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Inhibitory Effect of Nimbolide on Mast Cell Degranulation and Allergic Asthma in Mice
Yakhak Hoeji 2022;66(5):217-224
Published online October 31, 2022
© 2022 The Pharmaceutical Society of Korea.

Jung-Eun Lee and Dong-Soon Im#

Department of Biomedical and Pharmaceutical Sciences, and Department of Basic Pharmaceutical Science, Graduate School, College of Pharmacy, Kyung Hee University
Correspondence to: Dong-Soon Im, Laboratory of Pharmacology, College of Pharmacy, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea
Tel: +82-2-960-0355, Fax: +82-2-961-9580
E-mail: imds@khu.ac.kr
Received August 20, 2022; Revised September 6, 2022; Accepted September 13, 2022.
Abstract
The Indian neem tree has been used for treating several medical conditions. Nimbolide, an active compound present in the leaves of the Indian neem tree, has shown anti-inflammatory effects in several animal models. However, its efficacy against allergic asthma has not been examined. Therefore, we investigated the effects of nimbolide on mast cell degranulation and ovalbumin-induced allergic asthma in mice. Nimbolide administration inhibited antigen-induced degranulation of RBL-2H3 cells in a concentration-dependent manner and reduced the immune cell numbers by suppressing the expression of inflammatory cytokines, such as IL-4, IL-13, IFN-γ, IL-33, and thymic stromal lymphopoietin (TSLP) in the bronchoalveolar lavage fluid. Histological studies also demonstrated the in vivo efficacy of nimbolide, evident from the reduced number of periodic acid-Schiff-stained cells and inflammatory scores in the lungs. Furthermore, nimbolide administration inhibited the increase of IL-13 levels, but not that of serum IgE levels. These results demonstrate the therapeutic potential of nimbolide against allergic asthma.
Keywords : Asthma, Allergy, Neem, Nimbolide
Introduction

The Indian neem tree, Azadirachta indica, is a popular medicinal plant in Africa and Asia and has been used traditionally for treating many medical conditions, including Hansen’s disease, epistaxis, intestinal worms, anorexia, skin ulcers, and allergy.1,2) Neem oil shows good antiseptic properties and is used for treating skin diseases such as tinea corporis, burning sensation, wounds, itching, folliculitis, and eczema.3) Neem contains various compounds, including nimbolide, nimbidin, gedunin, nimbin, azadirachtin, mahmoodin, cyclic trisulphide, which show antiinflammatory, antibacterial, antiarthritic, antifungal, antimalarial, antitumor, and immunomodulatory activities.1,3,4,5)

Nimbolide, an active principal compound isolated from the leaves of Azadirachta indica, has drawn great attention in the past decades for owing to its anti-proliferative, anti-inflammatory, and anti-cancer potential.6-8) Recently, the anti-inflammatory effects of nimbolide have been reported in several animal models. For example, nimbolide was found to protect against acute respiratory distress syndrome induced by endotoxins through inhibition of TNF-α-mediated nuclear translocation of NF-κB and HDAC-3.9) Nimbolide ameliorates inflammation in the liver by regulating HDAC3.10) Nimbolide protects against inflammatory arthritis induced by complete Freund's adjuvant by inhibiting STAT-3/NF-κB/Notch-1 signaling.11) Nimbolide ameliorates pulmonary fibrosis by suppressing epithelial-to-mesenchymal transition driven by TGF-β1.12) Nimbolide induces a decrease in various proinflammatory cytokines, such as IL-1β, TNF-α, IL-6, IL-17, and TGF-β in experimental animals.6,9,11) However, the pharmacological efficacy of nimbolide has not been investigated in allergic asthma models, even though its effects has been positively proven in acute respiratory distress syndrome and pulmonary fibrosis.9,12) In this study, we aimed to examine the pharmacological efficacy of nimbolide in allergic asthma induced by ovalbumin (OVA) in mice.

Methods

Materials

Nimbolide, OVA, and aluminum hydroxide were purchased from Sigma-Aldrich (St. Louis, MO, USA).

Cell culture

Rat RBL-2H3 basophilic leukemia cells were obtained from the American Type Culture Collection (ATCC, Manassas, VA, USA). RBL-2H3 cells were cultured at 37°C in a 5% CO2-humidified incubator, and maintained in 10% (v/v) heat-inactivated fetal bovine serum containing high-glucose Dulbecco’s modified Eagle medium (DMEM) with 2 mM glutamine, 100 U/mL penicillin, 1 mM sodium pyruvate, and 50 μg/mL streptomycin.

