Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are produced in the cells through the mitochondrial respiratory chain during aerobic metabolism and in hypoxic conditions. Aged peoples have co-morbid diseases associated with depletion of endogenous anti-oxidants are in oxidative state, hyperresponsive lung with raised levels of IL-6.COVID-19 infection of the respiratory tract increases activation of pulmonary epithelial, endothelial cells and macrophages causes overproduction of cytokines, chemokines and free radicals induce massive sequestration of neutrophils within the pulmonary microvasculature transmigrate  into  alveolar space and release varieties of cytotoxic, pro-inflammatory compounds and free radicals prodigiously  that perpetuates a vicious circle by recruiting additional inflammatory cells. Overproduction ROS causes depletion of anti-oxidants leading to oxidative stress and induces bystander injury in the host. Any critical illness associated with  overproduction of ROS, which act as second messenger  to activate the nuclear factor kappa-β(NF-kβ) and  transcription factor activator protein-1(APC-1)  cause aberrant production of many cytokines (IL-2,IL-1,IL-6 and TNF-α), hematopoietic  growth factors and adhesion molecules. Cytokines such as IL-2, IL-1, IL-6 and TNFα have binding sites for NFkβ and APC-1 further perpetuating cytokine production in the vicious circle leading to cytokine storm with loss of immune regulation. Thus, ROS can regulate the production of cytokines. Edaravone as a broad spectrum anti-oxidant scavenges both water soluble and lipid soluble ROS have multiple pleotropic effects such as anti-inflammatory, immunomodulatory, anti-cytokine, anti-apoptotic, anti-necrotic, anti-fibrotic, membrane stabilizing, lung protective effects appears to be potentially useful agent in the prevention and therapy of COVID-19 induced cytokine storm and ARDS. 

Keywords: COVID-19, Edaravone, Cytokine storm, ARDS, Antioxidant, Free radicals, ROS.

1. Serena Colafrancesco, Cristiano Alessandri, Roberta Prion et al.COVID-19 gone bad. A new character in the spectrum of the hyperferritinemic syndrome? Autoimmunity Review.2020, May 5.102573.
2. Reuter S, Gupta SC, Chaturvedi MM, Aggrawal BB. Oxidative stress, inflammation and cancer: how are they linked? Free Radical Biology and Medicine. 2010; 49:1603-1616. Doi. 10.1016/j. freeradbiomed. 2010.09.006.
3. Poyton RO, Ball KA, Castello PR. Mitochondrial generation of free radicals and hypoxic signaling. Trends in Endocrinology and metabolism.2009; 20(7):332-340. Doi.10.1016/j tem.2009.04.001.
4. Eileenn M Bulger, Ronald V Meir. Antioxidants in critical illness. Arch Surg.2001; 136:1201-1207.
5. Kalid A Hanaty, Magdy H Selim. Antioxidant strategies in neurocritical care. Neurotherapeutics.2012; 9:44-55. doi.10.1007/s13311-011-0085-6.
6. JD Capro. Oxidative stress as an initiator of cytokine release and cell damage. Eur Respir J. 2003; 22. Suppl. 44.4565. Doi.10.1183/09031976.03.00000203a
7. Sahnoun Z, Jamoussi K, Zenghai KM .Free radicals and antioxidants: physiology, human pathology and therapeutic aspect. (Part II). Therape.1998;July-Aug.58 (4):315-339.
8. Perricene C, Shoenfeld Y, Gerli R.COVID-19 as part of hyperferritenemic syndrome. Implication for treatment. Autoimmun Rev.2020. (in press).
9. Sung Nim Han, Simin Nikbin Meydani. Antioxidants, Cytokines and influenza infection in aged Mice and Elderly Humans. Journal of Infectious Disease.2000; 182 (suppl):S74-80.
10. Meydani SN, Barklund MP, Liu S et al. Vitamin E supplementation enhances cell-mediated immunity in elderly healthy subjects. Am J Cli Nutr.1990; 52; 557-63
11. Sun Y, Oberly LW. Redox regulation of transcriptional activators. Free Radic Biol Med.1996; 21:335-348.
12. Hennet T, Peterhans E, Stocker R. Alternation in antioxidants defense in lung and liver of mice infected with influenza A virus. J Gen Viraol.1992; 73:39-46.
13. Han SN, Meydani M, Wu D et al. Effects of long-term antioxidant supplementation in influenza infection. J  2000. (In press).
