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Inhibitory Effects of Sildenafil and Tadalafil on Inflammation, Oxidative

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Inhibitory Effects of Sildenafil and Tadalafil on Inflammation, Oxidative Pharmacological Reports 71 (2019) 517–521 Contents lists available at ScienceDirect Pharmacological Reports journal homepage: www.elsevier.com/locate/pharep Original article Inhibitory effects of sildenafil and tadalafil on inflammation, oxidative stress and nitrosative stress in animal model of bronchial asthma a a, a b b Vijaya Laxmi , Rachna Gupta *, Swapan K. Bhattacharya , Arunabha Ray , Kavita Gulati a Department of Pharmacology, University College of Medical Sciences and GTB Hospital, New Delhi, India b Vallabhbhai Patel Chest Institute, New Delhi, India A R T I C L E I N F O A B S T R A C T Article history: Background: Cyclic neucleotides are involved in many cellular functions including smooth muscle Received 9 June 2018 relaxation, inflammation, and signal transduction. Sildenafil and tadalafil are phosphodiesterase-5 Received in revised form 22 January 2019 0 0 (PDE-5) inhibitors which prevent the degradation of cyclic neucleotide i.e. guanosine 3 ,5 cyclic Accepted 14 February 2019 monophosphate (cGMP) and increase the levels of cGMP. In this study sildenafil and tadalafil were Available online 15 February 2019 evaluated for their anti-inflammatory, anti-oxidative and anti-nitrosative stress potential in animal model of bronchial asthma. Keywords: Methods: Wistar rats were sensitized with 10 mg intraperitoneal (ip) ovalbumin adsorbed to 10 mg of Bronchial asthma aluminum hydroxide on day 0. Animals were given sildenafil (1 and 3 mg/kg ip) and tadalafil (1 and Inflammation 3 mg/kg ip) from day 1 to day 14. Also, on day 14 animals were challenged with ovalbumin (1 mg ip). After Oxidative stress Ovalbumin 24 h, samples were collected to analyze interleukin-4 (IL-4) and tumour necrosis factor-α (TNF-α), in Sildenafil serum and bronchoalveolar lavage fluid (BALF). The oxidative stress markers malondialdehyde (MDA), fi Tadala l reduced glutathione (GSH) and nitric oxide metabolites (NOx) were also measured in serum. Results: Pre-treatment with sildenafil(1and3mg/kg ip) and tadalafil (1 and 3 mg/kg ip) significantlyreduced the levels of pro-inflammatory cytokines IL-4 and TNF-α in rat serum and BALF. In addition, pre-treatment with both the drugs decreased the levels of MDA and NOx and increased the levels of GSH in serum. Conclusions: Sildenafil and tadalafil decreased pro-inflammatory cytokines in serum and BALF. Both drugs inhibit oxidative and nitrosative stress in animal model of bronchial asthma and could have a therapeutic potential in bronchial asthma. © 2019 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier B.V. All rights reserved. Introduction are integral to variety of cellular functions like smooth muscle relaxation, inflammation, and signal transduction [2,3]. Pharma- Bronchial asthma is a syndrome characterized by inflammation cotherapy of various inflammatory airway diseases like asthma followed by airflow obstruction and bronchial hyper-responsive- and chronic obstructive pulmonary disease (COPD) is now being ness to a variety of stimuli; resulting in episodic bronchocon- targeted at increasing the levels of cyclic adenosine mono- striction and increased mucus secretion, which are the hallmarks phosphate (cAMP) or cyclic guanosine monophosphate (cGMP). of the disease. Airway inflammation is central to the pathogenesis Increased cAMP or cGMP levels cause bronchodilatory, anti- of bronchial asthma. Besides, disturbances in pro/anti-oxidant inflammatory and pulmonary vasodilatory effects [4–6]. There are balance also have a key role to play. Asthma is associated with eleven known isoforms of PDEs, of which PDE-5 is widely increased oxidative stress as activated inflammatory cells such as expressed in the airway epithelium and preferentially hydrolyses macrophages and eosinophils give rise to generation of reactive cGMP [7,8]. Sildenafil and tadalafil are specific PDE-5 inhibitors, oxygen species [1]. The principal therapeutic objective in asthma is which have been used in airway diseases like COPD and pulmonary to reduce airway inflammation and to reverse bronchoconstriction. artery hypertension. Sildenafil/tadalafil cause bronchodilation by Phosphodiesterases (PDEs), a family of enzymes controls protein-kinase G dependent mechanism resulting from rise in degradation of intracellular cyclic neucleotides cAMP/cGMP that cGMP levels [9]. Zaprinast (a PDE-5 inhibitor) has produced bronchodilator effect in patients with asthma [10,11 ]. Also, vardenafil (another selective PDE-5 inhibitor) has shown an anti-allergic effect by * Corresponding author. E-mail address: [email protected] (R. Gupta). inhibiting immunologic and non-immunologic mast-cell- https://doi.org/10.1016/j.pharep.2019.02.008 1734-1140/© 2019 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier B.V. All rights reserved. 