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A 2-Substituted 8-Hydroxyquinoline Stimulates Neural Stem Cell Proliferation by Modulating ROS Signalling

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Abstract

Eight-hydroxyquinolines (8HQs) are a class of compounds that have been identified as potential therapeutics for a number of neurodegenerative diseases. Understanding the influence of structural modifications to the 8HQ scaffold on cellular behaviour will aid the identification of compounds that might be effective in treating dementias. In this study, we describe the action of 2-[(dimethylamino)methyl]-8-hydroxyquinoline (DMAMQ) on adult murine neural stem cells (NSCs) cultured in vitro. Treatment of NSCs with DMAMQ resulted in enhanced self-renewal and increased neurite outgrowth. Concurrent with the positive growth effects was an increase in intracellular reactive oxygen species, with the growth being inhibited by inactivation of the NADPH oxidase (Nox) enzyme family. Our results indicate that DMAMQ can stimulate neurogenesis via the Nox signalling pathway, which may provide therapeutic benefit in treating dementias of various types by replenishing neurones using the brain’s own reserves. The narrow concentration range over which these effects were observed, however, suggests that there may exist only a small therapeutic window for neuro-regenerative applications.

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References

  1. Gomez-Nicola, D., Suzzi, S., Vargas-Caballero, M., Fransen, N. L., Al-Malki, H., Cebrian-Silla, A., et al. (2014). Temporal dynamics of hippocampal neurogenesis in chronic neurodegeneration. Brain, 137, 2312–2328.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Jin, K., Peel, A. L., Mao, X. O., Xie, L., Cottrell, B. A., Henshall, D. C., & Greenberg, D. A. (2004). Increased hippocampal neurogenesis in Alzheimer’s disease. Proceedings of the National Academy of Sciences USA, 101, 343–347.

    Article  CAS  Google Scholar 

  3. Haughey, N. J., Nath, A., Chan, S. L., Borchard, A. C., Rao, M. S., & Mattson, M. P. (2002). Disruption of neurogenesis by amyloid beta-peptide, and perturbed neural progenitor cell homeostasis, in models of Alzheimer’s disease. Journal of Neurochemistry, 83, 1509–1524.

    Article  CAS  PubMed  Google Scholar 

  4. Jin, K., Galvan, V., Xie, L., Mao, X. O., Gorostiza, O. F., Bredesen, D. E., & Greenberg, D. A. (2004). Enhanced neurogenesis in Alzheimer’s disease transgenic (PDGF-APPSw, Ind) mice. Proceedings of the National Academy of Sciences USA, 101, 13363–13367.

    Article  CAS  Google Scholar 

  5. Kanemoto, S., Griffin, J., Markham-Coultes, K., Aubert, I., Tandon, A., George-Hyslop, P. S., & Fraser, P. E. (2014). Proliferation, differentiation and amyloid-beta production in neural progenitor cells isolated from TgCRND8 mice. Neuroscience, 261, 52–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Karkkainen, V., Magga, J., Koistinaho, J., & Malm, T. (2012). Brain environment and Alzheimer’s disease mutations affect the survival, migration and differentiation of neural progenitor cells. Current Alzheimer Research, 9, 1030–1042.

    Article  CAS  PubMed  Google Scholar 

  7. Lopez-Toledano, M. A., & Shelanski, M. L. (2007). Increased neurogenesis in young transgenic mice overexpressing human APP(Sw, Ind). Journal of Alzheimer’s Disease, 12, 229–240.

    CAS  PubMed  Google Scholar 

  8. Akers, K. G., Martinez-Canabal, A., Restivo, L., Yiu, A. P., De Cristofaro, A., Hsiang, H. L., et al. (2014). Hippocampal neurogenesis regulates forgetting during adulthood and infancy. Science, 344, 598–602.

    Article  CAS  PubMed  Google Scholar 

  9. Dupret, D., Revest, J. M., Koehl, M., Ichas, F., De Giorgi, F., Costet, P., et al. (2008). Spatial relational memory requires hippocampal adult neurogenesis. Plos One, 3, e1959.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Sahay, A., Scobie, K. N., Hill, A. S., O’Carroll, C. M., Kheirbek, M. A., Burghardt, N. S., et al. (2011). Increasing adult hippocampal neurogenesis is sufficient to improve pattern separation. Nature, 472, 466–470.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Leifer, W., & Steiner, K. (1949). Diodoquin as a topical therapeutic agent in cutaneous. Journal of Investigative Dermatology, 12, 203–204.

    Article  CAS  PubMed  Google Scholar 

  12. Gershon, H., Gershon, M., & Clarke, D. D. (2011). Antifungal activity of substituted 8-quinolinol-5- and 7-sulfonic acids: A mechanism of action is suggested based on intramolecular synergism. Mycopathologia, 155, 213–217.