14. Yang SN, Chen CS, Yiang GT, Cheng TL, Yong SB, Wu MY, Li CJ. New insight into the immune molecular regulation of the pathogenesis of acute respiratory distress syndrome. Int J Mol Sci. 2018; 19. doi.10.3390/ijms19020588.
15. Channappanavar R, Fehr AR, Vijoy R,Mack M, Zhao J, Meyorholz DK, Perlman J. Dysregulated type I interferon and inflammatory monocyte-macrophage response cause lethal pneumonia in SAR-infected mice. Cell Host Microbe. 2016;19:181-193. doi.10.1016/j.chem.2016.01.007.
16. Recalcati S, Invernizzi P, Arosio P,Cairo G. New functions for an iron storage protein: the role of ferritin in immunity and autoimmunity. J Autoimmun. 2008; 30:84-89.
17. Ruddell RG, Hoang-Le D, Barwood JM, Rutherford PS, Piva JJ, Watters DJ. Ferritin function as a pro-inflammatory cytokine via iron-independent protein kinase C zeta/nuclear factor kappaβ-regulated signaling in rat hepatic steallate cells. Hepatology. 2009; 49:887-900.
18. Dahan S, Katz I, Hellou T, Tietel M,Drob Y, Bry KG, et al. A fatal correlation: ferritin as a marker of severity in COVID-19 patients. Autoimmu Rev.2020 ;(in press).
19. Chung Wei Chow, Maria Teresa Herrera Abrece, Tomoko Suzuki, Gregory P Downey. Oxidative stress and Acute Lung Injury. Am J Respir Cell Mol Biol. 2003;29:p-427-431. doi.10.1165/ycmb. F278. www. atsjournals. org.
20. Mathew R Deshotel, Huijing Xia, Srinivas Sriramula, Eric Lazartigues, Catelin M Filipean. Angiotensin –II mediated Angiotensin converting enzyme type-2 internalization and degradation through an Angiotensin-II type 1 receptor dependent mechanism. Hypertension. 2014; 64: 13681375. https:// doi.10.1161/ HYPERTENSIONAHA 114.03743.
21. Shirin K Laleh, S Maryam BO,Ilianz R, Mine M, Mehrdad Z, Azahar S-jazi, Nagar K, Mohammad SD, Parisa S, Hosen K. The molecular story of COVID-19. NAD+ depletion addresses all questions in this infection. Preprints (www.priprint.org) posted on 23 March 2020. doi.10.20944/preprints 202003.0346.v1.
22. Martin Paspe Cruz. Edaravone (Radicava). A novel neuroprotective agent for the treatment of Amyotrophic lateral sclerosis.P.T.2018; 43(1):25-28.
23. Kazutoshi Wantanabe, Masahiko Tanaka, Satoshi Yuki, Manabu Hirai, Yorihiro Yamamoto.How is edaravone effective against acute ischemic stroke and amyotrophic lateral sclerosis? J Cli Biochem Nutr.2018 Jan; 62 (1): 20-38.Published online 2017 Nov 11.doi.10.3164/jcbn.17-62.
24. Reyes YA, Shimoyama J, Akamatsu H, Sunameri M. MCI-186 (edaravone) ,a free radical scavenger , attenuates ischemia–reperfusion injury and activation of phospholipase A₍₂₎ ,in an isolated rat lung model after 18hr of cold preservation. Eur J Cardiothoracic Surg.2006; 92:304-11.doi. 29304311200610.1016 // ijcts.2005.12.0051642799.
25. Yun Yuan, Hao Zha, Parakalan Rangarajan, Eng-Ang Ling, Chupyun Wu. Anti-inflammatory effects of Edaravone and scutellarin in activated microglia in experimentally induced ischemia injury in rats and in BV-2 microglia.BMC Neuroscience. 2014;15:125. https://www.biomedcentral,com/1371-2202/15/125.
26. Jie Yang, Xiaoyang Cui,Jie Li,Canfei Zhang, Jing Zhang, Ming Lie. Edaravone for acute stroke: Metaanalysis of data from random and control trials. Developmental Neurorehabilitation. Early online 1-6. doi. 10.3109/ 17518423.2013.830153. https;//informahealthcare.com/pdx.
