Skip to main content

Advertisement

SpringerLink
Log in

Effects of COX1-2/5-LOX blockade in Alzheimer transgenic 3xTg-AD mice

  • Original Research Paper
  • Published:
Inflammation Research Aims and scope Submit manuscript

Abstract

Objective and design

Alzheimer’s disease (AD) is associated with amyloid plaques (Aβ) and hyperphosphorylated tau protein tangles in the brain. We investigated the possible neuroprotective role of flavocoxid, a dual inhibitor of cyclooxygenases-1/2 (COX-1/2) and 5-Lipoxygenase (5-LOX), in triple-transgenic (3xTg-AD) mice.

Subjects

Mice were 3 months at the beginning of the study.

Treatment

Animals received once daily for 3-month saline solution or flavocoxid (20 mg/kg/ip).

Methods

Morris water maze was used to assess learning and memory. Histology was performed to evidence Aβ plaques and neuronal loss, while inflammatory proteins were determined by western blot analysis.

Results

Saline-treated 3xTg-AD mice showed an impairment in spatial learning and memory (assessed at 6 months of age), and increased expression of inflammatory and apoptotic molecules. Treatment of 3xTg-AD mice with flavocoxid reduced: (1) learning and memory loss; (2) the increased eicosanoid production and the phosphorylation level of amyloid precursor protein (APP-pThr668), Aβ 1–42, p-tau (pThr181), pERK, and the activation of the NLRP3 inflammasome; (3) Aβ plaques; and (4) neuronal loss, compared to saline-treated animals.

Conclusions

Pharmacological blockade of both COX-1/2 and 5-LOX was able to counteract the progression of AD by targeting pathophysiological mechanisms up- and downstream of Aβ and tau.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Galimberti D, Ghezzi L, Scarpini E. Immunotherapy against amyloid pathology in Alzheimer’s disease. J Neurol Sci. 2013;333:50–4.

    Article  CAS  PubMed  Google Scholar 

  2. Ittner LM, Götz J. Amyloid-β and tau—a toxic pas de deux in Alzheimer’s disease. Nat Rev Neurosci. 2011;12:65–72.

    Article  CAS  PubMed  Google Scholar 

  3. Tayeb HO, Yang HD, Price BH, Tarazi FI. Pharmacotherapies for Alzheimer’s disease: beyond cholinesterase inhibitors. Pharmacol Ther. 2012;134:8–25.

    Article  CAS  PubMed  Google Scholar 

  4. Giuliani D, Bitto A, Galantucci M, Zaffe D, Ottani A, Irrera N, Neri L, Cavallini GM, Altavilla D, Botticelli AR, Squadrito F, Guarini S. Melanocortins protect against progression of Alzheimer’s disease in triple-transgenic mice by targeting multiple pathophysiological pathways. Neurobiol Aging. 2014;35:537–47.

    Article  CAS  PubMed  Google Scholar 

  5. Kumar S, Wirths O, Theil S, Gerth J, Bayer TA, Walter J. Early intraneuronal accumulation and increased aggregation of phosphorylated Abeta in a mouse model of Alzheimer’s disease. Acta Neuropathol. 2013;125:699–709.

    Article  CAS  PubMed  Google Scholar 

  6. Munoz L, Ammit AJ. Targeting p38 MAPK pathway for the treatment of Alzheimer’s disease. Neuropharmacology. 2010;58:561–8.

    Article  CAS  PubMed  Google Scholar 

  7. Banerjee R, Beal MF, Thomas B. Autophagy in neurodegenerative disorders: pathogenetic roles and therapeutic implications. Trends Neurosci. 2010;33:541–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Zipp F, Aktas O. The brain as a target of inflammation: common pathways link inflammatory and nurodegenerative diseases. Trends Neurosci. 2006;29:518–27.

    Article  CAS  PubMed  Google Scholar 

  9. Klegeris A, McGeer PL. Cyclooxygenase and 5-lipoxygenase inhibitors protect against mononuclear phagocyte neurotoxicity. Neurobiol Aging. 2002;23:787–94.