Animals

Female five-week-old BALB/c mice were purchased from Daehan Biolink (Seoul, Korea). They were housed in the laboratory animal facility at University and provided ad libitum water and food. The University Institutional Animal Care Committee reviewed and approved the protocol with respect to ethical issues and scientific care.13)

Assessment of degranulation

By measuring b-hexosaminidase activity in the medium, degranulation of RBL-2H3 cells was assessed. Cells were sensitized with 0.2 μg/mL monoclonal anti-dinitrophenyl mouse immunoglobulin E overnight (Jeon et al., 2021). Cells were washed with PIPES buffer (pH 7.2), containing 25 mM PIPES, 0.05 mM NaOH, 110 mM NaCl, 5 mM KCl, 5.6 mM Glucose, 0.4 mM MgCl2, 1 mM CaCl2, 0.1% BSA to remove excess monoclonal anti-dinitrophenyl mouse immunoglobulin E before stimulation. Nimbolide dissolved in DMSO as a stock solution of 25 mM was diluted in PIPES buffer just before the experiment. Cells were incubating for 30 minutes with different concentrations of Nimbolide. To induce degranulation, cells were incubated for 15 minutes after added DNP-HSA. Following incubation, transfer 25 μL of supernatant and 25 μL medium and cell lysates to 96 well plates. And then cells were incubating for 2 hours, read OD of each reaction at 405 nm.

Establishment of a murine model of asthma and administration of nimbolide

Six-week-old BALB/c mice (22 g) were randomly divided into three groups (n=5): phosphate-buffered saline (PBS)-injected control group, ovalbumin (OVA)-injected asthma group, OVAinjected and 1 mg/kg nimbolide-treated group. Asthma was induced by intraperitoneal injection of OVA and aluminum hydroxide on D0 and D14. Mice were challenged by exposing to nebulized OVA for D28, D29, and D30. Nimbolide was dissolved in DMSO as a stock solution of 25 mM. The stock was diluted in corn oil (50 mL) just before the experiment. Nimbolide was treated via intraperitoneal injection 30 min before OVA challenge. We collected bronchoalveolar lavage fluid (BALF) from the lungs on D32, and cell population of BALF cells was analyzed after staining.

Cell counting and analysis in BALF

Using a Cellspin® centrifuge (Hanil Electric), immune cells in BALF were adhered to a glass slide and fixed in methanol for 30 s. Staining with May-Grünwald solution were conducted in the cells on slides for 8 min and subsequently by Giemsa solution for 12 min.

Quantitative Real-Time PCR (qRT-PCR)

Quantitative PCR was performed to analyze the expression levels of Th2 cells. Total RNA was isolated using TRIzolTM reagent (Invitrogen, Waltham, MA, USA), and used for cDNA synthesis. Promega GoTaq® DNA polymerase (Promega Corporation, Madison, WI, USA), primers for each gene, and the synthesized cDNA were reacted to amplify the specific genes. Quantitative PCR was done using Thunerbird Next SYBR Qpcr Mix (Toyobo, Osaka, Japan) and CFX Connect Real-Time System (Bio-Rad, Hercules, CA, USA). Forward primer sequence for mouse IL-4 was 5′-CCT CAC AGC AAC GAA GAA CA-3′ and reverse primer sequence was 5′-CTG CAG CTC CAT GAG AAC AC-3′. Forward primer sequence for mouse IL-13 was 5′-CAG CAT GGT ATG GAG TGT GG-3′ and reverse primer sequence was 5′-AGG CCA TGC AAT ATC CTC TG-3′. Forward primer sequence for mouse IL-17A was 5′-AAA GCT CAG CGT GTC CA AAC-3′and reverse primer sequence was 5′-ACG TGG AAC GGT TGA GGT AG-3′. Forward primer sequence for mouse IFN-γ was 5′-CAC GGC ACA GTC ATT GAA AG-3′ and reverse primer sequence was 5′-GTC ACC ATC CTT TTG CCA GT-3′. Forward primer sequence for mouse IL-33 was 5′-ATC GGG TAC CAA GCA TGA AG -3′ and reverse primer sequence was 5′-TTC CTT GGA TGC TCA ATG TG-3′. Forward primer sequence for mouse GAPDH was 5′-AAC TTT GGC ATT GTG GAA GG-3′ and reverse primer sequence was 5′-GGA TGC AGG GAT GAT GTT CT-3′.

Histological examination of the lungs and cell counting in BALF

Tissue sections of lungs from mice of each group were prepared. Hematoxylin and Eosin (H&E) staining and periodic acid-Schiff (PAS) staining were performed to find mucus-secreting goblet cells and eosinophil infiltration, respectively. For PAS staining, Schiff’s regent was used and for H&E staining, hematoxylin and eosin regents were used.