27. Kono H, Asakawa M, Fujii H, Maki A, Amemiya H, Yamamoto M, et al. (2003) Edaravone, a novel free radical scavenger, prevents liver injury and mortality in rats administered endotoxin. J Pharmacol Exp Ther 307:74–82.
28. Nomoto N (2004) Inhibitory effect of free radical scavenger, MCI-186, in the increase of hydroxyl radical induced by iminodipropionitrile in rats. J Neurol Sci 219:41–44.
29. Tanaka K, Takemoto T, Sugahara K, Okuda T, Mikuriya T, Takeno K, et al.(2005) Post-exposure administration of edaravone attenuates noise-induced hearing loss. Eur J Pharmacol 522:116–121.
30. Makawa K, Akamatsu H, Nishina K,Obara H, Niwa Y. Effects of edaravone on human neutrophil function. Acta Anaesthesiol Scand.2009;49:385-389.
31. Kiyoshi Kikuchi, Nobuyuki Takeshige, Naoki Miura, Yoko Morimato, Tkashi Ito, Salurya Tancharoen et al. Byond free radical scavenging: Beneficial effects of edaravone (Radicut) in various diseases with experimental and Therapeutic Medicine. Sept.20.2011;https://doi.org/10.3892/etm.2011.352.p-3-8.
32. T Akaol Takeyoshi, O Totsuka, K Arakawa, M Muraoka, K Kabayashi, K Konn,K Matsumoto, Y Morishita. Effects of free radical scavenger MCI-186 on pulmonary ischemia-reperfusion injury in dogs. Heart Lung Transplant. 25965871200610.1016/j healn. 2006.03.00416890118.
33. W Qiu, H Gul, Zhang J, Zhou D, Chen Y, Chen et al. Pretreatment with edaravone reduces lung mitochondrial damage in an infant rabbit ischemia-reperfusion model. J Pediatr Surg. 4320532060200810.1016/jpedsurg. 2008.05.-01918970940.
34. S Tajima, M Bando, Y Ishii, T Hosono, H Yamasawa, S Ohno, T Takada, E Suzuki, F Gejyo, Y Sugiyama. Effect of edaravone, a free radical scavenger on bleomycin–induced lung injury in mice. EUR Respir J. 3213371343200810.1183/09031936.0016440718614556.
35. S Tajima, M Soda, M Bando, M Enomoto, H Yamasawa, S Ohno, T Takada, E Suzuki, F Gejyo, Y Sugiyama. Preventive effects of edaravone, a free radical scavenger, on lipopolysaccharide-induced lung injury in mice. Respirology. 13646653200810. 1111/j.1440-1843.2008.01322.x18713088.
36. T Asai, Y Ohno, S Minatoguchi, N Funaguchi, H Yuhgetsu,M Sawada, G Takemura, A Komada,T Fujiwara, H Fujiwara. The specific free radical scavenger edaravone suppresses bleomycin-induced acute pulmonary injury in rabbits. Clin Exp Pharmacol Physiol. 342226200710.1111/j.1440-1681.2007.04528.x17201731.
37. Kiyosi Kikuchi, Salunya T, Nobuyuki T, Munetaka T, Motohiro M, Yoshinaka M,Eiichiro T. The efficacy of edaravone (Radicut), a free radical scavenger for cardiovascular disease. Int J Mol Sci.2013;14:13909-13930.doi.10.3390/ijms140713909.
38. Bingbin Wang, Wendong Lin. Edaravone protect against pancreatic and intestinal injury after acute pancreatitis via nuclear factor–kβ signaling in mice. Biol Pharm Bull.2020; 43(3):509-515.
39. Zhang Z, Luo Z, Bi A,Yang W, An W, Dong X, Chen R, Yang S et al. Compound edaravone alleviate lipopolysaccharide (LPS)–induced acute lung injury in mice. Eur J Pharmacol.2017; 811:1-11.
40. Zhang XP, Zhu CM, Wu DJ, Jing X. Possible role of Toll-like receptor-4 in acute pancreatitis. Pancreas. 2010; 39:819-824.                                                                                 
41. Li Yan,Xia A-Xhou, Xing Shu-hua. Protective effect of edaravone against renal ischemia/reperfusion injury and compared with ischemia postconditioning in rats. Acta Pharmaceutica Sinica.2010; 45(7):840-848.

Dr Butungeshwar Pradhan

Associate Professor, Department of internal medicine. Institution:-VSSIMSAR, Burla, Sambalpur, Odisha, India.768017