, Volume 26, Issue 1, pp 285–290 | Cite as

Alendronate treatment induces IL-1B expression and apoptosis in glioblastoma cell line

  • Paola Maura TricaricoEmail author
  • Angeladine Epate
  • Fulvio Celsi
  • Sergio Crovella
Short Communication


Alendronate (ALD), one among the nitrogen-containing bisphosphonates (NBPs), is currently used for the treatment of many pathological conditions. Unfortunately, although generally tolerated, NBPs treatment has been associated with central nervous system (CNS) adverse outcomes, such as amnesia, hallucinations and visual disturbances. So, we analyzed the effect of ALD treatment in glial cells, the main sources of cholesterol for neurons and principal cells involved in the immunological defense of the brain. We treated a glial cell line (U87-MG) with increasing doses of ALD (0.1, 1, 10, 25, 50 μM) for 48 h, aimed at evaluating the influence of this drug treatment on IL-1B expression, NLRP3 and CASP1 expression, mitochondrial activity and apoptotic cell death. We observed that ALD treatment, at the higher concentrations, induced a significant increase of IL-1B, NLRP3, CASP1 expression, provoked apoptosis and also mitochondrial damage in U87-MG. Considering the reported CNS adverse outcomes of NBPs treatment, our results confirm ALD side-effects on glial cell model.


Alendronate Nitrogen-containing bisphosphonates Glial cell line IL-1B expression NLRP3 inflammasome Apoptosis 



This work was supported by a grant from the Institute for Maternal and Child Health IRCCS “Burlo Garofolo” (RC 42/11). The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Compliance with ethical standards

Conflict of interest

The authors have no conflicts of interest to declare.


