Dengue extract of Carica papaya leaves (PLE) against dengue

 Dengue disease is characterized by markeddecrease in platelet count which is life threatening. In the present study, weinvestigated the anti-viral activity of aquous extract of Carica papaya leaves (PLE) againstdengue virus (DENV) and its effect on platelet augmentation. Anti-dengueactivity of PLE in DENV infected THP-1 cells was determined by immunoblottingand flow cytometry. Effect of PLE on erythrocyte damage was determined byhemolytic and anti-hemolytic assays. Virus infected THP-1 cells were assayedfor IFN-? secretion.  Its effect onplatelet augmentation in cyclophosphamide induced thrombocytopenic rats wasalso examined. The rats were divided into five groups, control,  cyclophosphamide control, PLE only treated group,cyclophosphamide induced rats in which PLE dose was given prophylactically andin fifth group PLE dose was given therapeutically after establishment ofthrombocytopenia.

Plateletcount of blood from retro orbital plexus of rats was examined atdifferent time interval of 1st, 4th, 7th, 11th and 14 thday of study.  On 14 th  dayrats were sacrificed for  histopathological examination  of  liver, kidney and spleen . Plasma of thrombocytopenicrats was examined for TPO and IL-6 secretion.

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 PLE significantlydecreased the expression of DENV envelope and NS1 protein in DENV infectedTHP-1 cells. Marked decrease in intracellular viral load by PLE confirmed itsantiviral activity.PLE was found to significantly decrease erythrocyte damageand hydrogen peroxide induced lipid peroxidation in vitro. In in vivothrombocytopenia study average platelet count in  control rats was 595.33±15.9 ×103/mm3 on day 1. Platelet count in cyclophosphamide group started to fall after Day3 (239.5± 40.

63×103/ mm3incyclophosphamide and  252.33 ± 20.36 × 103/ mm3in therapeutic) and remarkable thrombocytopeniadeveloped after day 7 (200.

5 ±31.26 × 103/mm3 incyclophosphamide  and 172.66 ± 14.

1 × 103/mm3in therapeutic). However in third groupinterestingly, there was only mild decrease in platelet count (415 ± 13.2 ×105/mm3)  and on day 11 it reaches normal level (606.17 ±65.

94 × 103/ mm3). PLEalso increases platelet count  significantly in the fourth group (578.33± 57 ×103/mm3) at day14. PLE was also found to increase rat IL-6 and TPO levels in thrombocytopenicrat plasma.

 Our findings suggestthat PLE can be used as a potential antiviral agent as it helps in plateletaugmentation and exhibits excellent antiviral activity against DENV.                                                                              IntroductionDengue is an  arboviral disease caused by dengue virus (DENV) belonging to the family Flaviviridae. It is endemic throughouttropical and sub-tropical regions of the world causing around 390 million newinfections annually (Bhatt S et al., 2013). It is asymptomatic in majority ofpeople but   may cause dengue fever in few cases but ifuntreated it may lead to dengue  hemorrhagic fever (DHF)  or in some instances results in a hypovolemicshock syndrome, dengue shock syndrome (DSS) with the hallmark symptom of thrombocytopenia  (Henchal et al.,1990). Studies suggest that the lowplatelet count is one of the major causes of bleeding in these patients. Theplatelet count drops below normal level (150,000–450,000 platelets/? L) and may reach as low as < 40000platelets/? L during day 3–7 of fever in manypatients.

Thrombocytopeniahas always been one of the most decisive criteria used by WHO guidelines as apotential indicator of clinical severity WHO book. In WHO guidelines, thedefinitions generally describe a rapid decline in platelet count or a plateletcount less than 150,000 per microliter of blood WHO book.Several reasons are held responsible for thrombocytopenia in dengue diseaselike bone marrow suppression, increased platelet destruction, plateletdysfunction, imbalance between coagulation, fibrinolysis and anti-coagulantpathways,  (Azeredo 2015). Recently  ojhaet.al.

has reported that platelet activation determines the severity ofthrombocytopenia in dengue infection (Ojha et al., 2017).  There is no approvedanti-dengue drug or vaccine available in the market although Dengvaxia vaccineof sanofi Pasteur has shown promising results in clinical trials but still itis not safe for use by children ( Guy et. al., 2011).

Natural productshave been the main source of test materials in the development of antiviraldrugs based on traditional medical practices (Jassim and Naji, 2003). Theseproducts are considered to be effective and non-toxic. Currently, not a singlenatural product has actually been approved as an antiviral drug against DENV,although few are reported to have antiviral activity ( Mishra, et al.,2013;  Latifah 2013; Zandi et al.,  2012, Sharma et al. 2016 ). Carica papaya, commonly known as papayais a tree-like herbaceous plant, belonging to the family Caricacea. It is cultivated globally mainly for its fruit (Silva etal.

, 2007). Its almost all parts are used for miscellaneous purposes likefruits beside being used for edible purpose, also have anti-bacterialproperties (Emeruwa1982)  Papaya leaves are  reported to reduce symptoms of asthma,worming and dysentery (Parle M and Guruditta 2011)it also has  anti-cancerous properties (Noriko O et. al.,  2010).

 Carica papaya leaf extracts areprescribed as a tonic for heart and also for the treatment of fever, pyrexia,diabetes, gonorrhea, syphilis, inflammation and dressing foul wounds (Hasheen2007, Aruoma 2006, Mehdipour 2006). Previousphytochemical analysis (Baskaran 2012)reveals the presence of flavonoids, alkaloids, carbohydrates, saponins,glycosides, phytosterols, phenolics, terpenoids and tannins in the leaves of Caricapapaya.There are fewstudies which reports an increase in platelet count by usage of PLE in denguepatients ( Subenthiran et al. 2013, Yunita et al. 2012 )  but effect of PLE on dengue virus infection in vitro has not been studied so far.Therefore, the objective of the presentstudy was to investigate the possible anti-dengue effects of papaya leafextract and its role in platelet augmentation. Present study gives a scientificsupport that PLE can be used a potential therapeutic drug against dengue virusinfection.