Can Crocin Protect as an Antioxidant and Anti-inflammatory Agent Against Coronavirus (COVID-19)? A combination of the ancient wisdom of natural healing with current research.

The pandemic of coronavirus (COVID-19) has infected more than 7 million people and caused over 400,000 deaths world-wide according to the dashboard at Johns Hopkins University Coronavirus Resource Center on June 8, 2020. It is not just a respiratory or lung disease, the COVID-19 virus affects multiple organs including the lungs, brain, heart, liver, kidneys, etc. The impact of COVID-19 on a patient could be long-term even after the infection is cleared. Vaccination is believed to the best way to prevent a virus, but it usually takes one and half to two years to develop vaccines for a new virus. Without a vaccine and cure available for this virus, an alternative for the prevention and mitigation of the impact of COVID-19 could come from unique natural products with multi-target and immune system boosting effects. A combination of ancient wisdom of natural remedies with the latest scientific research may offer a promising approach to battle COVID-19 effectively.

In the past few months, doctors and researchers have come to believe that COVID-19 induced excessive inflammation response or “cytokine storm” and blood clots are responsible for turning infected patients into serious cases. 1) When the body is infected by virus, the virus induces an inflammatory response, in which the immune system releases pro-inflammatory factors including cytokines to fight the virus. Cytokines are special proteins released to trigger inflammation when the body feels under attack from infection. With this covert COVID-19, doctors believe some people’s bodies are producing way too much of inflammatory response – A “cytokine storm” is formed. A “cytokine storm” can exert more harmful effects to critical organs like the lungs, brain, kidneys, heart, and body. In serious cases, it leads to impairments of organ functions and death. 2) Doctors also noticed many patients who contract the virus experience blood clotting and clots appear to scatter throughout the body, such as in the lungs and kidneys. Mild clots appear to cause rashes or swollen red toes (recently deemed “COVID toes”). In more severe cases, the clots may block arteries, cause pulmonary embolism, or trigger heart attacks and strokes.

Natural and new dietary ingredients with multi-target effects could be an effective part of natural remedies to prevent and treat patients of COVID-19 and assist recovery from the illness. Examples of natural ingredients that have anti-inflammatory properties include curcumin, resveratrol, nobiletin, green tea extract, garlic extract, etc. Among natural herbs and ingredients, saffron (Crocus sativus) has been used as spice and medicine for healing various health conditions since ancient time. Crocin is the main active constituent primarily responsible for the health effects of saffron. Saffron and crocin have been intensively investigated in recent years. Crocin, the unique water-soluble carotenoid with potent antioxidant and anti-inflammation effects, could be a promising natural agent to boost immune system and body defense against COVID-19. A brief review of the latest research on crocin’s protective effects and potential against the negative effects of COVID-19 is summarized below. 

Published study results have revealed multi-target effects of crocin in modulating antioxidant status and inflammatory cytokines, and in protecting multiple organs including brain, eye, heart, lungs, liver, kidney, etc. (Hosseinzadeh 2008, Jnaneshwari 2013, Bandegi 2014, Finley 2015, Akbari 2018, Pashirzad 2019, Sepahi 2020). Because saffron is an expensive spice and available crocin qualified for dietary or therapeutic use is limited, majority of clinical studies were carried out with saffron or its extract. Nonetheless, there is a growing trend of human studies conducted with crocin.

Protective effects of crocin on lungs

Lungs are initially believed to be the main organ affected by COVID-19. Crocin was recently reported to attenuate lung inflammation, pulmonary vascular dysfunction and associated pulmonary fibrosis, as well as alleviate acute respiratory distress syndrome in animal studies (Zaghloul 2019, Mehrabani 2020, Zhang 2020). Crocin was also reported to reduce cigarette smoke and Aspergillus fumigatus caused inflammation, oxidative stress, injury and toxicity in lung and airway in animal studies (Du 2018, Dianat 2018, Radan 2020). In addition to these recent animal studies showing protective effects of crocin for lung, an 8-week clinical study of saffron in patients with persistent allergic asthma found crocin containing saffron (100mg/day) improved the lung function and decreased inflammatory factors (Zilaee 2019). In this trial, symptoms of asthma including shortness of breath were markedly improved after the saffron supplementation. As many medications for treatment of asthma overlap with what is used to manage chronic obstructive pulmonary disease, crocin is expected to provide lung with protective effects against COVID-19.

