key: cord-0745649-ash4881c
authors: Song, Junke; Zhang, Li; Xu, Yanfeng; Yang, Dezhi; Zhang, Li; Yang, Shiying; Zhang, Wen; Wang, Jinhua; Tian, Shuo; Yang, Shengqian; Yuan, Tianyi; Liu, Ailin; Lu, Qi; Li, Fengdi; Liu, Hongqi; Hou, Biyu; Peng, Xiaozhong; Lu, Yang; Du, Guanhua
title: The comprehensive study on the therapeutic effects of baicalein for the treatment of COVID-19 in vivo and in vitro
date: 2020-10-27
journal: Biochem Pharmacol
DOI: 10.1016/j.bcp.2020.114302
sha: 63f8cec77930b2f5cd4d0f093eea398c3b2f6bf1
doc_id: 745649
cord_uid: ash4881c

Baicalein is the main active compound of Scutellaria baicalensis Georgi, a medicinal herb with multiple pharmacological activities, including the broad anti-virus effects. In this paper, the preclinical study of baicalein on the treatment of COVID-19 was performed. Results showed that baicalein inhibited cell damage induced by SARS-CoV-2 and improved the morphology of Vero E6 cells at a concentration of 0.1 μM and above. The effective concentration could be reached after oral administration of 200 mg/kg crystal form β of baicalein in rats. Furthermore, baicalein significantly inhibited the body weight loss, the replication of the virus, and relieved the lesions of lung tissue in hACE2 transgenic mice infected with SARS-CoV-2. In LPS-induced acute lung injury of mice, baicalein improved the respiratory function, inhibited inflammatory cell infiltration in the lung, and decreased the levels of IL-1β and TNF-α in serum. In conclusion, oral administration of crystal form β of baicalein could reach its effective concentration against SARS-CoV-2. Baicalein could inhibit SARS-CoV-2-induced injury both in vitro and in vivo. Therefore, baicalein might be a promising therapeutic drug for the treatment of COVID-19.

The Coronavirus Disease 2019 , caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to a global public health crisis. Some patients infected with SARS-CoV-2 showed respiratory distress or even respiratory failure. A massive number of non-invasive or invasive ventilators are needed for patients to achieve mechanical ventilation. Critical illness patients with respiratory failure or multiorgan failure require ICU monitoring treatment urgently [1] [2] [3] [4] . The pandemic brings a huge challenge to the public health-care system. Therefore, the drug discovery for the treatment of COVID-19 is urgent.

Several drugs have been tested for the efficacy and safety against COVID-19, such as remdesivir, chloroquine, hydroxychloroquine, and favipiravir, some of which have displayed antiviral effects against SARS-CoV-2 in vitro [5, 6] . It was reported that remdesivir, chloroquine, favipiravir could effectively protect Vero E6 cells by inhibiting the infection of SARS-CoV-2 with the half-maximal effective concentrations (EC 50 ) values of 0.77, 1.13, and 61.88 μM, respectively 5 . Unfortunately, there is still no ideal drug for the treatment of COVID-19 clinically. Although a multicenter prospective observational study demonstrated that chloroquine treatment could shorten the median time to achieve an undetectable viral RNA and the duration of fever compared to non-chloroquine control [7] , the benefit-risk ratio of chloroquine treatment needs to be considered due to its large volume of distribution, the long half-life, easy accumulation, and a lethal dose of 5 g in adults [8] . Several clinical trials have evaluated the efficacy and safety of hydroxychloroquine, but whether it is beneficial or not is not consistent [9, 10] . The clinical treatment effect of chloroquine and hydroxychloroquine still needs to be verified by large-scale randomized, double-blind, controlled trials.

Besides, a randomized controlled trial enrolling 240 patients, half receive favipiravir, and half receive arbidol, reported that the clinical recovery rate of favipiravir on Day 7 was not significantly different from that of arbidol [11] . In addition, an open-label RCT of lopinavir-ritonavir revealed no significant difference in the clinical improvement between lopinavir-ritonavir treatment and standard therapy [12] . The convalescent plasma therapy showed beneficial effects on severe COVID-19 patients, which could significantly improve the clinical symptoms of severe patients and decrease the viral load [13, 14] . However, this treatment also has disadvantages, including insufficient plasma supply and the risk of disease transmission. The drug discovery for COVID-19 could be a time-consuming process. And it is also a big challenge to elucidate the safety and toxicity of a new drug in a short time.

