Evaluation of Brilaroxazine (RP5063) in a Bleomycin-Induced Rodent Model of Idiopathic Pulmonary Fibrosis
Main Article Content
Abstract
Idiopathic pulmonary fibrosis pathology involves serotonin (5-HT), with an increased expression of 5-HT2A/2B/7 receptors in the lungs. This study tests the hypothesis that brilaroxazine (RP5063), an agent with a potent binding affinity for serotonin 5-HT1A/2A/2B/7 and dopamine D2/3/4 receptors, and moderate affinity for the 5-HT transporter, dosed at 15 mg twice daily (b.i.d.) shows efficacy as compared with placebo in a bleomycin (BLM)-induced model using Sprague Dawley rats.
On Day 0, four groups received BLM-induction, and one received placebo. On Day 1, one group started on brilaroxazine (RPT). On Day 10, two groups started on brilaroxazine (RPI) and one continued on the vehicle (BLM). All interventions continued until Day 20.
Compared with BLM, RPT and RPI sustained survival at 90.5% and 89.5%, respectively (P<0.05) and maintained weight (P<0.01). RPT normalized pulse pressure and cardiac output. It also lowered respiratory resistance, hydroxyproline, lung weight, bronchoalveolar lavage fluid cell counts, and total protein (P<0.05). RPI decreased hydroxyproline and reduced cell counts (P<0.01). Brilaroxazine lowered Ashcroft scores and Masson’s Trichome staining (P<0.001). Both brilaroxazine groups reduced proinflammatory and fibrotic cytokines (P<0.05).
Brilaroxazine attenuated BLM-induced pulmonary fibrosis, inflammation, and extracellular deposition and improved cardiac and pulmonary functions in rodents.
Keywords:
Anti-inflammatory, Anti-fibrotic, Brilaroxazine, Bleomycin-induced rat model, Idiopathic pulmonary fibrosis, Interstitial lung disease
Article Details
How to Cite
BHAT, Laxminarayan et al.
Evaluation of Brilaroxazine (RP5063) in a Bleomycin-Induced Rodent Model of Idiopathic Pulmonary Fibrosis.
Medical Research Archives, [S.l.], v. 11, n. 4, may 2023.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/3837>. Date accessed: 26 apr. 2024.
doi: https://doi.org/10.18103/mra.v11i4.3837.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
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29. Raghu, G., Rochwerg, B., Zhang, Y., et al., 2015. An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline: Treatment of Idiopathic Pulmonary Fibrosis. An Update of the 2011 Clinical Practice Guideline. Am J Respir Crit Care Med. 192(2), e3-19.
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32. Twafik, M.K., Makary, S., 2017. 5-HT7 receptor antagonism (SB-269970) attenuates bleomycin-induced pulmonary fibrosis in rats via downregulating oxidative burden and inflammatory cascades and ameliorating collagen deposition: Comparison to terguride. Eur J Pharmacol.814, 114-123.
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34. Walter, N., Collard, H.R., King, T.E., 2006. Current perspectives on the treatment of
idiopathic pulmonary fibrosis. Proc Am Thorac Soc. 3(4), 330-8.
35. Wynn, T.A. Integrating mechanisms of pulmonary fibrosis. The Journal of Experimental Medicine. 2011; 208(7):1339-1350.
2. Bhat, L., Hawkinson, J., Cantillon, M, et al., 2017 [a]. RP5063, a novel, multimodal, serotonin receptor modulator, prevents monocrotaline-induced pulmonary arterial hypertension in rats. Eur J Pharmacol. 810,92-99. https://doi: 10.1016/j.ejphar.2017.05.048.
3. Bhat, L., Hawkinson, J., Cantillon, M., et al., 2017 [b]. RP5063, a novel, multimodal, serotonin receptor modulator, prevents Sugen 5416-hypoxia-induced pulmonary arterial hypertension in rats. Eur J Pharmacol. 810,83-91.
https://doi: 10.1016/j.ejphar.2017.05.052.
