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\begin{document}


\def\RunningAuthor{Pallavi Moreshwar Kanitkar et al.}
\firstPage{1105}
\articleType{Original Article}
\receivedDate{15 Aug 2020}
\acceptedDate{21 Sep 2020}
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\title{Neem (\textit{Azadiracta indica}) a possible silver bullet in Covid 19}
\author{Pallavi~Moreshwar~Kanitkar\textsuperscript{*}\textsuperscript{1},  
            Shanmuga~Subramanian\textsuperscript{2},  
            Neeta~Deshpande\textsuperscript{3},  
            Shirish~K\textsuperscript{4}, 
            Meera~Dhengale~Patil\textsuperscript{5}~\\[5pt]{\textsuperscript{1}Department of Shalyatantra, SAI Ayurved College, Solapur-413401, Maharashtra, India}~\\{\textsuperscript{2}Department of Mechanical Engineering, Government College of Engineering, Tirunelveli-627001, Tamil Nadu, India}~\\{\textsuperscript{3}Department of Dravyaguna, RIARCH, Ayurved College Mayani, Satara-415102, Maharashtra, India}~\\{\textsuperscript{4}Department of Kaychikitsa, Ayurved College, Ahmadnagar-422605, Maharashtra, India}~\\{\textsuperscript{5}Department of Ayurved-Rasshastra, SAI Ayurved College, Solapur-413401, Maharashtra, India}}

\begin{abstract}
In past few years, multiple new viral diseases like SARS,MARS and Ebola are emerging all over the world. Due to global warming and pollution, people are becoming more susceptible to all infectious diseases. Recurrent mutations in these viruses make it difficult to create vaccine. So again there is need of safer and natural remedies which can help to sustain health of the present world and which can be used without potential hazards. The recent pandemic of Covid 19 is one of the example of a global crisis emerged by SARS-CoV-2 virus. It is causing acute as well as silent chronic damage to various systems in human body. Neem (\textit{Azadiracta indica)} is found to have following properties as per various studies- It has Broad spectrum antiviral, antibacterial, antifungal, antiretroviral and antimalerial effect. It has proinflammatory cytokine inhibitor and immunomodulator effect. It has hepatoprotective and antioxidant effect. It has thrombolytic properties. It has ACE inhibitor action. As per its docking study, it has high inhibition against COVID-19 Main Protease. As Covid 19 is responsible for severe cytokine storm induced complications and coagulopathies, the Neem can be useful as a single Silver bullet in Covid 19 in both prophylactic and curative aspect. It can even be helpful in post Covid complications. 
\end{abstract}\def\keywordstitle{Keywords}

\begin{keywords}Covid 19,\newline SARS-CoV-2,\newline Azadiracta indica,\newline Cytokine storm,\newline Immuno modulator
\end{keywords}
\twocolumn[ \maketitle {\printKwdAbsBox}]
\makeatletter{\raggedright\textsuperscript{*}Corresponding Author\par Name:\ Pallavi~Moreshwar~Kanitkar~\\ Phone:\ 7972036497~\\  Email:\ drpallavi0000@gmail.com
        \par}\vspace*{-11pt}\hrulefill\par{\fontsize{12}{14}\selectfont ISSN: 0975-7538}\par% 
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\section{Introduction}
The virus named SARS-CoV-2 was suspected of having its origin from bats. It is now transmitted in human beings as a causative organism of the disease named Covid 19. In Wuhan (a city of China), the first case of Covid 19 was found in December 2019. In a concise duration, the disease which started in China became a pandemic. It is spreading rapidly through touch, droplets and even aerosols. Millions of people have been affected physically, mentally, socially and economically by this pandemic. 

The virus not only affected comorbid and old patients, but so many healthy people also got affected and died due to this infection. Initially, it was supposed that it could affect the respiratory system only. But gradually it is found that it is affecting almost all systems of the body. Cardiovascular system, digestive system, hepatobiliary system and even nervous system is also found to be affected in many patients due to it. It is also causing severe cytokine storm and coagulopathy. 

The virus is new, and no perfect medicine which can resolve all complications is found till date. Many antiviral medicines have been tried, but they have their demerits, including unpredictable toxicities and adverse effects. Many cases with delayed complications like lung fibrosis are also emerging now. In such a situation, there emerged the need of a safer and perfect medicine which can work as immune modulator as well as antiviral and which can prevent all complications like cytokine storm, coagulopathy and lung fibrosis.
    
\section{Materials and Methods}
This is pure literary research done to explore various properties of neem which can propose its use as a preventive and curative option for Covid 19. Various books, research papers, journals and articles have been studied to understand the possible utility of neem in the treatment of Covid19.

\textbf{Neem in ancient context}

Neem is very commonly found in India and is called as ``Free tree of India''. ` Nimba' is another name of it which means 'giver of good health'. It is also called as ``40 cures''. In Ayurveda, Neem is known as a healer of all diseases (Sarva Roga Nivarini).

