Protective effect of silymarin in antigen challenge- and histamine-induced bronchoconstriction in in vivo guinea-pigs

doi:10.1016/S0014-2999(02)01265-7

European Journal of Pharmacology

Volume 437, Issues 1–2, 15 February 2002, Pages 91-95

https://doi.org/10.1016/S0014-2999(02)01265-7 Get rights and content

Abstract

The effects of silymarin on bronchoconstriction induced by antigen challenge and on post-antigen challenge hyperresponsiveness to substance P were evaluated in sensitized guinea-pigs. Silymarin significantly decreased the bronchoconstriction due to antigen administration in the early phase of the response. In contrast, the dose–response curve for substance P recorded 1 h after antigen challenge was not modified by pretreatment with silymarin. The influence of the flavonoid on hyperresponsiveness to histamine in propranolol- and PAF (platelet-activating factor)-treated animals was also assessed. Silymarin did not affect hyperresponsiveness to histamine induced by either propranolol or PAF although it had inhibitory activity on the bronchial contractile response to the autacoid. These results suggest that silymarin has a protective effect in the early phase of allergic asthma, an effect, which may be related to a negative influence of the flavonoid on bronchial responsiveness to histamine.

Introduction

Silymarin, the active principle from the fruit of Silybum marianum is known as a therapeutic agent for the treatment of liver disorders, in view of its antioxidant and membrane-stabilizing effects. As free radical production has been demonstrated in several pathological states, the activity of silymarin and other biologically active flavonoids has been investigated in acute inflammation models in vivo (De la Puerta et al., 1996).

Silymarin has a protective effect against stress-induced gastric ulcer (Alarcon De La Lastra et al., 1992), in which leukotrienes are involved (Ogle and Cho, 1989). In contrast, the flavonoid mixture is ineffective against ethanol-induced ulcer, a condition that is independent of the lipooxygenase pathway (Boughton-Smith and Whittle, 1988). An inhibitory action on lipooxygenase and on prostaglandin synthetase has been demonstrated in in vitro assays Fiebrich and Koch, 1979a, Fiebrich and Kock, 1979b, in the absence of an inhibition of phospholipase A₂ (De la Puerta et al., 1996); silibinin has been shown to inhibit leukotriene formation also in human cells (Dehmlow et al., 1996).

Silymarin thus seems to possess antiinflammatory properties by acting through different mechanisms such as its antioxidant action, membrane-stabilizing effect and inhibition of the production or release of inflammatory mediators such as arachidonic acid metabolites. This complex activity seems to justify the popular use of S. marianum extracts for the treatment of allergic states and asthma, but this has not been validated by experimental results.

Pulmonary inflammation is considered to be an important component in the pathogenesis of asthma, and the stabilization of mastocyte membranes represents a known target of antiasthmatic drugs.

A role for lipooxygenase has been demonstrated in allergic asthma: in sensitized guinea-pigs, an animal model of allergic asthma, leukotrienes are implicated in the bronchoconstriction induced by antigen challenge (Malo et al., 1994) and in the aspecific bronchial hyperreactivity in both intrinsic and extrinsic asthma (Seeds et al., 1995), as well as in propranolol-(Ney, 1983) or platelet-activating factor (PAF)-induced (Seeds et al., 1995) hyperreactivity.

The aim of the present work was thus to study the effects of silymarin on asthma. In particular, the activity of silymarin was examined against bronchial anaphylaxis and against post-anaphylactic, propranolol- or PAF-induced hyperreactivity in guinea-pigs.

Section snippets

General procedure

Male albino guinea-pigs, weighing 350–500 g, were used in agreement with Italian Government regulations (D.L. 27/01/1992 no. 116) concerning the care and use of laboratory animals; the protocol was approved by the institutional ethics committee and complies with the European Community guidelines for the use of experimental animals.