Degree of lung inflammation was evaluated using a subjective scale of 0-3 by a treatment-blind observer, as followings, 0 was assigned when no inflammation was detected, 1 when occasional cuffing and inflammatory cells were observed, 2 when most bronchi or vessels were surrounded by a thin layer (one to five cells thick) of inflammatory cells, and 3 when most bronchi or vessels were surrounded by a thick layer (>five cells thick) of inflammatory cells. Mucin-secreting cells stained with PAS in the airways were counted from two lung sections per mouse. At the same time we also measured the length of the bronchi basal lamina using ImageJ software (National Institute of Health). Mucous production was expressed by the number of PAS-positive cells per mm of bronchiole.

Measurement of total serum IgE levels and IL-13 cytokine levels Mouse IgE levels in the serum were determined using ELISA kits (eBioscience, San Diego, CA). IL-13 levels in BALF were quantitated using ELISA kits. Capture antibodies and biotinylated detection antibodies specific for IL-13 were obtained from eBioscience (IL-13: cat no. 14-7043-68 and 33-7135-68B, San Diego, CA, USA). Avidin-horseradish peroxidase was used and the absorbance was measured at 450 nm.

Statistical analysis

Results are expressed as means±standard errors (SEs). For statistical significance analysis of variance (ANOVA) was used, and followed by Turkey’s post hoc test using GraphPad Prism software (GraphPad Software, Inc., La Jolla, CA, USA). P values <0.05 indicated statistical significance.

Results

Nimbolide inhibits antigen-induced degranulation in RBL-2H3 cells

Mast cells play an important role in allergic and inflammatory responses of the airway tract in asthma.15) Mast cells express the high-affinity FcεRI receptor, which is cross-linked upon antigen exposure. FcεRI-activated mast cells release histamine, leukotrienes, and proteases via degranulation and contribute to asthma symptoms.16) Rat basophilic leukemia RBL-2H3 cells were used as a mast cell model to measure degranulation responses. As β- hexosaminidase release in the medium is well correlated with mat cell degranulation, β-hexosaminidase levels were determined as previously described.14,17) β-Hexosaminidase activity in the medium increased after antigen exposure in the RBL-2H3 cells (Fig. 1). Treatment with nimbolide suppressed the release of β-hexosaminidase in a concentration-dependent manner (Fig. 1). Further, inhibition by nimbolide was significant at a concentration of 0.5 mM (Fig. 1).



Fig. 1. Nimbolide inhibits antigen-induced degranulation in RBL-2H3 cells. RBL-2H3 cells were sensitized for 18 h with anti-DNP IgE and then challenged with DNP human serum albumin (HSA). Nimbolide was treated at the indicated concentrations, 30 min before the antigen challenge. Samples without IgE and HSA indicate basal degranulation from the cells, and samples with IgE and HSA indicate the positive control of antigen-induced degranulation, which was taken as 100%. The results are presented as the mean±SE of three independent experiments. ***p<0.001 vs. the HSA-untreated group. #p<0.05 vs. the HSA-treated group.

Nimbolide inhibits the increases of eosinophils and lymphocytes in BALF

Next, a murine OVA-induced allergic asthma model was used to verify the suppressive effects of nimbolide. In the animal model, the number of inflammatory cells in BALF was assessed 48 h after the last OVA challenge. Total leukocyte, eosinophil, and lymphocyte counts were higher in OVA-treated mice than PBStreated mice (Fig. 2A), and treatment of nimbolide (1 mg/kg) reduced the OVA-induced increase in BALF cell numbers (Fig. 2A). The total cell number and distribution of immune cell populations were evaluated in the BALF. The total cell number in the BALF increased to 251.02% in OVA-treated mice compared with that in the PBS-treated mice (Fig. 2B). Nimbolide administration significantly reduced the infiltration of total inflammatory cells by 51.01% (Fig. 2B). The eosinophil and macrophage numbers in the BALF increased after OVA treatment and were significantly reduced by 30.16% and 88.7%, respectively, upon by nimbolide treatment (Fig. 2B). Although the lymphocyte number was lower than the eosinophil number, OVA treatment increased whereas nimbolide treatment decreased the lymphocyte counts (Fig. 2C).



Fig. 2. Nimbolide inhibits OVA-induced immune cell accumulation in broncho-alveolar lavage fluid (BALF). (A) Mice were sensitized with OVA twice by i.p. injection on D0 and D14, and were later challenged on D28, D29, and D30 with nebulized OVA. Nimbolide was treated intraperitoneally at a dose of 1 mg/kg, 30 min before the OVA challenge. Cells in BALF were stained using May-Grünwald stain and counted. (B) Total cell counts, eosinophils, and macrophages in BALF. (C) Lymphocyte counts in BALF. The results are presented the mean±SE cell count values (n=5). ***p<0.001 vs. the PBS-treated group, ##p<0.01, ###p<0.001 vs. the OVA-treated group.

