in combination with ATRA on leukaemic cells. Arch Pharm Res, 30:844-849.
Zarubaev VV, Garshinina AV, Tretiak TS, Fedorova VA, Shtro AA, Sokolova AS, Yarovaya OI ,Salakhutdinov NF. 2015. Broad range of inhibiting action of novel camphor-based compound with anti-hemagglutinin activity against influenza viruses in vitro and in vivo. Antiviral Res, 120:126-133.
Zeng X, Dong Y, Sheng G, Dong X, Sun X ,Fu J. 2006. Isolation and structure determination of anti-influenza component from Mahonia bealei. J Ethnopharmacol, 108:317-319.
Zhang G, Zhang B, Zhang X ,Bing F. 2013. Homonojirimycin, an alkaloid from dayflower inhibits the growth of influenza A virus in vitro. Acta Virol, 57:85-86.
Zhao T, Wang ZT, Branford-White CJ, Xu H ,Wang CH. 2011. Classification and differentiation of the genus Peganum indigenous to China based on chloroplast trnL-F and psbA-trnH sequences and seed coat morphology. Plant Biol (Stuttg), 13:940-947.