Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
권호 표지
DOI QR코드

DOI QR Code

Neuroprotective Effect of β-Lapachone in MPTP-Induced Parkinson's Disease Mouse Model: Involvement of Astroglial p-AMPK/Nrf2/HO-1 Signaling Pathways

  • Park, Jin-Sun (Department of Molecular Medicine, Tissue Injury Defense Research Center, School of Medicine, Ewha Womans University) ;
  • Leem, Yea-Hyun (Department of Molecular Medicine, Tissue Injury Defense Research Center, School of Medicine, Ewha Womans University) ;
  • Park, Jung-Eun (Department of Molecular Medicine, Tissue Injury Defense Research Center, School of Medicine, Ewha Womans University) ;
  • Kim, Do-Yeon (Department of Molecular Medicine, Tissue Injury Defense Research Center, School of Medicine, Ewha Womans University) ;
  • Kim, Hee-Sun (Department of Molecular Medicine, Tissue Injury Defense Research Center, School of Medicine, Ewha Womans University)
  • Received : 2018.12.13
  • Accepted : 2019.01.04
  • Published : 2019.03.01
Download PDF
⟨ Previous Next ⟩

Abstract

Parkinson's disease is a neurodegenerative disease characterized by the progressive loss of dopaminergic neurons within the substantia nigra pars compacta. In the present study, we investigated whether ${\beta}-Lapachone$ (${\beta}-LAP$), a natural naphthoquinone compound isolated from the lapacho tree (Tabebuia avellanedae), elicits neuroprotective effects in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease mouse model. ${\beta}-LAP$ reduced the tyrosine hydroxylase (TH)-immunoreactive fiber loss induced by MPTP in the dorsolateral striatum, and alleviated motor dysfunction as determined by the rotarod test. In addition, ${\beta}-LAP$ protected against MPTP-induced loss of TH positive neurons, and upregulated B-cell lymphoma 2 protein (Bcl-2) expression in the substantia nigra. Based on previous reports on the neuroprotective role of nuclear factor-E2-related factor-2 (Nrf2) in neurodegenerative diseases, we investigated whether ${\beta}-LAP$ induces upregulation of the Nrf2-hemeoxygenae-1 (HO-1) signaling pathway molecules in MPTP-injected mouse brains. Western blot and immunohistochemical analyses indicated that ${\beta}-LAP$ increased HO-1 expression in glial fibrillary acidic protein-positive astrocytes. Moreover, ${\beta}-LAP$ increased the nuclear translocation and DNA binding activity of Nrf2, and the phosphorylation of upstream adenosine monophosphate-activated protein kinase (AMPK). ${\beta}-LAP$ also increased the localization of p-AMPK and Nrf2 in astrocytes. Collectively, our data suggest that ${\beta}-LAP$ exerts neuroprotective effect in MPTP-injected mice by upregulating the p-AMPK/Nrf2/HO-1 signaling pathways in astrocytes.