It does not need any pesticide or manure to grow and is in its most natural form because of its abundance. It is more commonly found in India and some Asian countries. Neem is a traditional medicine used in Ayurveda. 

All parts of neem have their medicinal properties. Leaves, seeds, flowers have different medicinal properties and are eaten as a part of the diet on the occasion of various festivals in India like Gudi padwa. It is the main content of Arogyawardhini Rasa as well as Panchatikta ghruta which are commonly used as blood purifiers and hepatoprotective in Ayurveda \unskip~\citep{901678:20485639}. 

It is a time tested and safe antiviral as well as antibacterial medicine. Even it possesses broad antifungal properties. Neem is a tree of Meliaceae family. Neem also has Latin name \textit{Azadirachta Indica}. There are two species in the genus \textit{Azadiracta } out of which one is neem.

\textbf{Neem in Research papers}

Research has been done on the use of neem in various infectious diseases, inflammatory conditions, degenerative diseases, as well as proliferative diseases. Several research papers on neem show its multifaceted range of action \unskip~\citep{901678:20485660}.

\textbf{Neem as an Anti Viral in animals and birds}

\textbf{Neem in Infectious Bursal Disease}

Neem in extract form was studied against Infectious Bursal Disease. It was used in Cockerels vaccinated as well as experimentally infected with the virus. Humoral antibody titer was raised in birds due to the use of neem. The use of Neem leaf extract diminished the clinical signs of disease, and the death rate was also reduced. Neem is advised to be given to birds before and after vaccinations. Also, it was advised as a therapeutic option \unskip~\citep{901678:20485638}.

\textbf{Neem bark extract on new castle disease virus}

Newcastle disease virus was found to be inhibited by Neem bark extract. But Neem leaves were not found effective against it \unskip~\citep{901678:20485641,901678:20485657}.

\textbf{Neem as an Antiviral in human beings}

Neem is a broad-spectrum antiviral medicine. It is effective against many human as well as bovine viruses. Neem leaves, bark and seeds have been used against seasonal viral fevers in Indian traditional medicinal systems like Ayurveda. Scientists have studied it worldwide and found it to be effective against many viruses. Various research studies have proved it effective against these viruses. 


  
  \begin{enumerate}
  \item \relax HIV \unskip~\citep{901678:20485654,901678:20485644}. In HIV, Neem is found to increase CD4 count and reduce viral load.
  \item \relax HSV - Herpes Simplex Virus- Neem bark extract was found to inhibit the virus \unskip~\citep{901678:20485653}. Antiherpes action of a glycolipid, derived from the leaves of \textit{Azadirachta indica} is found. The production of IL-12, TNF-\ensuremath{\alpha }, IL-1\ensuremath{\beta } and IL-6 was found reduced after use of Neem \unskip~\citep{901678:20485640}.
  \item \relax Dengue \unskip~\citep{901678:20485659,901678:20485658}- It is found to be effective against Dengue type 2 virus, Chickenpox, Smallpox \unskip~\citep{901678:20485651}
  \item \relax Coxsackie B viruses which cause Hand, Foot \& Mouth Disease (HFMD) \unskip~\citep{901678:20485636}
  \item \relax Hepatitis B and C \unskip~\citep{901678:20485661,901678:20485649}
  \item \relax Influenza Virus- Compounds found in Neem have potential to become a universal medicine against influenza strains \unskip~\citep{901678:20485666}
  \item \relax Research has shown that Neem leaves can be used to stop the spread of herpes viruses to cells which are not infected \unskip~\citep{901678:20485653}. 
  \end{enumerate}
  \textbf{Neem as Anti-Inflammatory \& Immunomodulator}

Neem leaves have potent antiviral action. It also shows anti-inflammatory and anti-proliferative properties \unskip~\citep{901678:20485642}. The comparative study of Neem and Dexamethasone indicated that Neem leaves do have anti-inflammatory properties which are comparable to Dexamethasone but not equivalent to it \unskip~\citep{901678:20485656}. Neem leaves are known to act as an immunomodulator \unskip~\citep{901678:20485663,901678:20485648}.

\textbf{Anti-Diabetic properties of neem}

Research papers have also proven that Neem leaves \& seeds also have anti-Diabetic properties by effectively lowering blood glucose level with minimal or no side-effects. They are known to possess hypolipidemic, hypoglycemic, immunostimulant and hepatoprotective properties \unskip~\citep{901678:20485662,901678:20485645}.

\textbf{Neem for angiotensin-converting enzyme Inhibition}

Neem is also known to possess angiotensin-converting enzyme inhibition properties. Neem has antioxidant action and is inhibitory to an angiotensin-converting enzyme \unskip~\citep{901678:20485637,901678:20485664}. Besides all these neems is known to reduce Blood pressure \unskip~\citep{901678:20485665,901678:20485650}. And it also used in the treatment of pulmonary inflammation \unskip~\citep{901678:20485635}.