The animals were anaesthetized with sodium pentobarbital (50 mg/kg b.w., i.p.). When a complete loss of reflexes was obtained, the trachea was cannulated and

Results

In sensitized guinea-pigs, the aerosol antigen challenge induced an immediate bronchospasm and a subsequent increase in pulmonary inflation pressure to 33.92±4.90 mm Hg, followed by a progressive but slow decrease in pulmonary inflation pressure to the basal value. Fig. 1 shows the pulmonary inflation pressure levels related to time after antigen administration. When the curves for silymarin-treated guinea-pigs and for control animals were compared, a significant decrease in the maximal

Discussion

Silymarin showed a moderately protective effect against the bronchospasm induced by aerosol antigen challenge in sensitized guinea-pigs. This action can be explained by the various biological effects of silymarin, i.e. to say, its membrane-stabilizing effect (Miadonna et al., 1987), its antinflammatory activity demonstrated in in vivo preparations (De la Puerta et al., 1996) and its inhibition of the arachidonic acid pathway Fiebrich and Koch, 1979a, Fiebrich and Kock, 1979b. The decrease in

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The food plant Silybum marianum (L.) Gaertn.: Phytochemistry, Ethnopharmacology and clinical evidence
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Moreover, it did not show any hyperresponsiveness to histamine induced by either propranolol although it had inhibitory activity on the bronchial contractile response. This result showed an important protection of allergic asthma in its early phase (Breschi et al., 2002). Khayyal et al. (2001) studied antiulcerogenic of S. marianum extract in rats.
Silybum marianum (L.) Gaertn. or Milk thistle is a medicinal plant native to Northern Africa, Southern Europe, Southern Russia and Anatolia. It also grows in South Australia, North and South America. In traditional knowledge, people have used S. marianum for liver disorders such as hepatitis, liver cirrhosis and gallbladder diseases. The main active compound of the plant seeds is silymarin, which is the most commonly used herbal supplement in the United States for liver problems. Nowadays, S. marianum products are available as capsules, powders, and extracts.
The aim of our study is to draw a more comprehensive overview of the traditional heritage, pharmacological benefits and chemical fingerprint of S. marianum extracts and metabolites; as well as their metabolism and bioavailability.
An extensive literature search has been conducted using relavant keywords and papers with rationale methodology and robust data were selected and discussed. Studies involving S. marianum or its main active ingredients with regards to hepatoprotective, antidiabetic, cardiovascular protection, anticancer and antimicrobial activities as well as the clinical trials performed on the plant, were discussed here.
S. marianum was subjected to thousands of ethnopharmacological, experimental and clinical investigations. Although, the plant is available for use as a dietary supplement, the FDA did not yet approve its use for cancer therapy. Nowadays, clinical investigations are in progress where a global evidence of its real efficiency is needed.
S. marianum is a worldwide used herb with unlimited number of investigations focusing on its benefits and properties, however, little is known about its clinical efficiency. Moreover, few studies have discussed its metabolism, pharmacokinetics and bioavailability, so that all future studies on S. marianum should focus on such areas.
Immunomodulatory effects of two silymarin isomers in a Balb/c mouse model of allergic asthma
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It also has protective effects against inflammatory stress in which leukotrienes are involved. The anti-inflammatory effects of silymarin have been attributed to its inhibiting effects on leukotrienes and prostaglandin production.11,13,14 Airway inflammation is an important event in the development of asthma.
Allergic asthma is a complex chronic disease of the respiratory system presenting with cough, dyspnea, wheezing and airway obstruction. More than 300 million people of all age spectrums suffer from asthma worldwide. Immunological and inflammatory processes are main contributors to asthma. Cytokines produced by T helper 2 lymphocytes play main roles in asthma development and progression. Silymarin, a therapeutic agent with anti-oxidative properties, is a main component of Silybium marinum. We herein aimed to compare the anti-inflammatory and anti-allergic effects of two silymarin isomers, isosilybin A and silydianin, in the treatment of allergic asthma.
After isolating and purifying isosilybin A and silydianin, Balb/c mouse model of allergic asthma was produced using ovalbumin injection. Seventy mice were categorized into five (1 normal and 4 asthmatic) groups (n = 14 per group). Mice in three of four asthmatic groups were treated with either isosilybin A, silydianin or budesonide. The 4th asthmatic group was used as positive control, with the non-asthmatic group serving as negative control. Airway hyperresponsiveness (AHR) and levels of IL-4, IL-5 and IL-13 in the BAL fluid were determined. Gene expressions of IL-4, IL-5, IL-13 and MUC5ac, as well as IgE serum level were also measured. Cellular composition of BAL fluid and lungs histopathology were finally investigated.