4. Bhat, L., Hawkinson, J., Cantillon, M., et al., 2018. Evaluation of the effects of RP5063, a novel, multimodal, serotonin receptor modulator, as single-agent therapy and co-administrated with sildenafil, bosentan, and treprostinil in a monocrotaline-induced pulmonary arterial hypertension rat model. Eur J Pharmacol. 827, 159-166. https://doi: 10.1016/j.ejphar.2018.02.017.
5. Bors, M., Tomic, R., Perlman, D.M., et al., 2015. Cognitive function in idiopathic pulmonary fibrosis. Chron Respir Dis. 12, 365-72. doi: 10.1177/147997231560355.
6. Calado, R.T., 2014. Telomeres in lung diseases. Prog Mol Biol Transl Sci. 125,173-83. https://doi: 10.1016/B978-0-12-397898-1.00008-6.
7. Canestaro, W.J., Forrester, S., Ho, L., Devine, B., 2015. Drug Therapy for Treatment of Idiopathic Pulmonary Fibrosis: A Systematic Review and Network Meta-Analysis. Value in Health. 18, A170. https://core.ac.uk/download/pdf/82056666.pdf. (Accessed 2 February 2018).
8. Cantillon, M., Prakash, A., Alexander, A., et al., 2017. Dopamine serotonin stabilizer RP5063: A randomized, double-blind, placebo-controlled multicenter trial of safety and efficacy in exacerbation of schizophrenia or schizoaffective disorder. Schizophr Res. 189, 126-133. https://doi: 10.1016/j.schres.2017.01.043.
9. Cantillon, M., Ings, R., Bhat, L., 2018 [a]. Pharmacokinetics of RP5063 Following Single Doses to Normal Healthy Volunteers and Multiple Doses Over 10 Days to Stable Schizophrenic Patients. Clin Transl Sci. 11, 378-386. https://doi: 10.1111/cts.12518.
10. Cantillon, M., Ings, R., Bhat, L., 2018 [b]. Initial clinical experience of RP5063 following single doses in normal healthy volunteers and multiple doses in patients with stable schizophrenia. Clin Transl Sci. 2018; 11:387-396. https://doi: 10.1111/cts.12545.
11. Dees, C., Akhmetshina, A., Zerr, P., et al., 2011. Platelet-derived serotonin links vascular disease and tissue fibrosis. The Journal of Experimental Medicine. 208, 961-72. https://doi: 10.1084/jem.20101629.
12. Dumitrascu, R., Kulcke, C., Königshoff, M., et al., 2011. Terguride ameliorates monocrotaline-induced pulmonary hypertension in rats. The European Respiratory Journal. 37(5), 1104–1118. https://doi: 10.1183/09031936.00126010.
13. ESBRIET® (pirfenidone) capsules, for oral use Initial U.S. Approval: 2014. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022535s000lbl.pdf. (Accessed 2 February 2018).
14. Fabre, A., Marchal-Sommé, J., Marchand-Adam, S., et al., 2008. Modulation of bleomycin-induced lung fibrosis by serotonin receptor antagonists in mice. Eur Respir J. 32(2), 426-36. https://doi: 10.1183/09031936.00126907.
15. Hutchinson, J., Fogarty, A., Hubbard, R., et al., 2015. Global incidence and mortality of idiopathic pulmonary fibrosis: a systematic review. Eur Respir J. 46, 795-806. https://doi: 10.1183/09031936.00185114.
16. Königshoff, M., Dumitrascu, R., Udalov, S., et al., 2010. Increased expression of 5-hydroxytryptamine2A/B receptors in idiopathic pulmonary fibrosis: a rationale for therapeutic intervention. Thorax. 65(11), 949–955. https://doi: 10.1136/thx.2009.134353.
17. Köster, L.S., Carbon, M., Correll, C.U., 2014. Emerging drugs for schizophrenia: an update. Expert Opinion on Emerging Drugs. 19,511-31. https://doi: 10.1517/14728214.2014.958148.
18. Liu, Y., Lu, F., Kang L, Wang, Z., et al. 2017. Pirfenidone attenuates bleomycin-induced pulmonary fibrosis in mice by regulating Nrf2/Bach1 equilibrium. BMC Pulmonary Medicine. 17, 63. https://doi: 10.1186/s12890-017-0405-7.
