O alendronato prejudica as bombas de íons chave e desencadeia danos estruturais na mucosa das vias aéreas superiores e no bulbo olfativo
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Abstract
Introdução: O alendronato (ALN) é um bisfosfonato usado na prática clínica para reduzir as consequências adversas de condições ósseas patológicas.
Objetivo: Investigar os efeitos da administração de alendronato (ALN) na imunoexpressão de Na+K+ATPase e v-ATPase na mucosa das vias aéreas superiores e no bulbo olfativo de ratos.
Método: Dezesseis animais foram distribuídos igualmente em grupos controle e experimental, com estes últimos recebendo doses diárias intraperitoneais de ALN (2,5 mg/kg). Após sete dias, os ratos foram eutanasiados e suas cabeças processadas para avaliação histológica e quantificação imunohistoquímica de ambas as bombas de prótons alvo para avaliar a integridade estrutural do tecido.
Resultados -. Amostras tratadas com ALN apresentaram diminuição da presença de Na+K+ATPase e v-ATPase tanto no epitélio respiratório quanto no bulbo olfatório. Esses achados coincidiram com vacuolização e perda de polaridade dentro do epitélio respiratório, juntamente com profunda degeneração celular no bulbo olfatório.
Conclusão: A administração de alendronato pode alterar a histomorfologia do epitelial respiratório, comprometendo adicionalmente a integridade do bulbo olfatório devido à regulação negativa da expressão de Na+K+ATPase e de v-ATPase.
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References
- Nayak S, Greenspan SL. A systematic review and meta-analysis of the effect of bisphosphonate drug holidays on bone mineral density and osteoporotic fracture risk. Osteoporos Int. 2019;30(4):705-20. https://doi.org/10.1007/s00198-018-4791-3
- de Oliveira Vicente A, Chandrasekhar SS, Yamashita HK, Cruz OL, Barros FA, Penido NO. Magnetic resonance imaging in the evaluation of clinical treatment of otospongiosis: a pilot study. Otolaryngol Head Neck Surg. 2015;152(6):1119-26. https://doi.org/10.1177/0194599815574698
- Glorieux FH, Bishop NJ, Plotkin H, Chabot G, Lanoue G, Travers R. Cyclic administration of pamidronate in children with severe osteogenesis imperfecta. N Engl J Med. 1998;339(14):947-52. https://doi.org/10.1056/nejm199810013391402
- Oyhanart SR, Escudero ND, Mandalunis PM. Effect of alendronate on the mandible and long bones: an experimental study in vivo. Pediatr Res. 2015;78(6):618-25. https://doi.org/10.1038/pr.2015.163
- Vieira JS, Cunha EJ, de Souza JF, Sant'Ana RD, Zielak JC, Costa-Casagrande TA, et al. Alendronate induces postnatal maxillary bone growth by stimulating intramembranous ossification and preventing premature cartilage mineralization in the midpalatal suture of newborn rats. Int J Oral Maxillofac Surg. 2019;48(11):1494-503. https://doi.org/10.1016/j.ijom.2019.04.002
- Vieira JS, Giovanini A, Görhinger I, Gonzaga CC, Costa-Casagrande TA, Deliberador TM. Use of Low-Dose Alendronate Improves Cranial Bone Repair and Is Associated With an Increase of Osteocalcin: An Experimental Study. J Oral Maxillofac Surg 2017; 75(9):1873-1881
- Chandran M, Zeng W. Severe Oral Mucosal Ulceration Associated with Oral Bisphosphonate Use: The Importance of Imparting Proper Instructions on Medication Administration and Intake. Case Rep Med. 2021;2021:6620489. https://doi.org/10.1155/2021/6620489
- Theodora P, Apostolos P, Vasileios P, Sofia K, Eva-Maria D, Antonia S. Histologic evaluation of femoral nerve demyelinating and axonal neuropathy in Wistar rats due to alendronate intake: a randomised study. J Biol Res (Thessalon). 2020;27:2. https://doi.org/10.1186/s40709-020-0112-z
- Ballester I, Daddaoua A, López-Posadas R, Nieto A, Suárez MD, Zarzuelo A, et al. The bisphosphonate alendronate improves the damage associated with trinitrobenzenesulfonic acid-induced colitis in rats. Br J Pharmacol. 2007;151(2):206-15. https://doi.org/10.1038/sj.bjp.0707227
- Som PM, Streit A, Naidich TP. Illustrated review of the embryology and development of the facial region, part 3: an overview of the molecular interactions responsible for facial development. AJNR Am J Neuroradiol. 2014;35(2):223-9. https://doi.org/10.3174/ajnr.a3453
