Possible role of traditional medicinal plant Neem (Azadirachta indica) for the management of COVID-19 infection

The novel corona virus disease (COVID-19) was originated from Wuhan, China. Afterwards, COVID-19 outbreak was declared as a Public Health Emergency of International Concern by the World Health Organization (WHO). Now, around two and a half million people are suffering and several thousand are deadworldwide due to the highly infectious and deadly nature of the virus. Unfortunately, no standard medicine or vaccine is available to treat the disease. Themajor clinical symptoms of COVID-19 are fever, chills, cough, fatigue, respiratory symptoms, diarrhoea, and shortness of breath. Clinical symptombased Indian traditional medicinal practices like Ayurveda and Siddha could be bene icial to treat and prevent the infection. Indian origin traditional medicinal plant Neem (Azadirachta indica) has been reported to have antiviral potential against bovine herpes virus type-1, poliovirus type 1, duck plague virus, dengue virus type-2, newcastle disease virus, infectious bursal disease virus, avian in luenza virus, and group B coxsackievirus. Neem is widely used as Ayurvedic medicine to treat fever, cough, asthma, and diarrhoea, which are also reported as the common clinical symptoms of COVID-19. Neem is reported to enhance both humoral and cell-mediated immune response during viral infection. Multidimensional antiviral therapeutic potentials of Neem insist on hypothesizing its probable application to control COVID-19 along with modern medicinal practices. But, a series of experimental database and translational research is required to establish the hypothesis.


COVID-19 outbreak
The World Health Organization (WHO) declared novel corona virus disease (COVID-19) outbreak as a Public Health Emergency of International Concern on January 30, 2020. Earlier, COVID-19 was also known as 2019-nCoV. It originated from Wuhan city of Hubei province in China (Xiang et al., 2020). On March 11, 2020, the WHO declared COVID-19 outbreak as a pandemic (Cucinotta and Vanelli, 2020) . According to the WHO, as of April 22, 2020 (05:30 GMT+5:30), about 24,71,136 people were suffering and over 1,69,006 had died due to corona virus infection from 213 countries worldwide. Corona virus infection might result in massive alveolar damage and progressive respiratory failure. The initial clinical symptoms are fever, chills, cough, fatigue, respiratory symptoms, diarrhoea, and shortness of breath (Xu et al., 2020;Chan et al., 2020). Standard vaccines and antiviral agents could be bene icial to prevent and treat this disease. Unfortunately, there is no such medicine identi ied yet to treat COVID-19. Development of antiviral drug or vaccine may require months or years when immediate treatment is required to stop this highly infectious disease. The Chinese government is appreciating the use of traditional herbal medicine for the treatment of COVID-19 patients (hai Zhang et al., 2020). Traditional Chinese medicine was found to be bene icial and effective to treat severe acute respiratory syndrome associated coronavirus (SARS-CoV) infection (Li et al., 2005;Wen et al., 2011). However, herbal treatments are mainly dependent on the sign and symptoms of the patients. Further studies are required to specifically target viral causes (hai Zhang et al., 2020). In this sense, traditional herbal plants having antiviral potential can be used to treat COVID-19 infection depending upon sign and symptoms.