Keywords

References

  1. Burton, N. C., Kensler, T. W. and Guilarte, T. R. (2006) In vivo modulation of the Parkinsonian phenotype by Nrf2. Neurotoxicology 27, 1094-1100. https://doi.org/10.1016/j.neuro.2006.07.019
  2. Chen, P. C., Vargas, M. R., Pani, A. K., Smeyne, R. J., Johnson, D. A., Kan, Y. W. and Johnson, J. A. (2009) Nrf2-mediated neuroprotection in the MPTP mouse model of Parkinson's disease: critical role for the astrocyte. Proc. Natl. Acad. Sci. U.S.A. 106, 2933-2938. https://doi.org/10.1073/pnas.0813361106
  3. Chen, W. F., Wu, L., Du, Z. R., Chen, L., Xu, A. L., Chen, X. H., Teng, J. J. and Wong, M. S. (2017) Neuroprotective properties of icariin in MPTP-induced mouse model of Parkinson's disease: involvement of PI3K/Akt and MEK/ERK signaling pathways. Phytomedicine 25, 93-99. https://doi.org/10.1016/j.phymed.2016.12.017
  4. Gan, L., Vargas, M. R., Johnson, D. A. and Johnson, J. A. (2012) Astrocyte-specific overexpression of Nrf2 delays motor pathology and synuclein aggregation throughout the CNS in the alpha-synuclein mutant (A53T) mouse model. J. Neurosci. 32, 17775-17787. https://doi.org/10.1523/JNEUROSCI.3049-12.2012
  5. Gomez Castellanos, J. R., Prieto, J. M. and Heinrich, M. (2009) Red Lapacho (Tabebuiaimpetiginosa)-a global ethnopharmacological commodity? J. Ethnopharmacol. 121, 1-13. https://doi.org/10.1016/j.jep.2008.10.004
  6. Jackson-Lewis, V. and Przedborski, S. (2007) Protocol for the MPTP mouse model of Parkinson's disease. Nat. Protoc. 2,141-151. https://doi.org/10.1038/nprot.2006.342
  7. Jakel, R. J., Townsend, J. A., Kraft, A. D. and Johnson, J. A. (2007) Nrf2-mediated protection against 6-hydroxydopamine. Brain Res. 1144, 192-201. https://doi.org/10.1016/j.brainres.2007.01.131
  8. Jo, M. G., Ikram, M, Jo, M. H., Yoo, L., Chung, K. C., Nah, S. Y., Hwang, H., Rhim, H. and Kim, M. O. (2019) Gintoin mitigates MPTP-induced loss of nigrostriatal dopaminergic neurons and accumulation of ${\alpha}$-synuclein via the Nrf2/HO-1 pathway. Mol. Neurobiol. 56, 39-55. https://doi.org/10.1007/s12035-018-1020-1
  9. Johnson, D. A. and Johnson, J. A. (2015) Nrf2-a therapeutic target for the treatment of neurodegenerative diseases. Free Radic. Biol. Med. 88, 253-267. https://doi.org/10.1016/j.freeradbiomed.2015.07.147
  10. Hussain, H. and Green, I. R. (2017) Lapachol and lapachone analogs: a journey of two decades of patent research (1997-2016). Expert. Opin. Ther. Pat. 27, 1111-1121. https://doi.org/10.1080/13543776.2017.1339792
  11. Kim, A. Y., Jeong, K. H., Lee, J. H., Kang, Y., Lee, S. H. and Baik, E. J. (2017) Glutamate dehydrogenase as a neuroprotective target against brain ischemia and reperfusion. Neuroscience 340, 487-500. https://doi.org/10.1016/j.neuroscience.2016.11.007
  12. Lee, E. J., Ko, H. M., Jeong, Y. H., Park, E. M. and Kim, H. S. (2015) ${\beta}$-Lapachone suppresses neuroinflammation by modulating the expression of cytokines and matrix metalloproteinases in activated microglia. J. Neuroinflammation 12, 133. https://doi.org/10.1186/s12974-015-0355-z
  13. Lee, M., Ban, J. J., Chung, J. Y., Im, W. and Kim, M. (2018) Amelioration of Huntington's disease phenotypes by ${\beta}$-lapachone is associated with increases in Sirt1 expression, CREB phosphorylation and PGC-$1{\alpha}$ deacetylation. PLoS ONE 9, e0195968.
  14. Liddell, J. R. (2017) Are astrocytes the predominant cell type for activation of Nrf2 in aging and neurodegeneration? Antioxidants 6, 65. https://doi.org/10.3390/antiox6030065
  15. Oh, G. S., Kim, H. J., Choi, J. H., Shen, A., Choe, S. K., Karna, A., Lee, S. H., Jo H. J., Yang, S. H., Kwak, T. H., Lee, C. H., Par, R. and So, H. S. (2014) Pharmacological activation of NQO1 increases $NAD^+$ levels and attenuates cisplatin-mediated acute kidney injury in mice. Kidney Int. 85, 547-560. https://doi.org/10.1038/ki.2013.330
  16. Park, J. S., Lee, Y. Y., Kim, J., Seo, H. and Kim, H. S. (2016) ${\beta}$-Lapachone increases phase II antioxidant enzyme expression via NQO1-AMPK/PI3K-Nrf2/ARE signaling in rat primary astrocytes. Free Radic. Biol. Med. 97, 168-178. https://doi.org/10.1016/j.freeradbiomed.2016.05.024
  17. Poewe, W., Seppi, K., Tanner, C. M., Halliday, G. M., Brundin, P., Volkmann, J., Schrag, A. E. and Lang, A. E. (2017) Parkinson disease. Nat. Rev. Dis. Primers 3, 17013. https://doi.org/10.1038/nrdp.2017.13
  18. Przedborski, S. (2017) The two-century journey of Parkinson disease research. Nat. Rev. Neurosci. 18, 251-259. https://doi.org/10.1038/nrn.2017.25
  19. Puspita, L., Chung, S. Y. and Shim, J. W. (2017) Oxidative stress and cellular pathologies in Parkinson's disease. Mol. Brain 10, 53. https://doi.org/10.1186/s13041-017-0340-9
  20. Schaffner-Sabba, K., Schmidt-Ruppin, K. H., Wehrli, W., Schuerch, A. R. and Wasley, J. W. (1984) ${\beta}$-Lapachone: synthesis of derivatives and activities in tumor models. J. Med. Chem. 27, 990-994. https://doi.org/10.1021/jm00374a010
  21. Tieu, K. (2011) A guide to neurotoxic animal models of Parkinson's disease. Cold Spring Harb. Perspect. Med. 1, a009316. https://doi.org/10.1101/cshperspect.a009316
  22. Vargas, M. R., Johnson, D. A., Sirkis, D. W., Messing, A. and Johnson, J. A. (2008) Nrf2 activation in astrocytes protects against neurodegeneration in mouse models of familial amyotrophic lateral sclerosis. J. Neurosci. 28, 13574-13581. https://doi.org/10.1523/JNEUROSCI.4099-08.2008
  23. Vargas, M. R. and Johnson, J. A. (2009) The Nrf2-ARE cytoprotective pathway in astrocytes. Expert Rev. Mol. Med. 11, e17. https://doi.org/10.1017/S1462399409001094
  24. Xu, J., Wagoner, G., Douglas, J. C. and Drew, P. D. (2013) ${\beta}$-Lapachone ameliorization of experimental autoimmune encephalomyelitis. J. Neuroimmunol. 254, 46-54. https://doi.org/10.1016/j.jneuroim.2012.09.004
  25. Yamada, M., Oligino, T., Mata, M., Goss, J. R., Glorioso, J. C. and Fink, D. J. (1999) Herpes simplex virus vector-mediated expression of Bcl-2 prevents 6-hydroxydopamine-induced degeneration of neurons in the substantia nigra in vivo. Proc. Natl. Acad. Sci. U.S.A. 96, 4078-4083. https://doi.org/10.1073/pnas.96.7.4078
  26. Zhang, M., An, C., Gao, Y., Leak, R. K., Chen, J. and Zhang, F. (2013) Emerging roles of Nrf2 and phase II antioxidant enzymes in neuroprotection. Prog. Neurobiol. 100, 30-47. https://doi.org/10.1016/j.pneurobio.2012.09.003

