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Molecules and Cells

, Volume 31, Issue 3, pp 209–215 | Cite as

p-hydroxybenzyl alcohol prevents brain injury and behavioral impairment by activating Nrf2, PDI, and neurotrophic factor genes in a rat model of brain ischemia

  • Kyung-Yoon Kam
  • Seong Jin Yu
  • Nahee Jeong
  • Jeong Hwa Hong
  • Angela M. A. Anthony Jalin
  • Sungja Lee
  • Yong Won Choi
  • Chae Kwan Lee
  • Sung Goo KangEmail author
Article

Abstract

The therapeutic goal in treating cerebral ischemia is to reduce the extent of brain injury and thus minimize neurological impairment. We examined the effects of p-hydroxybenzyl alcohol (HBA), an active component of Gastrodia elata Blume, on transient focal cerebral ischemia-induced brain injury with respect to the involvement of protein disulphide isomerase (PDI), nuclear factor-E2-related factor 2 (Nrf2), and neurotrophic factors. All animals were ovariectomized 14 days before ischemic injury. Ischemic injury was induced for 1 h by middle cerebral artery occlusion (MCAO) followed by 24-h reperfusion. Three days before MCAO, the vehicle-treated and the HBA-treated groups received intramuscular sesame oil and HBA (25 mg/kg BW), respectively. 2,3,5-Triphenyltetrazolium chloride (TTC) staining showed decreased infarct volume in the ischemic lesion of HBA-treated animals. HBA pretreatment also promoted functional recovery, as measured by the modified neurological severity score (mNSS; p < 0.05). Moreover, expression of PDI, Nrf2, BDNF, GDNF, and MBP genes increased by HBA treatment. In vitro, H2O2-induced PC12 cell death was prevented by 24 h HBA treatment, but bacitracin, a PDI inhibitor, attenuated this cytoprotective effect in a dose-dependent manner. HBA treatment for 2 h also induced nuclear translocation of Nrf2, possibly activating the intracellular antioxidative system. These results suggest that HBA protects against brain damage by modulating cytoprotective genes, such as Nrf2 and PDI, and neurotrophic factors.

Keywords

ischemia neuroprotection neurotrophic factor Nrf2 p-hydroxybenzyl alcohol (HBA) protein disulphide isomerase 