    Article  Google Scholar 

  13. Zhou, J., Zhang, H., Gu, P., Margolick, J. B., Yin, D., & Zhang, Y. (2009). Cancer stem/progenitor cell active compound 8-quinolinol in combination with paclitaxel achieves an improved cure of breast cancer in the mouse model. Breast Cancer Research Treatment, 115, 269–277.

    Article  CAS  PubMed  Google Scholar 

  14. Mohammed, I., Hampton, S. E., Ashall, L., Hildebrandt, E. R., Kutlik, R. A., Manandhar, S. P., et al. (2016). 8-Hydroxyquinoline-based inhibitors of the Rce1 protease disrupt Ras membrane localization in human cells. Bioorganic and Medicinal Chemistry, 24, 160–178.

    Article  CAS  PubMed  Google Scholar 

  15. Martirosyan, A., Leonard, S., Shi, X., Griffith, B., Gannett, P., & Strobl, J. (2006). Actions of a histone deacetylase inhibitor NSC3852 (5-nitroso-8-quinolinol) link reactive oxygen species to cell differentiation and apoptosis in MCF-7 human mammary tumor cells. Journal of Pharmacology and Experimental Therapeutics, 317, 546–552.

    Article  CAS  PubMed  Google Scholar 

  16. King, O. N. F., Li, X. S., Sakurai, M., Kawamura, A., Rose, N. R., Ng, S. S., et al. (2011). Quantitative high-throughput screening identifies 8-hydroxyquinolines as cell-active histone demethylase inhibitors. Plos One, 5, e15535.

    Article  Google Scholar 

  17. Tardiff, D. F., Tucci, M. L., Caldwell, K. A., Caldwell, G. A., & Lindquist, S. (2011). Different 8-hydroxyquinolines protect models of TDP-43 protein, α-synuclein, and polyglutamine proteotoxicity through distinct mechanisms. Journal of Biological Chemistry, 287, 4107–4120.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Crouch, P. J., Savva, M. S., Hung, L. W., Donnelly, P. S., Mot, A. I., Parker, S. J., et al. (2011). The Alzheimer’s therapeutic PBT2 promotes amyloid-β degradation and GSK3 phosphorylation via a metal chaperone activity. Journal of Neurochemistry, 119, 220–230.

    Article  CAS  PubMed  Google Scholar 

  19. Adlard, P. A., Bica, L., White, A. R., Nurjono, M., Filiz, G., Crouch, P. J., et al. (2011). Metal ionophore treatment restores dendritic spine density and synaptic protein levels in a mouse model of Alzheimer’s disease. Plos One, 6, e17669.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Gomes, L. M., Vieira, R. P., Jones, M. R., Wang, M. C., Dyrager, C., Souza-Fagundes, E. M., et al. (2014). 8-Hydroxyquinoline Schiff-base compounds as antioxidants and modulators of copper-mediated Aβ peptide aggregation. Journal of Inorganic Biochemistry, 139, 106–116.

    Article  CAS  Google Scholar 

  21. Mancin, F., & Chin, J. (2002). An artificial guanine that binds cytidine through the cooperative interaction of metal coordination and hydrogen bonding. Journal of the American Chemical Society, 124, 10946–10947.

    Article  CAS  PubMed  Google Scholar 

  22. Johnson, D. K., & Kline, S. J. (1991). 8-Hydroxyquinoline chelating agents. United States Patent No. 5021567 A, 4 June.

  23. Rajagopalan, R., Archilefu, S. I., Bugaj, J. E., & Dorshow, R. B. (2011). Quinoline ligands and metal complexes for diagnosis and therapy. United States Patent No. 6277841 B1, Aug. 21.

  24. Schwarcz, R., Bruno, J. P., Muchowski, P. J., & Wu, H. Q. (2012). Kynurenines in the mammalian brain: When physiology meets pathology. Nature Reviews Neuroscience, 13, 465–477.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Mossialos, D., Meyer, J.-M., Budzikiewicz, H., Wolff, U., Koedam, N., Baysse, C., et al. (2000). Quinolobactin, a new siderophore of Pseudomonas fluorescens ATCC 17400, the production of which is repressed by the cognate pyoverdine. Applied and Environmental Microbiology, 66, 487–492.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Pesek, J., Svoboda, J., Sattler, M., Bartram, S., & Boland, W. (2015). Biosynthesis of 8-hydroxyquinoline-2-carboxylic acid, an iron chelator from the gut of the lepidopteran Spodoptera littoralis. Organic & Biomolecular Chemistry, 13, 178–184.

    Article  CAS  Google Scholar 

  27. Kenche, V. B., Zawisza, I., Masters, C. L., Bal, W., Barnham, K. J., & Drew, S. C. (2013). Mixed ligand Cu2+ complexes of a model therapeutic with Alzheimer’s amyloid-β peptide and monoamine neurotransmitters. Inorganic Chemistry, 52, 4303–4318.