Cited by

  1. Neurological Enhancement Effects of Melatonin against Brain Injury-Induced Oxidative Stress, Neuroinflammation, and Neurodegeneration via AMPK/CREB Signaling vol.8, pp.7, 2019, https://doi.org/10.3390/cells8070760
  2. The phosphodiesterase 10 inhibitor papaverine exerts anti-inflammatory and neuroprotective effects via the PKA signaling pathway in neuroinflammation and Parkinson’s disease mouse models vol.16, pp.1, 2019, https://doi.org/10.1186/s12974-019-1649-3
  3. Ferulic Acid Ameliorates MPP+/MPTP-Induced Oxidative Stress via ERK1/2-Dependent Nrf2 Activation: Translational Implications for Parkinson Disease Treatment vol.57, pp.7, 2019, https://doi.org/10.1007/s12035-020-01934-1
  4. Neuroprotective Effect of Antioxidants in the Brain vol.21, pp.19, 2019, https://doi.org/10.3390/ijms21197152
  5. Natural Compounds for the Prevention and Treatment of Cardiovascular and Neurodegenerative Diseases vol.10, pp.1, 2021, https://doi.org/10.3390/foods10010029
  6. Pharmacological Modulation of Nrf2/HO-1 Signaling Pathway as a Therapeutic Target of Parkinson’s Disease vol.12, 2021, https://doi.org/10.3389/fphar.2021.757161
  7. Highlighting the Protective or Degenerative Role of AMPK Activators in Dementia Experimental Models vol.20, 2019, https://doi.org/10.2174/1871527320666210526160214
  8. Challenges and Opportunities of Targeting Astrocytes to Halt Neurodegenerative Disorders vol.10, pp.8, 2019, https://doi.org/10.3390/cells10082019
  9. The modulation of SIRT1 and SIRT3 by natural compounds as a therapeutic target in doxorubicin‐induced cardiotoxicity: A review vol.36, pp.1, 2019, https://doi.org/10.1002/jbt.22946