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References

  1. Bloom, D.A., and Jaiswal, A.K. (2003). Phosphorylation of Nrf2 at Ser40 by protein kinase C in response to antioxidants leads to the release of Nrf2 from INrf2, but is not required for Nrf2 stabilization/accumulation in the nucleus and transcriptional activation of antioxidant response element-mediated NAD(P)H:quinone oxidoreductase-1 gene expression. J. Biol. Chem. 278, 44675–44682.PubMedCrossRefGoogle Scholar
  2. Cadenas, E. (1989). Biochemistry of oxygen toxicity. Annu. Rev. Biochem. 58, 79–110.PubMedCrossRefGoogle Scholar
  3. Chen, J., Sanberg, P.R., Li, Y., Wang, L., Lu, M., Willing, A.E., Sanchez-Ramos, J., and Chopp, M. (2001). Intravenous administration of human umbilical cord blood reduces behavioral deficits after stroke in rats. Stroke 32, 2682–2688.PubMedCrossRefGoogle Scholar
  4. Conover, J.C., and Yancopoulos, G.D. (1997). Neurotrophin regulation of the developing nervous system: analyses of knockout mice. Rev. Neurosci. 8, 13–27.PubMedGoogle Scholar
  5. DeVries, A.C., Nelson, R.J., Traystman, R.J., and Hurn, P.D. (2001). Cognitive and behavioral assessment in experimental stroke research: will it prove useful? Neurosci. Biobehav. Rev. 25, 325–342.CrossRefGoogle Scholar
  6. Descamps, E., Petrault-Laprais, M., Maurois, P., Pages, N., Bac, P., Bordet, R., and Vamecq, J. (2009). Experimental stroke protection induced by 4-hydroxybenzyl alcohol is cancelled by bacitracin. Neurosci. Res. 64, 137–142.PubMedCrossRefGoogle Scholar
  7. Dirnagl, U., Iadecola, C., and Moskowitz, M.A. (1999). Pathobiology of ischaemic stroke: an integrated view. Trends Neurosci. 22, 391–397.PubMedCrossRefGoogle Scholar
  8. Freedman, R.B., Hawkins, H.C., and McLaughlin, S.H. (1995). Protein disulfide-isomerase. Methods Enzymol. 251, 397–406.PubMedCrossRefGoogle Scholar
  9. Fu, X., Wang, P., and Zhu, B.T. (2008). Protein disulfide isomerase is a multifunctional regulator of estrogenic status in target cells. J. Steroid Biochem. Mol. Biol. 112, 127–137.PubMedCrossRefGoogle Scholar
  10. Harvey, B.K., Hoffer, B.J., and Wang, Y. (2005). Stroke and TGFbeta proteins: glial cell line-derived neurotrophic factor and bone morphogenetic protein. Pharmacol. Ther. 105, 113–125.PubMedCrossRefGoogle Scholar
  11. Hill, M.D., Jackowski, G., Bayer, N., Lawrence, M., and Jaeschke, R. (2000). Biochemical markers in acute ischemic stroke. CMAJ. 162, 1139–1140.PubMedGoogle Scholar
  12. Hsieh, M.-T., Wu, C.-R., and Chen, C.-F. (1997). Gastrodin and phydroxybenzyl alcohol facilitate memory consolidation and retrieval, but not acquisition, on the passive avoidance task in rats. J. Ethnopharmacol. 56, 45–54.PubMedCrossRefGoogle Scholar
  13. Hwang, I.K., Yoo, K.Y., Kim, D.W., Han, B.H., Kang, T.C., Choi, S.Y., Kim, J.S., and Won, M.H. (2005). Protein disulfide isomerase immunoreactivity and protein level changes in neurons and astrocytes in the gerbil hippocampal CA1 region following transient ischemia. Neurosci. Lett. 375, 117–122.PubMedCrossRefGoogle Scholar
  14. Itoh, K., Chiba, T., Takahashi, S., Ishii, T., Igarashi, K., Katoh, Y., Oyake, T., Hayashi, N., Satoh, K., Hatayama, I., et al. (1997). An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements. Biochem. Biophys. Res. Commun. 236, 313–322.PubMedCrossRefGoogle Scholar
  15. Itoh, K., Mochizuki, M., Ishii, Y., Ishii, T., Shibata, T., Kawamoto, Y., Kelly, V., Sekizawa, K., Uchida, K., and Yamamoto, M. (2004). Transcription factor Nrf2 regulates inflammation by mediating the effect of 15-deoxy-Delta(12,14)-prostaglandin j(2). Mol. Cell. Biol. 24, 36–45.PubMedCrossRefGoogle Scholar
  16. Jeong, W.S., Keum, Y.S., Chen, C., Jain, M.R., Shen, G., Kim, J.H., Li, W., and Kong, A.N. (2005). Differential expression and stability of endogenous nuclear factor E2-related factor 2 (Nrf2) by natural chemopreventive compounds in HepG2 human hepatoma cells. J. Biochem. Mol. Biol. 38, 167–176.PubMedGoogle Scholar
  17. Jeong, W.S., Jun, M., and Kong, A.N. (2006). Nrf2: a potential molecular target for cancer chemoprevention by natural compounds. Antioxid. Redox. Signal. 8, 99–106.PubMedCrossRefGoogle Scholar
  18. Jung, T.Y., Suh, S.I., Lee, H., Kim, I.S., Kim, H.J., Yoo, H.S., and Lee, S.R. (2007). Protective effects of several components of Gastrodia elata on lipid peroxidation in gerbil brain homogenates. Phytother. Res. 21, 960–964.PubMedCrossRefGoogle Scholar
  19. Kim, H.J., Hwang, I.K., and Won, M.H. (2007). Vanillin, 4-hydroxybenzyl aldehyde and 4-hydroxybenzyl alcohol prevent hippocampal CA1 cell death following global ischemia. Brain Res. 1181, 130–141.PubMedCrossRefGoogle Scholar
  20. Ko, H.S., Uehara, T., and Nomura, Y. (2002). Role of ubiquilin associated with protein-disulfide isomerase in the endoplasmic reticulum in stress-induced apoptotic cell death. J. Biol. Chem. 277, 35386–35392.PubMedCrossRefGoogle Scholar