\textbf{Hepatoprotectve acton of Azadiracta indica leaves}

The study of the hepatoprotective effect of neem leaves on CCl\ensuremath{_{4\ }} induced liver damaged in rats showed that neem is having healing effects on injured hepatocytes. It is an effective hepatoprotective agent \unskip~\citep{901678:20485646}.

\textbf{Neem leaf extract has schizonticidal and gametocytocidal activities}

Neem is good antimalarial medicine as per in vitro studies done. An extract of Neem leaves was used against Plasmodium falciparum for both the asexual and the sexual forms and was found effective against it \unskip~\citep{901678:20485655}.

\textbf{Protective effects of neem on smoking-induced pulmonary inflammation}

It is found that neem reduces inflammatory changes occurred in lungs tissue due to chronic smoking. It has a protective and healing action on alveolar cells. Neutrophils and macrophages in alveolar cells were decreased after treatment with neem \unskip~\citep{901678:20485635}.

\textbf{Thrombolytic potential of Ocimum sanctum L., Curcuma longa L., Azadirachta indica L. and Anacardium occidentale L.}

It was concluded that the extracts of \textit{Ocimum sanctum, Curcuma longa, Azadirachta indica} \& \textit{Anacardium occidentale} showed thrombolytic activity \unskip~\citep{901678:20485647}.

\textbf{Neem against COVID-19 IN Docking study}

Neem leaves are known to have 100+ compounds \unskip~\citep{901678:20485643}. It was shown that 20+ compounds in Neem leaves show high inhibition against COVID-19 Main Protease (6LU7) with values ranging from -14.3 kcal/mol to a minimum of -9.1 kcal/mol and in-addition to those compounds there are other compounds from Neem leaves which exhibits medium binding affinity with COVID-19 Main Protease (6LU7) \unskip~\citep{901678:20485652}.
    
\section{Discussion}
Neem is a medicine which seems to cure so many aspects of Covid 19. Neem can be a very effective option against Covid 19 due to


  
  \begin{enumerate}
  \item \relax Broad-spectrum antiviral action
  \item \relax Antiretroviral and and antimalerial effect.
  \item \relax Antibacterial effect
  \item \relax Its action on lungs as proinflammatory cytokine inhibitor.
  \item \relax Immunomodulator effect.
  \item \relax Hepatoprotective effect.
  \item \relax Thrombolytic properties.
  \item \relax Its action as an ACE inhibitor
  \item \relax Antioxidant effect.
  \item \relax As per it's docking study, Neem shows high inhibitory action against Covid 19 virus.
  \end{enumerate}
  Neem leaves have not shown toxicity even at the dose of 6g/kg of body weight in vitro studies \unskip~\citep{901678:20485646}. As neem improves immunity and has antioxidant action, it can be advised to healthy people to take it in minimum dose. So it can be a possible prophylactic option for Covid 19.

Covid 19 is responsible for severe cytokine storm induced complications and coagulopathies. Neem inhibits proinflammatory cytokines. It also shows thrombolytic properties. Hence, Neem can be a single silver bullet due to its immunomodulator as well as thrombolytic properties other than its broad-spectrum antiviral action in mild, moderate and severe cases of Covid 19.

Yet it is unclear whether virus lingers in the body for a longer duration after acute infection. Neem has anti-inflammatory properties and protective action on alveolar cells which may prevent lung fibrosis. It may help in the healing of alveolar cells if taken over a more prolonged duration of time in post Covid cases. So Neem can have a possible role as prophylactic medicine, curative medicine and to avoid long term effects on lungs in post Covid cases. It may help in the healing of alveolar cells in post Covid cases. But it needs further clinical correlation.
    
\section{Conclusion}
The overview of properties of Neem shows that it can be a potential option as a natural prophylactic and curative medicine in Covid 19. Neem has a broad spectrum of antiviral action. As neem improves immunity and has antioxidant action, it can be advised to healthy people to take it in minimum dose. So it can be a possible prophylactic option for Covid 19. Covid 19 is responsible for severe cytokine storm induced complications and coagulopathies. Neem inhibits proinflammatory cytokines. It also shows thrombolytic properties. And hence it can be useful even in cytokine storm and complications related to it. Neem has anti-inflammatory properties and protective action on alveolar cells which may prevent lung fibrosis. It may help in the healing of alveolar cells in post Covid cases. Hence Neem can be a single silver bullet in mild, moderate and severe cases of Covid 19. It needs further in vitro studies and clinical trials to study its action in Covid 19.

\textbf{Funding support}

No funding support is taken for this study.

\textbf{Conflict of interest statement}

The Authors declare that they have no conflict of interest.
    

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