19. Löfdahl, A., Rydell‐Törmänen, K., Müller, C., et al., 2016. 5‐HT 2B receptor antagonists attenuate myofibroblast differentiation and subsequent fibrotic responses in vitro and in vivo. Physiol Rep. 4(15), pii, e12873. https://doi: 10.14814/phy2.12873.
20. Lovgren, A.K., Kovacs, J.J., Xie, T., et al., 2011. Β-Arrestin Deficiency Protects Against Pulmonary Fibrosis in Mice and Prevents Fibroblast Invasion of Extracellular Matrix. Sci Transl Med 2011; 3(74):74ra23. https://doi: 10.1126/scitranslmed.3001564.
21. Mann, D.A., Oakley, F., 2013. Serotonin paracrine signaling in tissue fibrosis. Biochimica et Biophysica Acta. 1832(7), 905-10. https://doi: 10.1016/j.bbadis.2012.09.009.
22. Meltzer, E.B., Noble, P.W., 2008. Idiopathic pulmonary fibrosis. Orphanet J Rare Dis. 3:8. https://doi: 10.1186/1750-1172-3-8.
23. Moeller, A., Ask, K., Warburton, D., et al., 2008. The bleomycin animal model: a useful tool to investigate treatment options for idiopathic pulmonary fibrosis? The international journal of biochemistry & cell biology. 40(3), 362-382.
24. Nalysnyk, L., Cid-Ruzafa, J., Rotella, P., Esser, D., 2012. Incidence and prevalence of idiopathic pulmonary fibrosis: a review of the literature. Eur Respir Rev. 21, 355-61.
25. OFEV® (nintedanib) capsules, for oral use Initial U.S. Approval: 2014 https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/205832s000lbl.pdf. Accessed February 16, 2018.
26. Pan, J., Copland, I., Post, M., Yeger, H., et al., 2006. Mechanical stretch-induced serotonin release from pulmonary neuroendocrine cells: implications for lung development. Am J Physiol Lung Cell Mol Physiol. 290(1), L185-93.
27. Puglisi, S., Torrisi, S.E., Vindigni, V., et al., 2016. New perspectives on the management of idiopathic pulmonary fibrosis. Ther Adv Chronic Dis. 7, 108-20.
28. Raghu, G., Weycker, D., Edelsberg, J., et al., 2006. Incidence and prevalence of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 174(7), 810-816.
29. Raghu, G., Rochwerg, B., Zhang, Y., et al., 2015. An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline: Treatment of Idiopathic Pulmonary Fibrosis. An Update of the 2011 Clinical Practice Guideline. Am J Respir Crit Care Med. 192(2), e3-19.
30. Todd, N.W., Luzina, I.G., Atamas, S.P., 2012. Molecular and cellular mechanisms of pulmonary fibrosis. Fibrogenesis and tissue repair. 5(1), 11.
31. Travis, W.D., Costabel, U., Hansell, D.M., et al., 2013. An official American Thoracic Society/European Respiratory Society statement: Update of the international multidisciplinary classification of the idiopathic interstitial pneumonias. Am J Respir Crit Care Med. 188(6), 733-748.
32. Twafik, M.K., Makary, S., 2017. 5-HT7 receptor antagonism (SB-269970) attenuates bleomycin-induced pulmonary fibrosis in rats via downregulating oxidative burden and inflammatory cascades and ameliorating collagen deposition: Comparison to terguride. Eur J Pharmacol.814, 114-123.
33. Tzouvelekis, A., Bonella, F., Spagnolo, P., 2015. Update on the therapeutic management of idiopathic pulmonary fibrosis. Ther Clin Risk Manag. 11, 359-370.
34. Walter, N., Collard, H.R., King, T.E., 2006. Current perspectives on the treatment of
idiopathic pulmonary fibrosis. Proc Am Thorac Soc. 3(4), 330-8.
35. Wynn, T.A. Integrating mechanisms of pulmonary fibrosis. The Journal of Experimental Medicine. 2011; 208(7):1339-1350.