Baicalein is an active compound isolated from Scutellaria baicalensis Georgi (Huangqin), a traditional medicine with the pharmacological effects of antiinflammation and anti-virus. Baicalein or the extract of Huangqin exhibited broadspectrum antiviral effects, including influenza A (H1N1) virus [15, 16] , Zika virus (ZIKV) [17] , and dengue virus (DENV) [18] , et al. Although Huangqin has been used for a long time as a traditional medicine, the plasma concentration of its active component (baicalein) after oral administration is relatively low, which weakens its efficacy. Thus, improving the absorption, tissue distribution, and bioavailability of baicalein is critical for its therapeutic effect. During the past decade, we have obtained a new crystal form of baicalein (crystal form β of baicalein) and found that this crystal form showed a higher bioavailability than the other crystal forms of baicalein. In the study, the therapeutic effects of baicalein against SARS-CoV-2 were investigated both in vivo and in vitro. An LPS-induced acute lung injury model was also carried out in mice to reveal the effects of baicalein on the related symptoms of COVID-19.

The crystal forms α and β of baicalein were prepared by the Institute of Materia Ltd., Shanghai China).

In the oral pharmacokinetic study of rats, 10 male SD rats (240-270 g) were divided into 2 groups (5 rats in each) and orally given 200 mg/kg crystal form α or β of baicalein, respectively. The blood sample was obtained from the posterior venous plexus of rat into a heparinized test tube before administration and at 0.33, 0.66, 1, 1.5, 2, 3, 5, 7, 9, 12, 24 h after administration. Then the sample was centrifuged, and plasma was collected. For intravenous injection, 10 rats (200 -240 g, half male and half female) were injected with 10 mg/kg of baicalein intravenously. At 0.03, 0.08, 0.17, 0.33, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, and 8 h after injection, blood sample was collected into heparinized test tube, and then centrifuged. 100 μL of plasma was collected. Previously, we have reported a method for simultaneous quantification of baicalein and its metabolite baicalin in monkey plasma [21] . With minor modification, the method was validated in rat plasma. And the concentration of baicalein and baicalin were simultaneously determined. The lower limit of quantitation (LLOQ) was 0.185 μM for baicalein and 0.112 μM for baicalin, respectively. All the protocols were approved by the Experimental Animal Care and Use Committee of the Institute of Materia Medica, CAMS and PUMC.

Two cytopathic effect (CPE) assays were carried out in this study. For one of the CPE assays, Vero E6 cells and SARS-CoV-2, with a titer of 10 5 TCID 50 /mL, were stored at -80 °C by the Pathogen Center of Institute of Laboratory Animal Science, CAMS and PUMC. Vero E6 cells were maintained in RPMI 1640 medium with 10% fetal bovine serum and cultured at 37 °C in a humidified incubator containing 5% CO 2 . Then, the culture medium was discarded, and the above mixture was added into each well. Subsequently, the cells were cultured for 5 days. Normal cell control, solvent control, positive control (remdesivir) and virus control (negative control) were used at the same time. The CPE was observed under a light microscope. An observable CPE was recorded as "+", no CPE was recorded as "-". All these experiments were carried out in biosafety level 3 laboratory in the Institute of Laboratory Animal Science, CAMS and PUMC.

For another CPE assay, SARS-CoV-2 (108) was provided by the Guangdong Provincial Center for Disease Control and Prevention with a virus titer of 10 6 pfu/mL.

During the experiment, DMEM medium was used to prepare baicalein into solutions of different concentrations. Then, Vero E6 cells were pretreated with baicalein for 1 h.

After that, SARS-CoV-2 was added at a multiplicity of infection (MOI) of 0.05 and incubated for 1 h. After discarding the baicalein-virus mixture, the normal culture medium containing baicalein was added, and the CPE was observed under a light microscope after 48 h. Remdesivir was used as a positive control.