Neem (Azadirachta indica) as an antiviral agent
Indian origin traditional medicinal plant Neem (Azadirachta indica) has been used to treat several acute and chronic diseases in different parts of Asia and Africa from the ancient period. The medicinal importance of Neem has been mentioned in the Indian, age-old medical systems like Ayurveda and Siddha. The insecticidal, antimicrobial, larvicidal, antimalarial, antibacterial, antiviral, and spermicidal effect of different parts of the plant, including lowers, leaves, seeds and barks, was found to bene icial to treat several microbial diseases (Gupta et al., 2017). Neem has been denoted as "the tree of the 21 st century" by the United Nations for its multi-therapeutic application (Tapanelli et al., 2016). Water extracted polysaccharides (pectic arabinogalactan) from Azadirachta indica leaves was found to have antiviral activity against bovine herpes virus type-1 (BoHV-1) (Kumar and Navaratnam, 2013) . Azadirachta indica leaves derived polysaccharides were also observed to have in vitro antiviral potential against poliovirus type 1 (PV-1) (Faccin-Galhardi et al., 2012). Neem seed kernel extract was observed to have in vitro antiviral effect against duck plague virus (Xu et al., 2012). Neem bark extract was found to be effective against herpes simplex virus type-1 under in vitro condition (Tiwari et al., 2009). Neem oil was found to have in vitro antiviral effect against polio (SaiRam et al., 2000). Aqueous extract of Neem leaves was found to have both in vivo and in vitro antiviral potential against dengue virus type-2 (Parida et al., 2002). Neem leaves in broiler feed were recorded to be bene icial for immunity of commercial broilers against Newcastle disease and infectious bursal dis-ease like viral infections (Zahid et al., 2013). Neem bark extract and leaf extract were found to have antiviral potential against highly pathogenic avian in luenza virus (H5N1) (Schoonheim-Klein et al., 2016) and group B coxsackieviruses (Badam et al., 1999), respectively.

Possible application of Neem for COVID-19 treatment
Fever, cough, respiratory symptoms, and shortness of breath are reported as the common clinical symptoms for COVID-19 infected patients (Xu et al., 2020). Neem leaf crude extract is a widely used Ayurvedic medicine to treat normal fever and malarial fever (Al-Hashemi and Hossain, 2016;Sujarwo et al., 2016). Crude aqueous extract of Neem leaves was also recorded to be effective against Dengue fever-related clinical symptoms in suckling mice model. The Neem leaves extract was observed to have inhibitory potential on Dengue virus type-2 replication under both in vivo and in vitro conditions (Parida et al., 2002). Neem twig had been mentioned in Ayurveda to relieve cough and asthma . Diarrhoea is another commonly observed clinical symptom for COVID-19 infected patients. Neem leaves are used to treat gastrointestinal disorder like diarrhoea in different parts of India as a traditional practice (Thakurta et al., 2007). Additionally, Neem leaf, lower, and stem bark extracts were observed to have strong antioxidant potential (Sithisarn et al., 2005). The extract of dried Neem leaves was recorded to enhance antioxidants in the rat model (Ghatule et al., 2012). Neem bark extract was observed to have antioxidant potential by directly scavenging the hydroxyl radical (OH) and preventing the hydroxyl radical-mediated oxidative damage in the rat model  . Most importantly, Neem leaves extract was reported to induce a cell-mediated and humoral immune response in albino mice model (Ray et al., 1996). Neem leaf glycoprotein was observed to be effective in maintaining normal immune homeostasis by upregulating type 1 response in mice (Bose et al., 2009). Aqueous preparation of Neem leaf was also observed to enhance Th1 type immune responses against breast tumour associated antigen in mice and rat (Mandal-Ghosh et al., 2007). Studies suggested that Neem leaves in broiler feed could be bene icial for the antibody production against the newcastle and infectious bursal disease viruses (Zahid et al., 2013) . Similarly, Neem leaf extract was found to enhance immunity in HIV/AIDS patients by increases CD4 + cell levels (Mbah et al., 2007). Even Neem leaf extract was reported to act as an adjuvant to increase the immunogenicity of poorly immuno-genic surface antigen vaccine in mice model (Baral et al., 2005) . Neem leaf glycoprotein was observed to induce dendritic cell maturation (Goswami et al., 2010) and macrophage-mediated antigen presentation in mice model (Sarkar et al., 2008).
No experimental data is available to correlate the medicinal potential of Neem for the treatment of COVID-19 patients. Due to its multidimensional therapeutic potential, it can be hypothesized that Neem could be an effective ayurvedic medicine for the prevention and treatment of COVID-19 in addition to modern medicinal practices. A series of experimental database and translational research is required to establish the standard formulation of Neem or Neem-derived components to treat or prevent highly infectious COVID-19.

CONCLUSIONS
Neem is a widely used ayurvedic medicine having antiviral potential. Neem could be a probable ayurvedic medicine to prevent and treat COVID-19 infection through enhancement of immune response. Strong antioxidant potential of Neem may play a bene icial role during the treatment of highly infectious and deadly viral disease.