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Current Pharmaceutical Biotechnology

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ISSN (Print): 1389-2010
ISSN (Online): 1873-4316

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General Research Article

A Novel Oral Glutarimide Derivative XC8 Suppresses Sephadex-Induced Lung Inflammation in Rats and Ovalbumin-induced Acute and Chronic Asthma in Guinea Pigs

Author(s): Boris Ferko, Julia Romanova*, Anastasia V. Rydlovskaya, Tatyana A. Kromova, Oxana V. Proskurina, Anna N. Amelina, Helmut Schmutz, Andreas Renner and Vladimir E. Nebolsin

Volume 20, Issue 2, 2019

Page: [146 - 156] Pages: 11

DOI: 10.2174/1389201020666190215103505

Price: $65

Abstract

Background: Corticosteroids are the preferred option to treat asthma, however, they possess serious side effects and are inefficient in 10% of patients. Thus, new therapeutic approaches for asthma treatment are required.

Objective: To study the efficacy of a novel glutarimide derivative XC8 in a Sephadex-induced lung inflammation in rats as well as in acute and chronic ovalbumin-induced allergic asthma in guinea pigs.

Method: Rats were treated with 0.18-18 mg/kg of XC8 intragastrically 4 times (24 h and 1 h prior to and 24 h and 45 h after endotracheal administration of Sephadex). The number of inflammatory cells in bronchoalveaolar lavages (BAL) was determined. Guinea pigs were treated with 0.045 -1.4 mg/kg (acute asthma) or with 1.4 and 7.0 mg/kg of XC8 (chronic asthma) intragastrically following the sensitization with ovalbumin and during aerosol challenge. Lung inflammation, numbers of eosinophils (BAL and lung tissue), goblet cells, degranulating mast cells and specific airway resistance (sRAW) were determined. The comparator steroid drug budesonide (0.5 mg/kg for rats and 0.16 mg/kg for guinea pigs) was administered by inhalation.

Results: XC8 reduced influx of eosinophils into BAL in Sephadex-induced lung inflammation model in rats (by 2.6-6.4 times). Treatment of acute asthma in guinea pigs significantly reduced eosinophils in guinea pigs in BAL (from 55% to 30%-39% of the total cell count) and goblet cells in lung tissue. In a model of acute and chronic asthma, XC8 reduced significantly the number of eosinophils and degranulating mast cells in the lung tissue. Treatment with XC8 but not with budesonide decreased the specific airway resistance in acute and chronic asthma model up to the level of naive animals.

Conclusion: XC8 induced a profound anti-inflammatory effect by reducing eosinophils in BAL and eosinophils and degranulating mast cell numbers in the airway tissue. The anti-asthmatic effect of XC8 is comparable to that of budesonide. Moreover, in contrast to budesonide, XC8 was capable to reduce goblet cells and airway resistance.

Keywords: Allergic lung inflammation, airway hyperresponsiveness, asthma, allergic asthma, glutarimide derivatives, XC8.