Isosilybin A and silydianin reduced eosinophilic infiltration of lungs, IL-4 and IL-5 levels in BAL fluid, IL-4 and IL-5 gene expressions, as well as AHR in Balb/c mouse model of asthma. However, no significant changes were observed in IL-13 level and mucus hyper-secretion.
According to our study, isosilybin A and silydianin can control main symptoms of asthma by modulating immune responses.
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NVE contains flavonoids which are known to have bronchodilatory effects [49,50]. Flavonoids inhibit antigen-induced release of histamine from mast cells [51] and also inhibit contractions induced by bronchoconstrictors such as histamine [52,53], among many other anti-asthmatic properties [54]. Many plants with similar phytoconstituents as NVE have also exhibited anti-asthmatic properties [36,37,55].
Napoleona vogelii is used in ethnomedicine for the treatment of asthma and cough. This study evaluated antiasthmatic and antitussive properties of its methanol leaf extract (NVE) in rodents. Phytochemical screening was conducted using established methods. Acute oral toxicity test was done in mice and guinea pigs. Ovalbumin (OA)-sensitized guinea pigs were orally pretreated with 100, 200 or 400 mg/kg/day of NVE or 0.5 mg/kg/day of salbutamol for 14 days before exposure to 0.2% histamine aerosol. Latency to preconvulsive dyspnea (PCD), tracheal fluid volume (TFV), flow rate (FR), and tracheal morphometry (TM) were evaluated. Tracheal rings from sensitized guinea pigs were tested in organ baths for antispasmodic and spasmolytic effects. Citric acid and ammonium hydroxide cough models were used to evaluate antitussive effects in guinea pigs and mice respectively. Tannins, alkaloids, flavonoids, and phenolic substances were found in NVE. LD₅₀ values in mice and guinea pigs were greater than 5000 mg/kg. NVE caused a significant (P < 0.05) increase in the latency to PCD and a decrease in TFV in the group treated with 200 mg/kg. TM indicated a reduction in airway narrowing in NVE-treated groups. The presence of NVE significantly attenuated responses of tracheal rings to carbachol. Its addition to carbachol precontracted rings resulted in significant relaxation. E_max for calcium concentration-response was significantly (P < 0.01) decreased in the presence of NVE. Cough bouts dose-dependently decreased significantly (P < 0.05) in guinea pigs and mice. We conclude that NVE seems safe and possesses anti-asthmatic effect that involves inhibition of calcium influx. It also has antitussive properties that may be peripherally mediated.
Neurotrophic and antioxidant effects of silymarin comparable to 4-methylcatechol in protection against gentamicin-induced ototoxicity in guinea pigs
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Both of group I and group II were given a vehicle of 1% carboxy methylcellulose (CMC). The animals were pre-treated 2 h before gentamicin by either 4-methylcatechol in group III (10 μg/kg by ip injection; dissolved in isotonic saline as 10 μg/ml solution) [35,36] or silymarin in group IV (100 mg/kg by oral gavage; prepared as 35 mg/ml solution in 1% CMC [37]. Silymarin pre-treatment was optimized to be 2 h prior to gentamicin administration, based on its reported rapid absorption and tissue distribution with a peak plasma concentration is achieved within 4 h after oral administration [38].
Despite that gentamicin is a very effective aminoglycoside, its potential ototoxicity which is of irreversible nature makes a challenge and limitation for its use. This study was designed to investigate possible neurotrophic and antioxidant effects of silymarin comparable to 4-methylcatechol in protection against gentamicin-induced ototoxicity.
Twenty pigmented guinea pigs were divided into four equal groups, where group I served as normal control group. The other groups received gentamicin (120 mg/kg/day, ip) for 19 days where group II given vehicle of 1% CMC, group III and group IV were pre-treated 2 h before gentamicin by 4-methylcatechol (10 μg/kg, ip) and silymarin (100 mg/kg, oral gavage), respectively. The main findings indicated that silymarin exhibited restoration of nerve growth factor (NGF) levels and increased tropomyosin-related kinase receptors-A (Trk-A) m-RNA expression in cochlear tissue and preservation of hair cells of organ of Corti by scanning electron microscopy (SEM) with significant decrease in auditory brainstem response (ABR) threshold compared to 4-methylcatechol. Only silymarin caused significant amelioration in oxidative stress state by reducing malondialdehyde (MDA) levels and increasing catalase activity.