The human angiotensin-converting enzyme 2 (hACE2) transgenic mice infected with SARS-CoV-2 was used to evaluate the drug efficacy, which cannot be achieved by the wild-type mice [22] Before the mice were administered by gavage, baicalein was suspended with 0.5% CMC-Na solution to form a suspension solution with a concentration of 10 mg/mL. The dose for each mouse was 200 mg/kg/day. Baicalein was administrated at 1 h after the infection of SARS-CoV-2 in mice, and once a day for 5 consecutive days, whereas the model group was given 0.5% CMC-Na solution in equal volume.

After mice were infected with SARS-CoV-2, their general symptoms were observed continuously for 5 days, and changes in body weight were recorded. On the load of lung tissue. On the 5 th day, the pathology of lung tissues was examined by hematoxylin and eosin (H & E) staining. Histopathology was reviewed and scored using the reported Lung Injury Scoring System from the Official American Thoracic Society Workshop Report in a blinded manner by three qualified investigators [23] . 

24 h after the establishment of the LPS-induced acute lung injury model, the EMKA non-invasive pulmonary function monitoring system (EMKA Technologies, Paris, France) was applied to record the lung function of mice in the conscious and unrestrained state. Respiratory function-related indicators, including peak expiratory flow (PEF), respiratory frequency, end-expiratory pause (EEP), and enhanced pause (Penh) were monitored and analyzed. Each mouse was recorded for 5 min.

H & E staining was used for the pathological analysis of lung tissues. Firstly, part of the left lung tissue of the mouse was immersed in 4% paraformaldehyde and fixed for 48 h. Then, the cut surface of the fixed lung tissue is trimmed, dehydrated, cleared, replaced, and embedded. The trimmed wax block was placed on the microtome, cut into 4 μm/piece, and placed in a 55 °C oven for 1 h. The sections were then dewaxed, replaced, washed with triply distilled water for 5 min, stained by hematoxylin for 8 min, and washed with water. Tissue sections were treated with 1% hydrochloric acid alcohol solution for 30 sec. After rinsed with water, the tissue sections were treated with 1% ammonia solution for 30 sec and followed by rinse. Finally, tissue sections were stained with eosin for 3 min, and the water in the sections was replaced with a gradient concentration of alcohol. The sections were put into xylene I for 5 min and then xylene II for 5 min. After covered with neutral gum, the sections were observed under a microscope (Nikon, Japan). Lung injury was scored in a blinded manner by three qualified investigators using the Lung Injury Scoring System from the Official American Thoracic Society Workshop Report [23] .

Cytokines play vital roles in inflammation response. To find out whether baicalein inhibited the release of cytokines in LPS-induced acute lung injury model, the cytokines in mice serum were measured at 24 h after LPS stimulation. The concentrations of IL-1β, TNF-α, and IL-6 were determined using the commercial ELISA kits (4A Biotech Co., Ltd, Beijing, China). All the experiments were carried out according to the manufactures' instructions.

For cell counting, the trachea near the neck of the mouse was exposed, and tracheal intubation was performed. The trachea was lavaged with pre-cold sterilized 0.3 mL PBS for three times to obtain BALF. Total cells were counted by a hemocytometer. The Wright-Giemsa stain assay was applied for the counting of neutrophil and macrophage cells.

The data were expressed as mean with standard deviation. Statistical analysis was carried out using GraphPad Prism 7.0 software (GraphPad Software Inc., CA, USA).

Unpaired t-test, one-way analysis of variance (ANOVA), or two-way ANOVA followed by Bonferroni's multiple comparisons were carried out. Results were considered statistically significant at P < 0.05.