Protective effects of crocin on clotting

Blood clotting and clots are unexpectedly happening in substantial percentage of COVID-19 patients and probably caused a surge of seizures and strokes in young patients. In autopsied patients who succumbed to COVID-19, the blood clots appeared to have formed within the lungs or other organs. Unlike typical large blood clot formed in main artery, broken off and ended up in the lungs and other organs, it is the tiny vessels that are blocked in COVID-19 patients. Blood clotting is a complex process that involves blood cells or platelets and clotting factors. Blood clotting occurs when they are damaged and clump together. Drugs or therapy to thin blood and prevent clotting have been explored and applied by doctors. Crocin has been reported in series of recent studies to suppress plasminogen activator inhibitor-1 (PAI-1) activity to ameliorate thrombosis (Tsantarliotou 2019), inhibit atheromatous plaque formation (He 2005, ), protect endothelial function (Yang 2018) and protect platelets from oxidative stress-induced apoptosis and inhibits platelet aggregation (Thushara 2013, 2014). Studies also demonstrated crocin protects blood cells against venom‐induced oxidative stress and hematological alterations (Santhosh 2013). Clots in tiny vessels can cause ischemic damage to multiple organs. Several preclinical studies have demonstrated crocin protects against ischemia-reperfusion injuries in multiple organs (Efentakis 2017, Mard 2017, Akbari 2018a). Recently, a clinical study reported saffron extract (100-200mg/day), which contains 20% crocin, could be used as an effective neuroprotective agent against acute ischemic stroke and it benefited recovery in short and long-term (Asadollahi 2019). These findings indicate effects of crocin could potentially prevent and reduce the impacts of COVID-19.

Protective effects of crocin on the brain

Some patients of COVID-19 reported to have declined memory and cognition. Others experienced loss of smell and taste. The neurologic deficits may occur as results of the viral invasion and damage to central or peripheral nerves or damage induced by immune response. It is also reported that COVID-19 can be found in the brain or cerebrospinal fluid of infected patients. Furthermore, brain tissue edema and partial neuronal degeneration were confirmed in autopsy reports of deceased patients (Xu 2020). Even if patients have recovered from the virus, they could suffer long term effects in the brain and increase the risks of developing neurodegenerative diseases such as Alzheimer’s.

Crocin as a potent antioxidant and anti-inflammatory agent has been extensively investigated along with saffron for its neuroprotective effects on brain health and against memory and cognition impairments in the past two decades (Finley 2015). Animal studies demonstrated crocin has protective effects against ischemia-reperfusion injury and cerebral edema of stroke through suppressing production of free radicals and increased antioxidant enzyme activity (Zheng 2007, Vakili 2014, Sarshoori 2014). Crocin was found to provide neuroprotection by reducing the production of various neurotoxic molecules from activated microglia, the brain’s immune system cells (Nam 2010, Lv 2016, Yang 2017, Yorgun 2017). Preclinical studies also revealed that crocin could help tighten blood-brain-barrier, protect neurons from death, support brain cell growth, improve memory and cognition, and reduce levels of neurotoxic factors including, Aβ (Finley 2015, Azari 2018). Clinical evidence from multiple human studies have shown saffron improve memory and cognition in patients with Alzheimer’s (Finley 2015), mild cognitive impairments (Tsolaki 2016), depression (Toth 2019), and age-related macular neurodegeneration (Sepahi 2020). Lately, a 4-week randomized clinical study further reported that crocin (30mg/day) significantly decreased levels of DNA damage, inflammation, and oxidative stress in multiple sclerosis patients (Ghiasian 2019). 

Protective effects of crocin on the heart

It is reported that COVID-19 can affect heart in many ways, from thickening blood, heart attacks, to rupture of heart. In studies of recent years, crocin is found to protect heart against various toxins and injuries in various animal models, as well as alleviate coronary atherosclerosis (Boussabbeh 2015, Elsherbiny 2016, Li 2018). Crocin attenuates oxidative stress, inflammation, arrhythmias, injuries and hemodynamic parameters from myocardial infarction and ischemic-reperfusion (Jahanbakhsh 2012, Dianat 2014, Joukar 2016, Akbari 2018b, Wang 2018). Recently, crocin is also revealed to attenuate myocardial fibrosis in animal study (Jin 2020).

A recent systemic review of meta-analysis of clinical evidence of saffron and crocin on cardiovascular risk factors has looked into 11 randomized clinical trials (Pourmasoumi 2019). By pooling results from these trials, crocin (30-100mg/day) is found to be safe and provides significant effects on diastolic blood pressure, body weight and waist circumstance. Among these 11 trials of saffron and crocin, 6 evaluated effects of crocin (15-100mg/day) and demonstrate its significant effects on patients with Schizophrenia, diabetic macular edema, metabolic syndrome (Roshanravan 2020), and coronary artery disease (Abedimanesh 2017, 2020).

Protective effects of crocin on the kidneys

According a report from Northwell Health, the largest health provider in New York state, among the first 5,449 patients treated for COVID-19, 36.6% developed acute kidney injury and nearly 15% of those with kidney failure required dialysis.

A number of preclinical studies have demonstrated crocin protected kidney from ischemia-reperfusion injury and induced restoration of normal kidney functions through multiple mechanisms including attenuation of oxidative stress and inflammation (Hosseinzadeh 2005, Adali 2016, Yarijani 2017, Abou-Han 2018). Crocin is also found to improve or recover kidney functions from oxidative stress and damages induced by toxic substances including cisplatin, zearalenone, methotrexate, etc. (Naghizadeh 2010, Bandegi 2014, Salem 2015, Qiu, 2020, Jalili 2020). The protective effects of crocin against nephrotoxic substance was reviewed in an earlier article (Samini 2018). More clinical evidence is still needed. Although a 12-week clinical study evaluated effects of saffron (100mg/day) in patients with type 2 diabetes mellitus in reducing diabetes-induced renal injury and only saw significant change in systolic blood pressure (Ebrahimi 2019), there is a current clinical study assessing effects of crocin in acute kidney injury in patients following coronary angiography or angioplasty (https://apps.who.int/trialsearch/Trial2.aspx?TrialID=IRCT20200202046335N1).