- Hollenhorst MI, Richter K, Fronius M. Ion transport by pulmonary epithelia. J Biomed Biotechnol. 2011;2011:174306. https://doi.org/10.1155/2011/174306
- Nagayama S, Homma R, Imamura F. Neuronal organization of olfactory bulb circuits. Front Neural Circuits. 2014;8:98. https://doi.org/10.3389/fncir.2014.00098
- Brézillon S, Zahm JM, Pierrot D, Gaillard D, Hinnrasky J, Millart H, et al. ATP depletion induces a loss of respiratory epithelium functional integrity and down-regulates CFTR (cystic fibrosis transmembrane conductance regulator) expression. J Biol Chem. 1997;272(44):27830-8. https://doi.org/10.1074/jbc.272.44.27830
- Clausen MV, Hilbers F, Poulsen H. The Structure and Function of the Na,K-ATPase Isoforms in Health and Disease. Front Physiol. 2017;8:371. https://doi.org/10.3389/fphys.2017.00371
- Meisami E, Mousavi R. Lasting effects of early olfactory deprivation on the growth, DNA, RNA and protein content, and Na-K-ATPase and AchE activity of the rat olfactory bulb. Brain Res. 1981;254(2):217-29. https://doi.org/10.1016/0165-3806(81)90033-x
- Breton S, Brown D. New insights into the regulation of V-ATPase-dependent proton secretion. Am J Physiol Renal Physiol. 2007;292(1):F1-10. https://doi.org/10.1152/ajprenal.00340.2006
- Figueres-Oñate M, Gutiérrez Y, López-Mascaraque L. Unraveling Cajal's view of the olfactory system. Front Neuroanat. 2014;8:55. https://doi.org/10.3389/fnana.2014.00055
- Drake MT, Clarke BL, Khosla S. Bisphosphonates: mechanism of action and role in clinical practice. Mayo Clin Proc. 2008;83(9):1032-45. https://doi.org/10.4065/83.9.1032
- Luckman SP, Hughes DE, Coxon FP, Graham R, Russell G, Rogers MJ. Nitrogen-containing bisphosphonates inhibit the mevalonate pathway and prevent post-translational prenylation of GTP-binding proteins, including Ras. J Bone Miner Res. 1998;13(4):581-9. https://doi.org/10.1359/jbmr.1998.13.4.581
- Dunford JE, Thompson K, Coxon FP, Luckman SP, Hahn FM, Poulter CD, et al. Structure-activity relationships for inhibition of farnesyl diphosphate synthase in vitro and inhibition of bone resorption in vivo by nitrogen-containing bisphosphonates. J Pharmacol Exp Ther. 2001;296(2):235-42.
- Stevens VL. Regulation of glycosylphosphatidylinositol biosynthesis by GTP. Stimulation of N-acetylglucosamine-phosphatidylinositol deacetylation. J Biol Chem. 1993;268(13):9718-24
- Paulick MG, Bertozzi CR. The glycosylphosphatidylinositol anchor: a complex membrane-anchoring structure for proteins. Biochemistry. 2008;47(27):6991-7000. https://doi.org/10.1021/bi8006324
- Rajasekaran SA, Palmer LG, Quan K, Harper JF, Ball WJ Jr, Bander NH, et al. Na,K-ATPase beta-subunit is required for epithelial polarization, suppression of invasion, and cell motility. Mol Biol Cell. 2001;12(2):279-95. https://doi.org/10.1091/mbc.12.2.279
- Rajasekaran SA, Palmer LG, Moon SY, Peralta Soler A, Apodaca GL, Harper JF, et al. Na,K-ATPase activity is required for formation of tight junctions, desmosomes, and induction of polarity in epithelial cells. Mol Biol Cell. 2001;12(12):3717-32. https://doi.org/10.1091/mbc.12.12.3717
- Parker D, Prince A. Innate immunity in the respiratory epithelium. Am J Respir Cell Mol Biol. 2011;45(2):189-201. https://doi.org/10.1165/rcmb.2011-0011RT
- Gohy ST, Hupin C, Pilette C, Ladjemi MZ. Chronic inflammatory airway diseases: the central role of the epithelium revisited. Clin Exp Allergy. 2016;46(4):529-42. https://doi.org/10.1111/cea.12712
- Vavassori S, Mayer A. A new life for an old pump: V-ATPase and neurotransmitter release. J Cell Biol. 2014;205(1):7-9. https://doi.org/10.1083/jcb.201403040
- Paunescu TG, Jones AC, Tyszkowski R, Brown D. V-ATPase expression in the mouse olfactory epithelium. Am J Physiol Cell Physiol. 2008;295(4):C923-30. https://doi.org/10.1152/ajpcell.00237.2008
- Breton S, Brown D. Regulation of luminal acidification by the V-ATPase. Physiology (Bethesda). 2013;28(5):318-29. https://doi.org/10.1152/physiol.00007.2013