    Article  CAS  PubMed  Google Scholar 

  28. Haigh, C. L., McGlade, A. R., Lewis, V., Masters, C. L., Lawson, V. A., & Collins, S. J. (2011). Acute exposure to prion infection induces transient oxidative stress progressing to be cumulatively deleterious with chronic propagation in vitro. Free Radical Biology and Medicine, 51, 594–608.

    Article  CAS  PubMed  Google Scholar 

  29. Collins, S. J., Tumpach, C., Li, Q.-X., Lewis, V., Ryan, T. M., Roberts, B., et al. (2015). The prion protein regulates β-amyloid mediated self-renewal of neural stem cells. Stem Cell Research & Therapy, 6, 60.

    Article  Google Scholar 

  30. Haigh, C. L., Drew, S. C., Boland, M., Masters, C. L., Barnham, K. J., Lawson, V. A., & Collins, S. J. (2009). Dominant roles of the polybasic proline motif and copper in PrP23–89 mediated stress protection response. Journal of Cell Science, 122, 1518–1528.

    Article  CAS  PubMed  Google Scholar 

  31. Sinclair, L., Lewis, V., Collins, S. J., & Haigh, C. L. (2013). Cytosolic caspases mediate mislocalised SOD2 depletion in an in vitro model of chronic prion infection. Disease Models and Mechanisms, 6, 952–963.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Haigh, C. L., Lewis, V. A., Vella, L. J., Masters, C. L., Hill, A. F., Lawson, V. A., & Collins, S. J. (2009). PrPC-related signal transduction is influenced by copper, membrane integrity and the alpha cleavage site. Cell Research, 19, 1062–1078.

    Article  CAS  PubMed  Google Scholar 

  33. Lang, C., Mix, E., Frahm, J., Glass, Ä., Müller, J., Schmitt, O., et al. (2011). Small molecule GSK-3 inhibitors increase neurogenesis of human neural progenitor cells. Neuroscience Letters., 488, 36–40.

    Article  Google Scholar 

  34. Morales-Garcia, J. A., Luna-Medina, R., Alonso-Gil, S., Sanz-Sancristobal, M., Palomo, V., Gil, C., et al. (2012). Glycogen synthase kinase 3 inhibition promotes adult hippocampal neurogenesis in vitro and in vivo. ACS Chemical Neuroscience, 3, 963–971.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Tonelli, F. M., Santos, A. K., Gomes, D. A., da Silva, S. L., Gomes, K. N., Ladeira, L. O., & Resende, R. R. (2012). Stem cells and calcium signalling. Advances in Experimental Medicine and Biology, 740, 891–916.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Bogeski, I., Kappl, R., Kummerow, C., Gulaboski, R., Hoth, M., & Niemeyer, B. A. (2011). Redox regulation of calcium ion channels: Chemical and physiological aspects. Cell Calcium, 50, 407–423.

    Article  CAS  PubMed  Google Scholar 

  37. Panday, A., Sahoo, M. K., Osorio, D., & Batra, A. (2015). NADPH oxidases: An overview from structure to innate immunity-associated pathologies. Cell & Molecluar Immunology, 12, 5–23.

    Article  CAS  Google Scholar 

  38. Le Belle, J. E., Orozco, N. M., Paucar, A. A., Saxe, J. P., Mottahedeh, J., Pyle, A. D., et al. (2011). Proliferative neural stem cells have high endogenous ROS levels that regulate self-renewal and neurogenesis in a PI3K/Akt-dependant manner. Cell Stem Cell, 8, 59–71.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Walton, N. M., Shin, R., Tajinda, K., Heusner, C. L., Kogan, J. H., Miyake, S., et al. (2012). Adult neurogenesis transiently generates oxidative stress. Plos One, 7, e35264.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Yoneyama, M., Kawada, K., Gotoh, Y., Shiba, T., & Ogita, K. (2010). Endogenous reactive oxygen species are essential for proliferation of neural stem/progenitor cells. Neurochemistry International, 56, 740–746.

    Article  CAS  PubMed  Google Scholar 

  41. Menon, S. G., & Goswami, P. C. (2007). A redox cycle within the cell cycle: Ring in the old with the new. Oncogene, 26, 1101–1109.

    Article  CAS  PubMed  Google Scholar 

  42. Sarsour, E. H., Kalen, A. L., & Goswami, P. C. (2014). Manganese superoxide dismutase regulates a redox cycle within the cell cycle. Antioxidants & Redox Signaling, 20, 1618–1627.