    Article  CAS  PubMed  Google Scholar 

  10. Yang H, Chen C. Cyclooxygenase-2 in synaptic signaling. Curr Pharm Des. 2008;14:1443–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Firuzi O, Zhuo J, Chinnici CM, Wisniewski T, Praticò D. 5-Lipoxygenase gene disruption reduces amyloid-beta pathology in a mouse model of Alzheimer’s disease. FASEB J. 2008;22:1169–78.

    Article  CAS  PubMed  Google Scholar 

  12. Pasinetti GM. From epidemiology to therapeutic trials with anti-inflammatory drugs in Alzheimer’s disease: the role of NSAIDs and cyclooxygenase in beta-amyloidosis and clinical dementia. J Alzheimers Dis. 2002;4:435–45.

    CAS  PubMed  Google Scholar 

  13. Heneka MT, Kummer MP, Stutz A, Delekate A, Schwartz S, Vieira-Saecker A, Griep A, Axt D, Remus A, Tzeng TC, Gelpi E, Halle A, Korte M, Latz E, Golenbock DT. NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice. Nature. 2013;493:674–8.

    Article  CAS  PubMed  Google Scholar 

  14. Tan MS, Yu JT, Jiang T, Zhu XC, Tan L. The NLRP3 inflammasome in Alzheimer’s disease. Mol Neurobiol. 2013;48:875–82.

    Article  CAS  PubMed  Google Scholar 

  15. Ghosh S, Wu MD, Shaftel SS, Kyrkanides S, LaFerla FM, Olschowka JA, O’Banion MK. Sustained interleukin-1β overexpression exacerbates tau pathology despite reduced amyloid burden in an Alzheimer’s mouse model. J Neurosci. 2013;33:5053–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Sorbara MT, Girardin SE. Mitochondrial ROS fuel the inflammasome. Cell Res. 2011;21:558–60.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Burnett BP, Bitto A, Altavilla D, Squadrito F, Levy RM, Pillai L. Flavocoxid inhibits phospholipase A2, peroxidase moieties of the cyclooxygenases (COX), and 5-lipoxygenase, modifies COX-2 gene expression, and acts as an antioxidant. Mediators Inflamm. 2011;2011:385780.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Bitto A, Squadrito F, Irrera N, Pizzino G, Pallio G, Mecchio A, Galfo F, Altavilla D. Flavocoxid, a nutraceutical approach to blunt inflammatory conditions. Mediators Inflam. 2014;2014:790851.

    Article  Google Scholar 

  19. Bitto A, Minutoli L, David A, Irrera N, Rinaldi M, Venuti FS, Squadrito F, Altavilla D. Flavocoxid, a dual inhibitor of COX-2 and 5-LOX of natural origin, attenuates the inflammatory response and protects mice from sepsis. Crit Care. 2012;16:32.

    Article  Google Scholar 

  20. Burnett BP, Jia Q, Zhao Y, Levy RM. A medicinal extract of Scutellaria baicalensis and Acacia catechu acts as a dual inhibitor of cyclooxygenase and 5-lipoxygenase to reduce inflammation. J Med Food. 2007;10:442–51.

    Article  CAS  PubMed  Google Scholar 

  21. Minutoli L, Marini H, Rinaldi M, Bitto A, Irrera N, Pizzino G, Pallio G, Calò M, Adamo EB, Trichilo V, Interdonato M, Galfo F, Squadrito F, Altavilla D. A dual inhibitor of cyclooxygenase and 5-lipoxygenase protects against kainic Acid-induced brain injury. Neuromolecular Med. 2015;17:192–201.

    Article  CAS  PubMed  Google Scholar 

  22. Youdim KA, Qaiser MZ, Begley DJ, Rice-Evans CA, Abbott NJ. Flavonoid permeability across an in situ model of the blood-brain barrier. Free Radic Biol Med. 2004;36:592–604.