518 V. Laxmi et al. / Pharmacological Reports 71 (2019) 517–521 mediated allergic reactions in murine models [12]. Sildenafil is stored at À80 C for analysis of TNF-α, IL-4, MDA, GSH, and nitric more selective for PDE-5 and is more potent than zaprinast. oxide metabolites (NOx). BALF was obtained after cannulating the Various studies have shown anti-inflammatory, anti-oxidative and trachea of the rats. BALF sample were centrifuged at 1000 rpm for anti-nitrosative stress potential of sildenafil [13,14] but the same 10 min at 4 C, and the resultant cell-free supernatant was used for remains unexplored in a model of bronchial asthma. Therefore, in estimation of cytokines (TNF-α and IL-4). the present study we investigate the effect of two PDE-5 inhibitors i.e. sildenafil and tadalafil on inflammation, oxidative stress and Cytokines (TNF-α, IL-4) measurement in serum and BALF nitrosative stress in experimentally induced bronchial asthma. An animal model of allergic asthma was developed in rats as described TNF-α and IL-4 levels were estimated in serum and BALF sample earlier [15–17]. The effects of sildenafil and tadalafil were using ELISA kits. The detection limits of kits were 20 pg/ml and evaluated on markers of inflammation – interleukin-4 (IL-4) and 15 pg/ml for TNF-α and IL-4, respectively. Microtiter plates were tumour necrosis factor-α (TNF-α) in serum and bronchoalveolar pre-coated with antibody against the rat cytokines being lavage fluid (BALF). Additionally, oxidative stress markers malon- measured. Standards of the analyte and serum/BALF samples dialdehyde (MDA), reduced glutathione (GSH), and nitrosative (50 ml) were added to the wells and incubated for 3 h (4 h for IL-4). stress markers were measured in serum. After washings 100 ml of antibody solution was added and incubated for 1 h. Then, 100 mL of avidin-horseradish peroxidase Material and methods solution was added and after 30 min, 100 ml of tetramethylben- zidine was added. After 15–20 minutes, 100 ml of 1 M sulphuric Wistar rats (220–250 g) of either sex were used in the study. The acid was added. The absorbance was read at 450 nm and the study protocol was approved by the Institutional animal ethics standard curves were plotted. committee. Animal experiments and procedures were conducted as per CPCSEA (Committee for the Purpose of Control and Estimation of GSH in serum Supervision of Experiments on Animals) guidelines for the use and care of laboratory animals. The animals were housed in GSH was estimated by the method described by Ellman [23]. standard laboratory conditions. The animals had free access to Briefly, 1 ml TCA (5%) was added to 0.5 ml of serum sample and the standard pellet diet and water. mixture centrifuged to remove the proteins. To 0.1 ml of this The drugs and chemical used in the study were: Sildenafil TM homogenate, 4 ml of phosphate buffer (pH 8.4), 0.5 ml of DTNB and [Silagra 50 , Cipla India (with calcium hydrogen phosphate 0.4 ml double distilled water were added. The mixture was anhydrous, cellulose microcrystalline, croscarmellose sodium, vortexed and absorbance read at 412 nm within 15 min. Also, silica colloidal anhydrous, magnesium stearate, lactose monohy- the same above steps were subjected with concentrations of drate, hypromellose, titanium dioxide (E171), triacetin as exci- TM standard glutathione (1–100 mg). The readings of absorbance were pients)], tadalafil [Tadacip 20 , Cipla India (with lactose plotted against the concentration of GSH to produce standard monohydrate, hypromellose, triacetin, titanium dioxide (E171), curve. The concentration of GSH was determined by linear iron oxide yellow (E172), talc, lactose monohydrate, croscarmel- standard graph. lose sodium, hydroxypropylcellulose, microcrystalline cellulose, sodium laurilsulfate, magnesium stearate as excipients) and TM Estimation of malondialdehyde (MDA) in serum prednisolone (Wysolone 5 Wyeth India), Ovalbumin (Sigma- Aldrich, USA) and aluminum hydroxide (Sigma-Aldrich, USA). All MDA (indicator of lipid peroxidation) was estimated as drugs/chemical were of high analytical grade. Drug/chemical described by Okhawa et al. [24]. In serum sample (0.5 ml), acetic solutions were freshly prepared using physiological saline. acid (20%, pH 3.5) 1.5 ml, thiobarbituric acid (0.8%), sodium lauryl sulfate (8.1%) 0.2 ml were added. The mixture was heated at 100 C Sensitization and challenge schedule in animals [18] for 1 h in boiling water bath and cooled with tap water. Five ml of butanol: pyridine (15:1% v/v) and 1 ml of distilled water were Wistar rats were sensitized with ovalbumin (10 mg per rat, ip) added in the mixture. The mixture was centrifuged at 4000 rpm for adsorbed to 10 mg of aluminum hydroxide on day 0. After 10 min. Thereafter, absorbance measured at 532 nm using a sensitization, rats were divided into six groups (n = 12): spectrophotometer. Group 1 (disease-control) normal saline (2 ml/kg ip) was given to disease-control group from day 1 to day 14. Group 2 received sildenafil (1 mg/kg/day, ip) from day 1 to day Estimation of nitrates and nitrites (NOx) in serum 14 and group 3 received sildenafil in the doses of 3 mg/kg/day ip from day 1 to day 14.
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