Nimbolide suppresses Th2 cytokine expression in the BALF

Proinflammatory cytokines like IL-4 and IL-13 play a pivotal role in orchestrating the airway inflammatory response in allergic asthma and are defined as Th2 cytokines.18) Th2 cytokines promote the hallmark features of asthma, such as eosinophilia, mucus hypersecretion in epithelial cells, metaplasia of goblet cells, bronchial hyperresponsiveness, and IgE production.19) Th2 cytokines IL-4 and IL-13 are found in eosinophilic asthma, whereas the Th1 cytokine IFN-γ and Th17 cytokine IL-17A are found in neutrophilic asthma.20) IFN-γ and IL-17A levels are correlated with asthma severity in steroid resistant patients.20) In patients with seasonal allergic rhinitis, IL-33 expression is increased in the lower airways.21) Thymic stromal lymphopoietin (TSLP) is an important cytokine involved in human asthma.22) The expression levels of Th2/Th1/Th17 cytokine mRNAs, as well as IL-33 and TSLP, were measured in BALF cells by qRT-PCR (Fig. 3A). The levels of IL-4, IL-13, IFN-γ, IL-33, and TSLP mRNAs were significantly increased by 10006.87, 459.87, 964.67, 656.78 and 263.79%, respectively, in the BALF from OVA group mice, whereas IL-17A was not increased (Fig. 3). OVA-induced increases in the expression of these cytokines were suppressed upon nimbolide treatment (Fig. 3).



Fig. 3. Nimbolide inhibits the mRNA expression levels of inflammatory cytokines in BALF-associated cells. mRNA expression of Th2 cytokines (IL-4 and IL-13), Th17 cytokine (IL-17A), Th1 cytokine (IFN-γ), IL-33, and TSLP in BALF cells. The mRNA levels of cytokines were quantified as ratios to GAPDH mRNA level. Values represent mean±SE (n=5). *p<0.05, ***p<0.001 vs. the PBS-treated group, #p<0.05, ##p<0.01 vs. the OVA-treated group.

Nimbolide inhibits the mucin secretion and inflammation in the lungs

Histological assessment of lung tissues was also conducted. Mucus hypersecretion is a characteristic feature of airway remodeling. Lung tissues were stained with Periodic Acid-Schiff (PAS) stain to measure mucus hyperproduction caused by goblet cell hyperplasia. Mucus hyperproduction was clearly observed as a blue-violet color in the bronchial airways as shown in Fig. 4. However, the extent of mucin production was markedly diminished in OVA-challenged mice treated with nimbolide (Fig. 4). Furthermore, in the semi-quantitative analysis of mucin production, approximately 90 PAS-positive cells/mm were counted and nimbolide administration was found to reduce the number of PAS-positive cells (Fig. 4B).



Fig. 4. Nimbolide protects against mucin production. (A) Panels show periodic acid-Schiff (PAS)/hematoxylin-stained sections of lung tissues from the PBS, OVA, and nimbolide (1 mg/kg)-treated OVA groups. In PAS staining, mucin is stained purple. In the OVA group, a darker and thicker purple color is observed surrounding the bronchioles compare with that in the PBS group. (B) Mucous production was evaluated by counting the number of PAS-positive cells (red arrows) per mm of bronchioles (n=5 per group). ***p<0.001 vs. the PBS-treated group, #p<0.05 vs. the OVA-treated group.

In H&E staining, we observed marked infiltration of inflammatory cells into the peribronchial and perivascular areas in the OVA group; in contrast, only a few eosinophils were observed in the PBS group (Fig. 5A). Nimbolide administration reduced the number of eosinophils around the bronchioles (Fig. 5A). Using a subjective scale of 0-3, semi-quantitative evaluation of lung inflammation indicated an average inflammation score of 2.1 in the OVA-treated group, whereas treatment with nimbolide reduced the score (Fig. 5B).



Fig. 5. Nimbolide protects against airway inflammation. (A) Panels show H&E-stained sections of lung tissues from the PBS, OVA, and nimbolide (1 mg/kg)-treated OVA groups. Small navy blue dots around the bronchioles are eosinophils. Eosinophils were rarely observed in the PBS group, whereas they accumulated densely around the bronchioles in the OVA group (green arrows). However, eosinophil accumulation was less obvious in the OVA+nimbolide groups than in the OVA group. (B) Lung inflammation was semi-quantitatively evaluated; histological findings were scored as described in the Materials and methods section. Values represent the mean±SE (n=5). **p<0.01 vs. the PBS-treated group, #p<0.05 vs. the OVA-treated group.