    Article  CAS  PubMed  Google Scholar 

  23. Giuliani D, Mioni C, Altavilla D, Leone S, Bazzani C, Minutoli L, Bitto A, Cainazzo MM, Marini H, Zaffe D, Botticelli AR, Pizzala R, Savio M, Necchi D, Schiöth HB, Bertolini A, Squadrito F, Guarini S. Both early and delayed treatment with melanocortin 4 receptor-stimulating melanocortins produces neuroprotection in cerebral ischemia. Endocrinology. 2006;147:1126–35.

    Article  CAS  PubMed  Google Scholar 

  24. Giuliani D, Neri L, Canalini F, Calevro A, Ottani A, Vandini E, Sena P, Zaffe D, Guarini S. NDP-α-MSH induces intense neurogenesis and cognitive recovery in Alzheimer transgenic mice through activation of melanocortin MC4 receptors. Mol Cell Neurosci. 2015;67:13–21.

    Article  CAS  PubMed  Google Scholar 

  25. Giuliani D, Ottani A, Minutoli L, Stefano VD, Galantucci M, Bitto A, Zaffe D, Altavilla D, Botticelli AR, Squadrito F, Guarini S. Functional recovery after delayed treatment of ischemic stroke with melanocortins is associated with overexpression of the activity-dependent gene Zif268. Brain Behav Immun. 2009;23:844–50.

    Article  CAS  PubMed  Google Scholar 

  26. Sabogal-Guáqueta AM, Muñoz-Manco JI, Ramírez-Pineda JR, Lamprea-Rodriguez M, Osorio E, Cardona-Gómez GP. The flavonoid quercetin ameliorates Alzheimer’s disease pathology and protects cognitive and emotional function in aged triple transgenic Alzheimer’s disease model mice. Neuropharmacology. 2015;93:134–45.

    Article  PubMed  Google Scholar 

  27. Hsiao K, Chapman P, Nilsen S, Eckman C, Harigaya Y, Younkin S, Yang F, Cole G. Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice. Science. 1996;274:99–102.

    Article  CAS  PubMed  Google Scholar 

  28. Lilja AM, Röjdner J, Mustafiz T, Thomé CM, Storelli E, Gonzalez D, Unger-Lithner C, Greig NH, Nordberg A, Marutle A. Age-dependent neuroplasticity mechanisms in Alzheimer Tg2576 mice following modulation of brain amyloid-β levels. PLoS One. 2013;8:e58752.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Fernandez JW, Rezai-Zadeh K, Obregon D, Tan J. EGCG functions through estrogen receptor-mediated activation of ADAM10 in the promotion of non-amyloidogenic processing of APP. FEBS Lett. 2010;584:4259–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Yin F, Liu J, Ji X, Wang Y, Zidichouski J, Zhang J. Baicalin prevents the production of hydrogen peroxide and oxidative stress induced by Aβ aggregation in SH-SY5Y cells. Neurosci Lett. 2011;492:76–9.

    Article  CAS  PubMed  Google Scholar 

  31. Ben Menachem-Zidon O, Menahem YB, Hur TB, Yirmiya R. Intra-hippocampal transplantation of neural precursor cells with transgenic over-expression of IL-1 receptor antagonist rescues memory and neurogenesis impairments in an Alzheimer’s disease model. Neuropsychopharmacology. 2014;39:401–14.

    Article  CAS  PubMed  Google Scholar 

  32. Feld M, Krawczyk MC, Sol Fustiñana M, Blake MG, Baratti CM, Romano A, Boccia MM. Decrease of ERK/MAPK overactivation in prefrontal cortex reverses early memory deficit in a mouse model of Alzheimer’s disease. J Alzheimers Dis. 2014;40:69–82.

    CAS  PubMed  Google Scholar 

  33. Gasparini L, Ongini E, Wenk G. Non-steroidal anti-inflammatory drugs (NSAIDs) in Alzheimer’s disease: old and new mechanisms of action. J Neurochem. 2004;91:521–36.

    Article  CAS  PubMed  Google Scholar 

  34. Thomas T, Nadackal TG, Thomas K. Aspirin and non-steroidal anti-inflammatory drugs inhibit amyloid-beta aggregation. Neuroreport. 2001;12:3263–7.