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[1]
Masoli, M.; Fabian, D.; Holt, S.; Beasley, R. Global Initiative for Asthma, P. The global burden of asthma: Executive summary of the GINA Dissemination Committee report. Allergy, 2004, 59(5), 469-478.
[2]
Tattersfield, A.E.; Postma, D.S.; Barnes, P.J.; Svensson, K.; Bauer, C.A.; O’Byrne, P.M.; Lofdahl, C.G.; Pauwels, R.A.; Ullman, A. Exacerbations of asthma: A descriptive study of 425 severe exacerbations. The FACET International Study Group. Am. J. Respir. Crit. Care Med., 1999, 160(2), 594-599.
[3]
Miller, M.K.; Lee, J.H.; Miller, D.P.; Wenzel, S.E.; Group, T.S. Recent asthma exacerbations: A key predictor of future exacerbations. Respir. Med., 2007, 101(3), 481-489.
[4]
ten Brinke, A.; Sterk, P.J.; Masclee, A.A.; Spinhoven, P.; Schmidt, J.T.; Zwinderman, A.H.; Rabe, K.F.; Bel, E.H. Risk factors of frequent exacerbations in difficult-to-treat asthma. Eur. Respir. J., 2005, 26(5), 812-818.
[5]
Seemungal, T.; Harper-Owen, R.; Bhowmik, A.; Moric, I.; Sanderson, G.; Message, S.; Maccallum, P.; Meade, T.W.; Jeffries, D.J.; Johnston, S.L.; Wedzicha, J.A. Respiratory viruses, symptoms, and inflammatory markers in acute exacerbations and stable chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med., 2001, 164(9), 1618-1623.
[6]
Green, R.M.; Custovic, A.; Sanderson, G.; Hunter, J.; Johnston, S.L.; Woodcock, A. Synergism between allergens and viruses and risk of hospital admission with asthma: Case-control study. BMJ, 2002, 324(7340), 763.
[7]
Rodrigo, G.J.; Rodrigo, C.; Hall, J.B. Acute asthma in adults: A review. Chest, 2004, 125(3), 1081-1102.
[8]
Cooper, V.; Metcalf, L.; Versnel, J.; Upton, J.; Walker, S.; Horne, R. Patient-reported side effects, concerns and adherence to corticosteroid treatment for asthma, and comparison with physician estimates of side-effect prevalence: A UK-wide, cross-sectional study. NPJ Prim. Care Respir. Med., 2015, 25, 15026.
[9]
Doull, I.J.; Lampe, F.C.; Smith, S.; Schreiber, J.; Freezer, N.J.; Holgate, S.T. Effect of inhaled corticosteroids on episodes of wheezing associated with viral infection in school age children: Randomised double blind placebo controlled trial. BMJ, 1997, 315(7112), 858-862.
[10]
Kaba, R.A.; Ahmed, O.; Cannie, D. Response to ‘Lack of reversibility for NOACs’. Glob. Cardiol. Sci. Pract., 2014, 2014(1), 2.
[11]
Hayward, G.; Thompson, M.J.; Perera, R.; Del Mar, C.B.; Glasziou, P.P.; Heneghan, C.J. Corticosteroids for the common cold. Cochrane Database Syst. Rev., 2015, (10), CD008116.
[12]
Reichelt, K.L.; Edminson, P.D.; Kvamme, E. The formation of peptido-amines from constituent amino acids and histamine in hypothalamic tissue. J. Neurochem., 1976, 26(4), 811-815.
[13]
McCaman, M.W.; Stetzler, J.; Clark, B. Synthesis of gamma-glutamyldopamine and other peptidoamines in the nervous system of Aplysia californica. J. Neurochem., 1985, 45(6), 1828-1835.
[14]
Stein, C.; Weinreich, D. An in vitro characterization of gamma-glutamylhistamine synthetase: A novel enzyme catalyzing histamine metabolism in the central nervous system of the marine mollusk, Aplysia californica. J. Neurochem., 1982, 38(1), 204-214.
[15]