Nimbolide suppresses OVA-induced increase in serum IgE and BALF IL-13 levels

Serum IgE levels were assessed to confirm the immunological effects of OVA and nimbolide. IgE production was increased in the sera of OVA-treated mice (Fig. 6A). The OVA-induced increase in serum IgE levels was not significantly altered by nimbolide treatment. The protein levels of the Th2 cytokine IL-13 in BALF were measured using ELISA. IL-13 levels were increased in the OVA-induced group compared with those in the vehicle-treated control group; the increased IL-13 levels induced by OVA were significantly suppressed by nimbolide treatment (Fig. 6B).



Fig. 6. Effect of nimbolide on IgE levels in serum and IL-13 levels in BALF. (A) Serum IgE levels. Results are presented as means±SEM (n=5). ***p<0.001 vs. the PBS-treated group. (B) ELISA was used to measure the IL-13 protein levels in BALF. The results represent the mean±SE of protein levels (n=5). **p<0.01 vs. the PBS-treated group, ##p<0.01 vs. the OVA-treated group.
Discussion

Indian folk medicines are well known for their efficacy and are widely accepted in Ayurvedic treatment regimes. For example, the polyherbal Ayurvedic formulation ‘Peedantak Vati’ has been studied as an alternative treatment for its anti-inflammatory and analgesic properties.23) In the present study, we investigated the therapeutic potential and pharmacological efficacy of nimbolide in OVA-induced allergic asthma. Furthermore, we demonstrated the inhibitory effects of nimbolide on antigen-induced mast cell degranulation and on OVA-induced increases in proinflammatory cytokines in BALF. When antigens are exposed to the airway tract, mast cells recognize antigens by cross-linking FcεRI receptors and releases histamine, leukotrienes, and proteases by degranulation.15,16) Therefore, suppression of mast cell degranulation could primarily contribute to the anti-asthma efficacy of nimbolide, as proven by the reduced immune cell numbers in the BALF and lungs. Suppression of proinflammatory cytokine expression may also contribute to the in vivo efficacy of nimbolide because Th2 cytokines are very important in allergic diseases.18) We found that nimbolide suppressed the Th2 cytokines IL-4 and IL-13, as well as the Th1 cytokines IFN-γ, IL-33, and TSLP in BALF. However, nimbolide did not affect serum IgE levels and IL-17A expression, implying a unique mechanism of action for nimbolide.

Although this study presents the first report that nimbolide inhibits mast cell degranulation, the anti-inflammatory effects of nimbolide has been previously demonstrated in several animal models. Nimbolide suppresses acute respiratory distress syndrome by inhibiting TNF-α-mediated nuclear translocation of NF-κB and HDAC3.9) In a liver model, nimbolide was found to attenuate inflammation via HDAC3 regulation.10) HDAC3 has been reported to play key roles in the regulation of allergic responses via deacetylating histone proteins 24,25) and an HDAC3 selective inhibitor, RGFP966 ameliorated OVA-induced allergic responses in a murine rhinitis model.26) Therefore, HDAC3 might mediate the action of nimbolide in the present study. In contrast, nimbolide ameliorates inflammatory arthritis induced by complete Freund's adjuvant by inhibiting STAT-3/NF-κB/Notch-1 signaling;11) further, it inhibits pulmonary fibrosis by attenuating TGF-β1-induced epithelial-to-mesenchymal transition.12) As previously reported, nimbolide induces decreases in inflammatory cytokines in several experimental animals6,9,11) implying that inhibition of inflammatory cytokine expression is a common feature of nimbolide action in previously reported inflammatory animal models and the present allergic asthma model.

Conclusion

In the present study, we can conclude that nimbolide ameliorates OVA-induced allergic asthma by suppressing mast cell degranulation and inflammatory cytokine expression in a murine animal model, although further investigation is needed to elucidate the precise mode of action of nimbolide.

Acknowledgment

This research was supported by the Basic Research Laboratory Program (BRL) and the Basic Science Research Program of the Korean National Research Foundation funded by the Korean Ministry of Science, ICT and Future Planning (NRF-2020R1A4A1016142 and NRF-2019R1A2C1005523).

Conflict of Interest

The authors declare that there is no conflict of interest.

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Funding Information
  • Ministry of Science, ICT and Future Planning
      10.13039/501100003621
      NRF-2020R1A4A1016142, NRF-2019R1A2C1005523