    Article  CAS  PubMed  Google Scholar 

  35. Kotilinek LA, Westerman MA, Wang Q, Panizzon K, Lim GP, Simonyi A, Lesne S, Falinska A, Younkin LH, Younkin SG, Rowan M, Cleary J, Wallis RA, Sun GY, Cole G, Frautschy S, Anwyl R, Ashe KH. Cyclooxygenase-2 inhibition improves amyloid-beta-mediated suppression of memory and synaptic plasticity. Brain. 2008;131:651–64.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Chakrabarty P, Tianbai L, Herring A, Ceballos-Diaz C, Das P, Golde TE. Hippocampal expression of murine IL-4 results in exacerbation of amyloid deposition. Mol Neurodegener. 2012;7:36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Gustavsson A, Svensson M, Jacobi F, Allgulander C, Alonso J, Beghi E, Dodel R, Ekman M, Faravelli C, Fratiglioni L, Gannon B, Jones DH, Jennum P, Jordanova A, Jönsson L, Karampampa K, Knapp M, Kobelt G, Kurth T, Lieb R, Linde M, Ljungcrantz C, Maercker A, Melin B, Moscarelli M, Musayev A, Norwood F, Preisig M, Pugliatti M, Rehm J, Salvador-Carulla L, Schlehofer B, Simon R, Steinhausen HC, Stovner LJ, Vallat JM, Van den Bergh P, van Os J, Vos P, Xu W, Wittchen HU, Jönsson B, Olesen J. Cost of disorders of the brain in Europe 2010. Eur Neuropsychopharmacol. 2011;21:718–79.

    Article  CAS  PubMed  Google Scholar 

  38. Caberlotto L, Nguyen TP. A systems biology investigation of neurodegenerative dementia reveals a pivotal role of autophagy. BMC Syst Biol. 2014;8:65.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Lu G, Kwong WH, Li Q, Wang X, Feng Z, Yew DT. Bcl2, bax, and nestin in the brains of patients with neurodegeneration and those of normal aging. J Mol Neurosci. 2005;27:167–74.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

The work was supported by Departmental fundings. Flavocoxid was a kind gift of Primus Pharmaceuticals Inc., Scottsdale, AZ.

Author information

Authors and Affiliations

  1. Department of Clinical and Experimental Medicine, Section of Pharmacology, University of Messina, Torre Biologica 5th floor, c/o AOU Policlinico G. Martino, Via C. Valeria Gazzi, 98125, Messina, Italy

    Alessandra Bitto, Giovanni Pallio, Natasha Irrera, Letteria Minutoli, Mariagrazia Rinaldi & Francesco Squadrito

  2. Department of Biomedical, Metabolic and Neural Sciences, Section of Pharmacology and Molecular Medicine, University of Modena and Reggio Emilia, Via G. Campi 287, 41125, Modena, Italy

    Daniela Giuliani, Eleonora Vandini, Fabrizio Canalini, Alessandra Ottani & Salvatore Guarini

  3. Department of Biomedical, Metabolic and Neural Sciences, Section of Human Morphology, University of Modena and Reggio Emilia, Modena, Italy

    Davide Zaffe

  4. Department of Biomedical Sciences, Morphological and Functional Images, University of Messina, Via C. Valeria, Torre Biologica 1st floor, 98125, Messina, Italy

    Domenica Altavilla

Authors
  1. Alessandra Bitto
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Daniela Giuliani
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Giovanni Pallio
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Natasha Irrera
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Eleonora Vandini
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Fabrizio Canalini
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Davide Zaffe
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Alessandra Ottani
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Letteria Minutoli
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Mariagrazia Rinaldi
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Salvatore Guarini
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Francesco Squadrito
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Domenica Altavilla
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Alessandra Bitto.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All applicable international, national, and institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

Additional information

Responsible Editor: Ji Zhang.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bitto, A., Giuliani, D., Pallio, G. et al. Effects of COX1-2/5-LOX blockade in Alzheimer transgenic 3xTg-AD mice. Inflamm. Res. 66, 389–398 (2017). https://doi.org/10.1007/s00011-017-1022-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00011-017-1022-x

Keywords

Search

Navigation