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Silymarin is a well-known hepatoprotective agent having an exceptional safety profile. It exerts its action by antioxidant, anti-inflammatory, immunomodulatory, antiproliferative, antifibrotic, and antiviral activities. Silymarin is composed of an isomeric mixture of seven flavonolignans silybin A, silybin B, isosilybin A, isosilybin B, silychristin A, silychristin B, and silydianin and one flavonoid taxifolin. Silibinin, a mixture of silybin A and silybin B, is considered responsible for the hepatoprotective functions of silymarin. Purification of these compounds in gram scale allowed for testing the hepatoprotective effects of pure compounds in various assays. Some individual flavonolignans showed stronger hepatoprotective functions than silymarin. Only isosilybin B showed high toxicity to human hepatoma cell line. Isosilybin A, taxifolin, and silibinin were the most effective hepatoprotectors. Isosilybin B showed the highest antiproliferative activity against human prostate carcinoma cell lines.
Biosynthesis of silymarin flavonolignans occurs by oxidative coupling between the phenylpropanoid coniferyl alcohol and the flavonoid taxifolin. Flavonoid biosynthesis involves phenylpropanoid and polyketide pathways. Plant tissue culture studies have largely contributed to our current understanding of silymarin biosynthesis. Production of silymarin in Silybum marianum cultures can be stimulated by treatment with elicitors such as yeast extract and methyl jasmonate. The components of phenylpropanoid pathway are not modified by elicitation of cell cultures of S. marianum with yeast extract or methyl jasmonate. This was concluded when the overall metabolic changes in elicitor-treated cultures were studied using nuclear magnetic spectroscopy. The flavonoid biosynthesis, not coniferyl alcohol biosynthesis, may be the candidate component of the signaling pathway involved in stimulation of flavonolignan biosynthesis with elicitors. Understanding the basic signaling components in the transduction of the elicitor signal to downstream responses such as silymarin production is mandatory for biotechnological exploitation of this valuable pharmaceutical raw material. Lipoxygenase involvement in the elicitor-induced accumulation of silymarin is well established. Inhibition of external and internal calcium fluxes significantly increases flavonolignan production. Activation of phospholipase D after elicitor treatment mediates silymarin secretion into the culture medium, indicating possible involvement of the enzyme in deposition of silymarin in the external cover of the fruits of S. marianum.
Silibinin attenuates allergic airway inflammation in mice
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In addition, several studies have focused on its anti-allergic properties, and silibinin has been shown to abrogate ovalbumin (OVA)-induced anaphylactic shock in mice as well as to suppress histamine release from human basophils [9,10]. Interestingly, it has been reported that silymarin has a protective effect against the bronchospasm induced by antigen challenge in sensitized guinea pigs, and reduces atopic dermatitis-like skin lesions in NC/Nga mice [11,12]. We have also demonstrated in a previous study that silibinin attenuates IgE-mediated allergic response in rodent mast cells [3].
Allergic asthma is a chronic inflammatory disease regulated by coordination of T-helper2 (Th2) type cytokines and inflammatory signal molecules. Silibinin is one of the main flavonoids produced by milk thistle, which is reported to inhibit the inflammatory response by suppressing the nuclear factor-kappa B (NF-κB) pathway. Because NF-κB activation plays a pivotal role in the pathogenesis of allergic inflammation, we have investigated the effect of silibinin on a mouse ovalbumin (OVA)-induced asthma model. Airway hyperresponsiveness, cytokines levels, and eosinophilic infiltration were analyzed in bronchoalveolar lavage fluid and lung tissue. Pretreatment of silibinin significantly inhibited airway inflammatory cell recruitment and peribronchiolar inflammation and reduced the production of various cytokines in bronchoalveolar fluid. In addition, silibinin prevented the development of airway hyperresponsiveness and attenuated the OVA challenge-induced NF-κB activation. These findings indicate that silibinin protects against OVA-induced airway inflammation, at least in part via downregulation of NF-κB activity. Our data support the utility of silibinin as a potential medicine for the treatment of asthma.

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Protective effect of silymarin in antigen challenge- and histamine-induced bronchoconstriction in in vivo guinea-pigs

Abstract

Introduction

Section snippets

General procedure

Results

Discussion

Trends Pharmacol. Sci.

Life Sci.

Eur. J. Pharmacol.

Pulm. Pharmacol.

Biochem. Pharmacol.

Eur. J. Pharmacol.

Gastric anti-ulcer activity of silymarin, a lipoxygenase inhibitor, in rats

J. Pharm. Pharmacol.

Failure of the inhibition of rat gastric mucosal 5-lipoxygenase by novel acetohydroxamine acids to prevent ethanol-induced damage

Br. J. Pharmacol.

Immediate anaphylactic bronchoconstriction induces airway hyperreactivity in anaesthetized guinea-pigs

Br. J. Pharmacol.

Effect of silymarin on different acute inflammation models and on leukocyte migration

J. Pharm. Pharmacol.