Protective effects of crocin on the liver

Liver fibrosis and dysfunction are indicated as major health concern that could result in significant morbidity and mortality among patients infected by COVID-19. Although there is no standard treatment for fibrosis because of its complex pathogenesis, crocin is found to provide protection against liver fibrosis in pre-clinical study through evaluation of gene expression and liver functions (Algandaby 2018). Crocin potentiates antioxidant defense system, protects liver cells and improves oxidative damage in liver tissue (Altinoz 2014, Akbari 2017, Yousefsani 2017, Yaribeygi 2018, Kalantar 2019). Recent clinical study also indicates crocin (15mg/day) considerably improved liver functions and triglycerides levels in patients with non-alcoholic fatty liver disease in an 8-week randomized clinical trial (Parsi 2020).

Summary

Results from the above animal and human studies support crocin as a promising natural antioxidant and anti-inflammatory agent. Based on these clinical studies, intake of crocin (15-30mg/day) or saffron (30-125mg/day) may provide nutritional preconditioning against infection and mitigation of the virus induced injuries to multiple organs. Other natural anti-inflammatory ingredients and herb extracts are available, such as curcumin, resveratrol, green tea extract and garlic extract. Whether crocin or other natural ingredients could be used for preventing or alleviating severe illness of COVID-19 is still to be proven. Formulation of crocin with other dietary antioxidants and anti-inflammatory ingredients may be clinically proven to provide synergistic, protective and multi-target effects. Because there are no known side effects, crocin products can be taken in safe doses. Further clinical research should be done to determine their effectiveness in prophylaxis treatment or used to alleviate symptoms of influenza or the current pandemic corona virus, COVID-19. 

 

References

Abedimanesh N, et al (2017) Effects of Saffron Aqueous Extract and Its Main Constituent, Crocin, on Health-Related Quality of Life, Depression, and Sexual Desire in Coronary Artery Disease Patients: A Double-Blind, Placebo-Controlled, Randomized Clinical Trial. Iran Red Crescent Med J. 2017, 19 (9); e13676

Abedimanesh N, et al (2020) Effects of crocin and saffron aqueous extract on gene expression of SIRT1, AMPK, LOX1, NF-κB, and MCP-1 in patients with coronary artery disease: A randomized placebo-controlled clinical trial. Phytother Res. 2020, 34(5): 1114-1122.

Abou-Han HO, et al (2018) Crocin reverses unilateral renal ischemia reperfusion injury-induced augmentation of oxidative stress and toll like receptor-4 activity. Environ Toxi and Pharm. 2018, 59: 182-189.

Adali F, et al. (2016) Investigation of the effect of crocin pretreatment on renal injury induced by infrarenal aortic occlusion. J Surgi Res. 2016, 203: 145-153.

Akbari G, et al. (2018) A comprehensive review on regulatory effects of crocin on ischemia/reperfusion injury in multiple organs. Biomedicine & Pharmacotherapy 2018, 99: 664–670

Akbari G, et al. (2017) The Hepatoprotective and MicroRNAs Downregulatory Effects of Crocin Following Hepatic Ischemia-Reperfusion Injury in Rats. Oxidative medicine and cellular longevity. 2017(2): 1-11

Akbari G, et al. (2018) Effect of crocin on cardiac antioxidants, and hemodynamic parameters after injuries induced by hepatic ischemia-reperfusion in rats. Iran J Basic Med Sci 2019, 22:277-281

Algandaby MM. (2018) Antifibrotic effects of crocin on thioacetamide-induced liver fibrosis in mice. Saudi J of Bio Sci. 2018, 25(4): 747-754.

Altinoz E, et al. (2014) Protective effect of saffron (its active constituent, crocin) on oxidative stress and hepatic injury in streptozotocin induced diabetic rats. Gene Ther Mol Biol 2014, 16: 160-171.

Asadollahi M, et al. (2019) Protective Properties of the Aqueous Extract of Saffron (Crocus Sativus L.) in Ischemic Stroke, Randomized Clinical Trial. J Ethnopharmacol. 2019, Jun 28;238:111833.

Ashrafizadeh M, et al. (2020) Curcumin activates the Nrf2 pathway and induces cellular protection against oxidative injury. Current Molecular Medicine, 2020, 20(2): 116-133.

Azari H, et al. (2018) The Effect of Saffron Aquatic Extract and Crocin on the Differentiation of Neural Stem Cells Into Oligodendrocyte Precursor Cells. Shiraz E-Med J. 2018 ; 19(3):e60190. doi: 10.5812/semj.60190.

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