  21. Kokaia, Z., Zhao, Q., Kokaia, M., Elmer, E., Metsis, M., Smith, M.L., Siesjo, B.K., and Lindvall, O. (1995). Regulation of brain-derived neurotrophic factor gene expression after transient middle cerebral artery occlusion with and without brain damage. Exp. Neurol. 136, 73–88.PubMedCrossRefGoogle Scholar
  22. Liu, J., and Mori, A. (1993). Antioxidant and pro-oxidant activities of p-hydroxybenzyl alcohol and vanillin: effects on free radicals, brain peroxidation and degradation of benzoate, deoxyribose, amino acids and DNA. Neuropharmacology 32, 659–669.PubMedCrossRefGoogle Scholar
  23. Mandel, R., Ryser, H.J., Ghani, F., Wu, M., and Peak, D. (1993). Inhibition of a reductive function of the plasma membrane by bacitracin and antibodies against protein disulfide-isomerase. Proc. Natl. Acad. Sci. USA 90, 4112–4116.PubMedCrossRefGoogle Scholar
  24. Mattson, M.P., and Cheng, A. (2006). Neurohormetic phytochemicals: Low-dose toxins that induce adaptive neuronal stress responses. Trends Neurosci. 29, 632–639.PubMedCrossRefGoogle Scholar
  25. Mattson, M.P., Lovell, M.A., Furukawa, K., and Markesbery, W.R. (1995). Neurotrophic factors attenuate glutamate-induced accumulation of peroxides, elevation of intracellular Ca2+ concentration, and neurotoxicity and increase antioxidant enzyme activities in hippocampal neurons. J. Neurochem. 65, 1740–1751.PubMedCrossRefGoogle Scholar
  26. Miyazaki, H., Nagashima, K., Okuma, Y., and Nomura, Y. (2001). Expression of glial cell line-derived neurotrophic factor induced by transient forebrain ischemia in rats. Brain Res. 922, 165–172.PubMedCrossRefGoogle Scholar
  27. Snider, W.D. (1994). Functions of the neurotrophins during nervous system development: what the knockouts are teaching us. Cell 77, 627–638.PubMedCrossRefGoogle Scholar
  28. Sofroniew, M.V., Howe, C.L., and Mobley, W.C. (2001). Nerve growth factor signaling, neuroprotection, and neural repair. Annu. Rev. Neurosci. 24, 1217–1281.PubMedCrossRefGoogle Scholar
  29. Surh, Y.J., Kundu, J.K., and Na, H.K. (2008). Nrf2 as a master redox switch in turning on the cellular signaling involved in the induction of cytoprotective genes by some chemopreventive phytochemicals. Planta Med. 74, 1526–1539.PubMedCrossRefGoogle Scholar
  30. Taguchi, H., Yoshioka, I., Yamasak, K., and Kim, I.H. (1981). Studies on the constituents of Gastrodia elata Blume. Chem. Pharm. Bull. 29, 55–62.Google Scholar
  31. Tanaka, S., Uehara, T., and Nomura, Y. (2000). Up-regulation of protein-disulfide isomerase in response to hypoxia/brain ischemia and its protective effect against apoptotic cell death. J. Biol. Chem. 275, 10388–10393.PubMedCrossRefGoogle Scholar
  32. Tong, K.I., Kobayashi, A., Katsuoka, F., and Yamamoto, M. (2006). Two-site substrate recognition model for the Keap1-Nrf2 system: a hinge and latch mechanism. Biol. Chem. 387, 1311–1320.PubMedCrossRefGoogle Scholar
  33. Uehara, T. (2007). Accumulation of misfolded protein through nitrosative stress linked to neurodegenerative disorders. Antioxid. Redox. Signal. 9, 597–601.PubMedCrossRefGoogle Scholar
  34. Won, M.H., Kang, T.C., Jeon, G.S., Lee, J.C., Kim, D.Y., Choi, E.M., Lee, K.H., Choi, C.D., Chung, M.H., and Cho, S.S. (1999). Immunohistochemical detection of oxidative DNA damage induced by ischemia-reperfusion insults in gerbil hippocampus in vivo. Brain Res. 836, 70–78.PubMedCrossRefGoogle Scholar
  35. Wu, C.R., Hsieh, M.T., and Liao, J. (1996). p-Hydroxybenzyl alcohol attenuates learning deficits in the inhibitory avoidance task: involvement of serotonergic and dopaminergic systems. Chin. J. Physiol. 39, 265–273.PubMedGoogle Scholar
  36. Yu, S.J., Kim, J.R., Lee, C.K., Han, J.E., Lee, J.H., Kim, H.S., Hong, J.H., and Kang, S.G. (2005). Gastrodia elata blume and an active component, p-hydroxybenzyl alcohol reduce focal ischemic brain injury through antioxidant related gene expressions. Biol. Pharm. Bull. 28, 1016–1020.PubMedCrossRefGoogle Scholar
  37. Yu, S.S., Zhao, J., Zheng, W.P., and Zhao, Y. (2010). Neuroprotective effect of 4-hydroxybenzyl alcohol against transient focal cerebral ischemia via anti-apoptosis in rats. Brain Res. 1308, 167–175.PubMedCrossRefGoogle Scholar

Copyright information

© The Korean Society for Molecular and Cellular Biology and Springer Netherlands 2011

Authors and Affiliations

  • Kyung-Yoon Kam
    • 1
    • 2
    • 3
  • Seong Jin Yu
    • 4
  • Nahee Jeong
    • 4
  • Jeong Hwa Hong
    • 5
  • Angela M. A. Anthony Jalin
    • 4
  • Sungja Lee
    • 1
  • Yong Won Choi
    • 1
  • Chae Kwan Lee
    • 6
  • Sung Goo Kang
    • 2
    • 4
    Email author
  1. 1.Department of Occupational TherapyInje UniversityGimhaeKorea
  2. 2.FIRST Research GroupInje UniversityGimhaeKorea
  3. 3.Institute of Aged Life RedesignInje UniversityGimhaeKorea
  4. 4.School of Biological SciencesInje UniversityGimhaeKorea
  5. 5.School of Food and Life ScienceInje UniversityGimhaeKorea
  6. 6.Institute of Environmental and Occupational Medicine, Department of Occupational and Environmental Medicine, Busan Paik HospitalInje UniversityBusanKorea

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