  1. Body JJ (2001) Dosing regimens and main adverse events of bisphosphonates. Semin Oncol 28:49–53CrossRefPubMedGoogle Scholar
  2. Burnet SP, Petrie JP (1999) ‘Wake up and smell the roses’—a drug reaction to etidronate. Aust N Z J Med 29:93CrossRefPubMedGoogle Scholar
  3. Cibickova L, Hyspler R, Cibicek N et al (2008) Alendronate lowers cholesterol synthesis in the central nervous system of rats—a preliminary study. Physiol Res 58:455–458PubMedGoogle Scholar
  4. Citraro R, Gallelli L, Leo A et al (2015) Effects of chronic sodium alendronate on depression and anxiety in a menopausal experimental model. Pharmacol Biochem Behav 129:65–71. doi: 10.1016/j.pbb.2014.12.006 CrossRefPubMedGoogle Scholar
  5. Coleman CI, Perkerson KA, Lewis A (2004) Alendronate-induced auditory hallucinations and visual disturbances. Pharmacotherapy 24:799–802. doi: 10.1592/phco.24.8.799.36062 CrossRefPubMedGoogle Scholar
  6. Di Paolo NC, Shayakhmetov DM (2016) Interleukin 1α and the inflammatory process. Nat Immunol 17:906–913. doi: 10.1038/ni.3503 CrossRefPubMedPubMedCentralGoogle Scholar
  7. Drake MT, Clarke BL, Khosla S (2008) Bisphosphonates: mechanism of action and role in clinical practice. Mayo Clin Proc 83:1032–1045CrossRefPubMedPubMedCentralGoogle Scholar
  8. Ebetino FH, Hogan AM, Sun S et al (2011) The relationship between the chemistry and biological activity of the bisphosphonates. Bone 49:20–33CrossRefPubMedGoogle Scholar
  9. Foley-Nolan D, Daly MJ, Williams D et al (1992) Pamidronate-associated hallucinations [letter]. Ann Rheum Dis 51:927–928CrossRefPubMedPubMedCentralGoogle Scholar
  10. Granovsky-Grisaru S, Belmatoug N, vom Dahl S et al (2011) The management of pregnancy in Gaucher disease. Eur J Obstet Gynecol Reprod Biol 156:3–8CrossRefPubMedGoogle Scholar
  11. Kleiner G, Celsi F, Tricarico PM et al (2013) Systemic and neuronal inflammatory markers in a mouse model of mevalonate kinase deficiency: a strain-comparative study. In Vivo 27:715–722PubMedGoogle Scholar
  12. Lesclous P, Abi Najm S, Carrel JP et al (2009) Bisphosphonate-associated osteonecrosis of the jaw: a key role of inflammation? Bone 45:843–852CrossRefPubMedGoogle Scholar
  13. Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 25:402–408CrossRefPubMedGoogle Scholar
  14. Loeb JA (1998) Functional improvement in a patient with cerebral calcinosis using a bisphosphonate. Mov Disord 13:345–349CrossRefPubMedGoogle Scholar
  15. Loeb JA, Sohrab SA, Huq M et al (2006) Brain calcifications induce neurological dysfunction that can be reversed by a bone drug. J Neurol Sci 243:77–81CrossRefPubMedGoogle Scholar
  16. Marcuzzi A, Piscianz E, Girardelli M et al (2011) Defect in mevalonate pathway induces pyroptosis in Raw 264.7 murine monocytes. Apoptosis 16:882–888. doi: 10.1007/s10495-011-0621-1 CrossRefPubMedGoogle Scholar
  17. Marcuzzi A, Tricarico PM, Piscianz E et al (2013) Lovastatin induces apoptosis through the mitochondrial pathway in an undifferentiated SH-SY5Y neuroblastoma cell line. Cell Death Dis 4:e585. doi: 10.1038/cddis.2013.112 CrossRefPubMedPubMedCentralGoogle Scholar
  18. Massa LF, Bradaschia-Correa V, Arana-Chavez VE (2006) Immunocytochemical study of amelogenin deposition during the early odontogenesis of molars in alendronate-treated newborn rats. J Histochem Cytochem 54:713–725CrossRefPubMedGoogle Scholar
  19. McCarthy EA, Raggio CL, Hossack MD et al (2002) Alendronate treatment for infants with osteogenesis imperfecta: demonstration of efficacy in a mouse model. Pediatr Res 52:660–670CrossRefPubMedGoogle Scholar
  20. Moutinho M, Nunes MJ, Rodrigues E (2017) The mevalonate pathway in neurons: it’s not just about cholesterol. Exp Cell Res. doi: 10.1016/j.yexcr.2017.02.034 PubMedGoogle Scholar
  21. Norton JT, Hayashi T, Crain B et al (2012) Cutting edge: nitrogen bisphosphonate-induced inflammation is dependent upon mast cells and IL-1. J Immunol 188:2977–2980. doi: 10.4049/jimmunol.1100830 CrossRefPubMedPubMedCentralGoogle Scholar
  22. Oliveira JR, Oliveira MF (2016) Primary brain calcification in patients undergoing treatment with the biphosphanate alendronate. Sci Rep 6:22961. doi: 10.1038/srep22961 CrossRefPubMedPubMedCentralGoogle Scholar
  23. Ornoy A, Wajnberg R, Diav-Citrin O (2006) The outcome of pregnancy following pre-pregnancy or early pregnancy alendronate treatment. Reprod Toxicol 22:578–579CrossRefPubMedGoogle Scholar
  24. Papapetrou PD (2009) Bisphosphonate-associated adverse events. Hormones (Athens) 8:96–110CrossRefGoogle Scholar
  25. Pazianas M, Clark EM, Eiken PA et al (2013) Inflammatory eye reactions in patients treated with bisphosphonates and other osteoporosis medications: cohort analysis using a national prescription database. J Bone Miner Res 28:455–463. doi: 10.1002/jbmr.1783 CrossRefPubMedGoogle Scholar
  26. Reddy DS (2010) Neurosteroids: endogenous role in the human brian and therapeutic potentials. Prog Brain Res 186:113–137. doi: 10.1016/B978-0-444-53630-3.00008-7 CrossRefPubMedPubMedCentralGoogle Scholar
  27. Soares AP, do Espírito Santo RF, Line SR et al (2016) Bisphosphonates: pharmacokinetics, bioavailability, mechanisms of action, clinical applications in children, and effects on tooth development. Environ Toxicol Pharmacol 42:212–217. doi: 10.1016/j.etap.2016.01.015 CrossRefPubMedGoogle Scholar
  28. Tricarico PM, Crovella S, Celsi F (2015a) Mevalonate pathway blockade, mitochondrial dysfunction and autophagy: a possible link. Int J Mol Sci 16:16067–16084. doi: 10.3390/ijms160716067 CrossRefPubMedPubMedCentralGoogle Scholar
  29. Tricarico PM, Girardelli M, Kleiner G et al (2015b) Alendronate, a double-edged sword acting in the mevalonate pathway. Mol Med Rep 12:4238–4242. doi: 10.3892/mmr.2015.3957 CrossRefPubMedPubMedCentralGoogle Scholar
  30. Tricarico PM, Piscianz E, Monasta L et al (2015c) Microglia activation and interaction with neuronal cells in a biochemical model of mevalonate kinase deficiency. Apoptosis 20:1048–1055. doi: 10.1007/s10495-015-1139-8 CrossRefPubMedGoogle Scholar
  31. Zhou R, Yazdi AS, Menu P, Tschopp J (2011) A role for mitochondria in NLRP3 inflammasome activation. Nature 469:221–225. doi: 10.1038/nature09663 CrossRefPubMedGoogle Scholar
  32. Zorumski CF, Paul SM, Izumi Y et al (2013) Neurosteroids, stress and depression: potential therapeutic opportunities. Neurosci Biobehav Rev 37:109–122CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  • Paola Maura Tricarico
    • 1
    Email author
  • Angeladine Epate
    • 2
  • Fulvio Celsi
    • 1
  • Sergio Crovella
    • 1
    • 2
  1. 1.Institute for Maternal and Child Health-IRCCS “Burlo Garofolo”TriesteItaly
  2. 2.University of TriesteTriesteItaly

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