Sloley, B.D.; Juorio, A.V.; Durden, D.A. High-performance liquid chromatographic analysis of monoamines and some of their gamma-glutamyl conjugates produced by the brain and other tissues of Helix aspersa (Gastropoda). Cell. Mol. Neurobiol., 1990, 10(2), 175-192.
[16]
Battelle, B.A.; Hart, M.K. Histamine metabolism in the visual system of the horseshoe crab Limulus polyphemus. Comp. Biochem. Physiol. A Mol. Integr. Physiol., 2002, 133(1), 135-142.
[17]
Kovaleva, V.L.; Nebol’sin, V.E.; Karabinenko, A.A.; Zheltukhina, G.A.; Uteshev, D.B. The protector properties of a pseudopeptide drug ingamine studied on a model of bronchospasm in guinea pigs. Eksp. Klin. Farmakol., 2005, 68(2), 21-24.
[18]
Kovaleva, V.L.; Nebol’sin, V.E.; Makarova, O.V.; Noseikina, E.M.; Mikhailova, L.P. The effect of a potential drug ingamine on a model of noninfectious pneumonia. Eksp. Klin. Farmakol., 2004, 67(4), 30-34.
[19]
Nebol’sin, V.E.; Zheltukhina, G.A.; Krzhechkovskaia, V.V.; Kovaleva, V.L.; Evstigneeva, R.P. The effect of gamma-L-glutamylhistamine analogues on the severity of experimental anaphylactic reaction, hormonal status and liver cytochrome P450 system. Vopr. Med. Khim., 2001, 47(3), 301-307.
[20]
Finsnes, F.; Lyberg, T.; Christensen, G.; Skjonsberg, O.H. Leukotriene antagonism reduces the generation of endothelin-1 and interferon-gamma and inhibits eosinophilic airway inflammation. Respir. Med., 2002, 96(11), 901-906.
[21]
Mojtabavi, N.; Dekan, G.; Stingl, G.; Epstein, M.M. Long-lived Th2 memory in experimental allergic asthma. J. Immunol., 2002, 169(9), 4788-4796.
[22]
In Guide for the Care and Use of Laboratory Animals, th, Ed. Washington (DC), 2011. Available from: https://www.ncbi.nlm. nih.gov/pubmed/?term=Mojtabavi%2C+N.%3B+Dekan%2C+G.+2002
[23]
Meurs, H.; Santing, R.E.; Remie, R.; van der Mark, T.W.; Westerhof, F.J.; Zuidhof, A.B.; Bos, I.S.; Zaagsma, J. A guinea pig model of acute and chronic asthma using permanently instrumented and unrestrained animals. Nat. Protoc., 2006, 1(2), 840-847.
[24]
Maarsingh, H.; Dekkers, B.G.; Zuidhof, A.B.; Bos, I.S.; Menzen, M.H.; Klein, T.; Flik, G.; Zaagsma, J.; Meurs, H. Increased arginase activity contributes to airway remodelling in chronic allergic asthma. Eur. Respir. J., 2011, 38(2), 318-328.
[25]
Lee, J.Y.; Lee, J.G.; Sim, S.S.; Whang, W.K.; Kim, C.J. Anti-asthmatic effects of phenylpropanoid glycosides from Clerodendron trichotomum leaves and Rumex gmelini herbes in conscious guinea-pigs challenged with aerosolized ovalbumin. Phytomedicine, 2011, 18(2-3), 134-142.
[26]
Hirasawa, M.; Ito, Y.; Shibata, M.A.; Otsuki, Y. Mechanism of inflammation in murine eosinophilic myocarditis produced by adoptive transfer with ovalbumin challenge. Int. Arch. Allergy Immunol., 2007, 142(1), 28-39.
[27]
Ellis, R.; Leigh, R.; Southam, D.; O’Byrne, P.M.; Inman, M.D. Morphometric analysis of mouse airways after chronic allergen challenge. Lab. Invest., 2003, 83(9), 1285-1291.
[28]
Hamelmann, E.; Schwarze, J.; Takeda, K.; Oshiba, A.; Larsen, G.L.; Irvin, C.G.; Gelfand, E.W. Noninvasive measurement of airway responsiveness in allergic mice using barometric plethysmography. Am. J. Respir. Crit. Care Med., 1997, 156(3 Pt 1), 766-775.
[29]