    Article  CAS  Google Scholar 

  43. Lee, J. E., Cho, K. E., Lee, K. E., Kim, J., & Bae, Y. S. (2014). Nox4-mediated cell signaling regulates differentiation and survival of neural crest stem cells. Molecules and Cells, 37, 907–911.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Nayernia, Z., Jaquet, V., & Krause, K. H. (2014). New insights on NOX enzymes in the central nervous system. Antioxidants & Redox Signaling, 20, 2815–2837.

    Article  CAS  Google Scholar 

  45. Topchiy, E., Panzhinskiy, E., Griffin, W. S., Barger, S. W., Das, M., & Zawada, W. M. (2013). Nox4-generated superoxide drives angiotensin II-induced neural stem cell proliferation. Developmental Neuroscience, 35, 293–305.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Barnham, K. J., Masters, C. L., & Bush, A. I. (2004). Neurodegenerative diseases and oxidative stress. Nature Reviews Drug Discovery, 3, 205–214.

    Article  CAS  PubMed  Google Scholar 

  47. Zheng, M., Liu, J., Ruan, Z., Tian, S., Ma, Y., Zhu, J., & Li, G. (2013). Intrahippocampal injection of Abeta1-42 inhibits neurogenesis and down-regulates IFN-gamma and NF-kappaB expression in hippocampus of adult mouse brain. Amyloid, 20, 13–20.

    Article  Google Scholar 

  48. Haughey, N. J., Liu, D., Nath, A., Borchard, A. C., & Mattson, M. P. (2002). Disruption of neurogenesis in the subventricular zone of adult mice, and in human cortical neuronal precursor cells in culture, by amyloid β-peptide: Implications for the pathogenesis of Alzheimer’s disease. Neuromolecular Medicine, 1, 125–135.

    Article  CAS  PubMed  Google Scholar 

  49. Díaz-Moreno, M., Hortigüela, R., Gonçalves, A., García-Carpio, I., Manich, G., García-Bermúdez, E., et al. (2013). Aβ increases neural stem cell activity in senescence-accelerated SAMP8 mice. Neurobiology of Aging, 34, 2623–2638.

    Article  PubMed  Google Scholar 

  50. Gonzalez, D. R., Treuer, A. V., Lamirault, G., Mayo, V., Cao, Y., Dulce, R. A., & Hare, J. M. (2014). NADPH oxidase-2 inhibition restores contractility and intracellular calcium handling and reduces arrhythmogenicity in dystrophic cardiomyopathy. American Journal of Physiology Heart and Circulatory Physiology, 307, H710–H721.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Zhang, M., Prosser, B. L., Bamboye, M. A., Gondim, A. N., Santos, C. X., Martin, D., et al. (2015). Contractile function during angiotensin-II activation: Increased Nox2 activity modulates cardiac calcium handling via phospholamban phosphorylation. Journal of the American College of Cardiology, 66, 261–272.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Rada, B., & Leto, T. L. (2008). Oxidative innate immune defenses by Nox/Duox family NADPH oxidases. Contributions to Microbiology, 15, 164–187.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Cooney, S. J., Bermudez-Sabogal, S. L., & Byrnes, K. R. (2013). Cellular and temporal expression of NADPH oxidase (NOX) isotypes after brain injury. Journal of Neuroinflammation, 10, 155.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Fukui, T., Asakura, K., Hikichi, C., Ishikawa, T., Murai, R., Hirota, S., et al. (2015). Histone deacetylase inhibitor attenuates neurotoxicity of clioquinol in PC12 cells. Toxicology, 331, 112–118.

    Article  CAS  PubMed  Google Scholar 

  55. Sampson, E. L., Jenagaratnam, L., & McShane, R. (2014). Metal protein attenuating compounds for the treatment of Alzheimer’s dementia. Cochrane Database of Systematic Reviews. 2, CD005380.

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Acknowledgments

This work was supported by a Future Fellowship (FT110100199) administered by the Australian Research Council (S.C.D.), a Program Grant (#628946; S.J.C.) and Practitioner Fellowship (APP1005816; S.J.C.) administered by the National Health and Medical Research Council of Australia.

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Authors and Affiliations

  1. Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Victoria, 3010, Australia

    Cathryn L. Haigh & Steven J. Collins

  2. Florey Department of Neuroscience and Mental Health, The University of Melbourne, Victoria, 3010, Australia

    Carolin Tumpach & Simon C. Drew

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  1. Cathryn L. Haigh
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  2. Carolin Tumpach
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  3. Steven J. Collins
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  4. Simon C. Drew
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Correspondence to Cathryn L. Haigh or Simon C. Drew.

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Haigh, C.L., Tumpach, C., Collins, S.J. et al. A 2-Substituted 8-Hydroxyquinoline Stimulates Neural Stem Cell Proliferation by Modulating ROS Signalling. Cell Biochem Biophys 74, 297–306 (2016). https://doi.org/10.1007/s12013-016-0747-4

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