The absorption of different crystal states of baicalein (α and β form, Fig. 1A ) were studied. Baicalin is the main Phase II metabolite of baicalein (Fig. 1B) . The plasma concentration-time curves of baicalein and baicalin were shown ( Fig. 1C and D) . After oral administration of α crystal form of baicalein (200 mg/kg), the plasma concentration of the parent drug baicalein was lower than its LLOQ (0.185 μM), while that of the metabolite baicalin was higher than its LLOQ (0.112 μM). Therefore, only the metabolite baicalin could be detected, but not the parent drug baicalein. The peak plasma concentration (C max ) of the metabolite was 2.85 ± 1.21 μM, and the AUC 0-24 h of the metabolite was 23.66 ± 8.80 μM·h. After oral administration of crystal form β of baicalein, the C max of baicalein was 1.04 ± 0.22 μM, and the AUC 0-24 h of baicalein was 6.44 ± 3.00 μM·h. The C max of baicalin was 17.27 ± 2.98 μM, and the AUC 0-24 h was 146.94 ± 51.60 μM·h. Taking the crystal form α as a reference, the relative bioavailability of the crystal form β is 648.33% of crystal form α, indicating that the absorption of baicalein after the change of the crystal form from α to β is obviously improved. The plasma concentration-time curves after the intravenous injection of 10 mg/kg baicalein in rats were shown (Fig. 1E) . The AUC 0-8 h of baicalein was 5.18 ± 0.96 μM·h, and the AUC 0-8 h of baicalin was 11.00 ± 3.34 μM·h. Based on the AUC values of baicalein and baicalin after 200 mg/kg oral and 10 mg/kg intravenous administration in rats, the absolute bioavailability of crystal forms α and β of baicalein was calculated to be 7.31% and 47.40%, respectively. The crystal form β of baicalein was prepared and used in the major experiments because of its higher bioavailability than crystal form α.

To investigate whether baicalein has the anti-SARS-CoV-2 effect, two CPE assays were carried out. For one of the CPE assays (Table 1) (Fig. 2) . Taken together, these results suggested that baicalein had a significant anti-SARS-CoV-2 effect at the concentration of 0.1 μM and above.

The general condition of mice was observed during the experiment. The hairs and body weight were lost in some mice of the model group. The loss rate of average body weight is up to 4.55% on the 5 th day in the model group, while the baicalein treatment group showed an increasing rate of 1.59% on the 5 th day. The average body weight of mice in the baicalein group was significantly higher than that in the model group on the 1 st , 3 rd , and 5 th day (P < 0.01, P < 0.001 and P < 0.001, Fig. 3A ). In the model group, the virus load of the lung tissue on the 3 rd and 5 th days after infection was 10 5.94 and 10 4.14 copies/mL, while the viral load in baicalein group on the 3 rd and 5 th days after the infection was 10 4.45 and 10 3.36 copies/mL, which were significantly lower than that in the model group, respectively (P < 0.01 and P < 0.05, Fig. 3B) . The widening and cell infiltration of the alveolar septum, and a small amount of cell infiltration around the blood vessels were observed in the lung tissue of the hACE2 transgenic mice infected with SARS-CoV-2 on the 5 th day. These pathological injuries have also been observed in the baicalein treatment group, compared with the model group, the treatment of baicalein relieved the inflammatory cell infiltration of lung tissue (Fig. 3C) .

To check if baicalein could alleviate the acute lung injury induced by LPS, baicalein was orally administrated to mice. Compared with the normal control group, the EEP of the LPS model group was significantly longer (P < 0.001), the PEF/body weight and the Penh were significantly increased (P < 0.001), and the respiratory frequency was significantly decreased (P < 0.001). Whereas baicalein at a dose of 50 mg/kg had a significant effect on shortening the EEP in mice with lung injury compared with the LPS model group (P < 0.01, Fig. 4A ). Baicalein also significantly reduced the PEF/body weight of mice with lung injury (P < 0.01, Fig. 4B) , and remarkably reduced the Penh in mice with lung injury (P < 0.001, Fig. 4C ). In addition, baicalein also increased the respiratory frequency of mice injured by LPS (P < 0.05, Fig. 4D ). Fig. 4E , in the lung tissue of BALB/c mice inhaled by LPS, the alveolar space was replaced by a large number of infiltrated cells, and the structure of alveoli was changed. However, compared with the LPS model group, the treatment of baicalein reduced lung cell infiltration. Compared with the normal control group, the total cells, neutrophils, and macrophages were significantly increased in BALF of the LPS model group (P < 0.001). Baicalein could significantly reduce the total cell in BALF at the doses of 50, 100, and 200 mg/kg (Fig. 4F) . In addition, baicalein could also dose-dependently reduce the neutrophils and macrophages in BALF of mice with lung injury (Fig. 4G and H) . The concentrations of inflammatory cytokines in serum of mice, including IL-1β, TNF-α, and IL-6, were significantly increased in the LPS model group (Fig. 4I -K) . Baicalein significantly reduced the concentration of IL-1β

and TNF-α compared with the LPS model group at 50, 100, and 200 mg/kg.