Cotgreave, I.A.; Duddy, S.K.; Kass, G.E.; Thompson, D.; Moldeus, P. Studies on the anti-inflammatory activity of ebselen. Ebselen interferes with granulocyte oxidative burst by dual inhibition of NADPH oxidase and protein kinase C? Biochem. Pharmacol., 1989, 38(4), 649-656.
[30]
Kallos, P.; Kallos, L. Experimental asthma in guinea pigs revisited. Int. Arch. Allergy Appl. Immunol., 1984, 73(1), 77-85.
[31]
Aun, M.V.; Bonamichi-Santos, R.; Arantes-Costa, F.M.; Kalil, J.; Giavina-Bianchi, P. Animal models of asthma: Utility and limitations. J. Asthma Allergy, 2017, 10, 293-301.
[32]
Chen, Z.; Bai, F.F.; Han, L.; Zhu, J.; Zheng, T.; Zhu, Z.; Zhou, L.F. Targeting neutrophils in severe asthma via Siglec-9. Int. Arch. Allergy Immunol., 2018.
[33]
Bruijnzeel, P.L.; Uddin, M.; Koenderman, L. Targeting neutrophilic inflammation in severe neutrophilic asthma: Can we target the disease-relevant neutrophil phenotype? J. Leukoc. Biol., 2015, 98(4), 549-556.
[34]
Pesci, A.; Rossi, G.A.; Bertorelli, G.; Aufiero, A.; Zanon, P.; Olivieri, D. Mast cells in the airway lumen and bronchial mucosa of patients with chronic bronchitis. Am. J. Respir. Crit. Care Med., 1994, 149(5), 1311-1316.
[35]
Carroll, N.G.; Mutavdzic, S.; James, A.L. Distribution and degranulation of airway mast cells in normal and asthmatic subjects. Eur. Respir. J., 2002, 19(5), 879-885.
[36]
Kandeel, M.; Balaha, M.; Inagaki, N.; Kitade, Y. Current and future asthma therapies. Drugs Today (Barc), 2013, 49(5), 325-339.
[37]
British Thoracic. S.; Scottish Intercollegiate Guidelines, N. British guideline on the management of asthma. Thorax, 2014, 69(Suppl. 1), 1-192.
[38]
Lane, N.E. An update on glucocorticoid-induced osteoporosis. Rheum. Dis. Clin. North Am., 2001, 27(1), 235-253.
[39]
Busby, W.H., Jr; Quackenbush, G.E.; Humm, J.; Youngblood, W.W.; Kizer, J.S. An enzyme(s) that converts glutaminyl-peptides into pyroglutamyl-peptides. Presence in pituitary, brain, adrenal medulla, and lymphocytes. J. Biol. Chem., 1987, 262(18), 8532-8536.
[40]
Shahabuddin, S.; Ponath, P.; Schleimer, R.P. Migration of eosinophils across endothelial cell monolayers: Interactions among IL-5, endothelial-activating cytokines, and C-C chemokines. J. Immunol., 2000, 164(7), 3847-3854.
[41]
Palmqvist, C.; Wardlaw, A.J.; Bradding, P. Chemokines and their receptors as potential targets for the treatment of asthma. Br. J. Pharmacol., 2007, 151(6), 725-736.
[42]
Wang, A.; Wang, Z.; Cao, Y.; Cheng, S.; Chen, H.; Bunjhoo, H.; Xie, J.; Wang, C.; Xu, Y.; Xiong, W. CCL2/CCR2-dependent recruitment of Th17 cells but not Tc17 cells to the lung in a murine asthma model. Int. Arch. Allergy Immunol., 2015, 166(1), 52-62.
[43]
Castro, M.; Wenzel, S.E.; Bleecker, E.R.; Pizzichini, E.; Kuna, P.; Busse, W.W.; Gossage, D.L.; Ward, C.K.; Wu, Y.; Wang, B.; Khatry, D.B.; van der Merwe, R.; Kolbeck, R.; Molfino, N.A.; Raible, D.G. Benralizumab, an anti-interleukin 5 receptor alpha monoclonal antibody, versus placebo for uncontrolled eosinophilic asthma: A phase 2b randomised dose-ranging study. Lancet Respir. Med., 2014, 2(11), 879-890.
[44]
de Oliveira Henriques, M.D.; Penido, C. γδ T lymphocytes coordinate eosinophil influx during allergic responses. Front. Pharmacol., 2012, 3, 200.

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