Baicalein is the main active compound in Huangqin, a traditional medicinal herb with multiple pharmacological activities. Our previous results showed that baicalein protected against MPTP-induced neurotoxicity in mice [24, 25] , inhibited 6hydroxydopamine-induced neurotoxicity in vitro and in vivo [26, 27] , and alleviated dementia caused by chronic cerebral hypoperfusion [28] . In this study, baicalein was found to have anti-SARS-CoV-2 activity and reduce lung injury caused by SARS-CoV-2 in mice. In addition, baicalein could alleviate LPS-induced acute lung injury, regulate the respiratory function, and reduce the inflammatory cells in BALF in mice with acute lung injury.

virus [32] , human immunodeficiency virus (HIV) [33, 34] , DENV [35, 36] , Sendai virus [37] , ZIKV [17] , and Japanese encephalitis virus (JEV) [38] , et al. Baicalein (240, 480, and 960 mg/kg/day) prevented the death of mice, increased the mean time to death, alleviated lung consolidation, and decreased the lung virus titer of BALB/c mice infected with the influenza A/FM1/1/47(H1N1) virus [16] . Baicalein showed synergistic activity with ribavirin against influenza A (H1N1) virus infection in mice, especially at doses of baicalein (400 mg/kg/day) and ribavirin (50 mg/kg/day) [29] .

Baicalein could significantly inhibit the in vitro replication of Pandemic 2009 H1N1 virus (IC 50 = 0.018 μM), as well as the Seasonal 2007 influenza A virus [30] . Baicalein concentration-dependently inhibited the A/FM1/1/47 (H1N1) and A/Beijing/32/92 (H3N2) influenza viruses via interference with the mid-late mRNA synthesis [31] . It reduced H5N1 infectious titers, and inhibited H5N1-induced the release of IL-6 and IL-8, indicating an additional anti-inflammation effect [32] . Baicalein also showed activity against HIV-l integrase [33, 34] . To improve the bioavailability of baicalein, its different crystal forms were prepared. Polymorphism is a common phenomenon in small molecule drugs. The characteristics of different crystal forms not only affect the physical and chemical properties of the drugs, but also change their pharmacokinetic properties. Good pharmacokinetic property includes a reasonable absorption rate and an adequate blood concentration, which could be achieved after oral administration. The absolute bioavailability of baicalein was previously reported to be 7.46% [40] . In this study, the absolute bioavailability of different crystal forms of baicalein was calculated based on the AUC values of 200 mg/kg oral and 10 mg/kg intravenous administration in rats.

Crystal form β of baicalein showed a higher absolute bioavailability than that of crystal form α of baicalein (47.40% vs. 7.31%), which indicated that the absorption of baicalein after the change of the crystal form from α to β was obviously improved. It is worth mentioning that due to the different species, the dose of 200 mg/kg for rats in the pharmacokinetic study cannot be equivalently converted with the dose of 200 mg/kg/day for hACE2 transgenic mice in the anti-SARS-CoV-2 experiment. The pharmacokinetic studies of baicalein were also performed in dogs and monkeys in our lab to support the clinical trial [21, 41] . Based on the findings of the new advantage crystal form of baicalein, the Baicalein Chewable Tablets were prepared for the patients. have shown that cytokine storms are common in severely infected patients, which could cause damage to pulmonary capillary endothelial cells, lung and alveolar epithelial cells, resulting in acute respiratory distress syndrome or multiple organ dysfunction syndromes. The cytokine storm is closely related to the severity of the patient's condition, and the concentration of IL-1β and other inflammatory cytokines in the patient's blood is significantly higher than that of healthy adults [42] . The infiltration of inflammatory cells is one of the signs of lung injury [22] . Our previous research showed that baicalein had anti-inflammatory effects in some disease models [43] [44] [45] 

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. . The values are presented as mean + SD. Statistical significance was assessed using one-way ANOVA with Bonferroni's multiple comparisons test. ## P < 0.01 and ### P < 0.001 vs. control group, * P < 0.05, ** P < 0.01 and *** P < 0.001 vs. LPS model group. 

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