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Cellular and Molecular Neurobiology

, Volume 34, Issue 4, pp 591–602 | Cite as

Gastrodin Inhibits Glutamate-Induced Apoptosis of PC12 Cells via Inhibition of CaMKII/ASK-1/p38 MAPK/p53 Signaling Cascade

  • Genling Jiang
  • Haiyun Wu
  • Yuqin Hu
  • Jun Li
  • Qinling Li
Original Research

Abstract

Previous research demonstrated that glutamate induces neuronal injury partially by increasing intracellular Ca2+ concentrations ([Ca2+]i), and inducing oxidative stress, leading to a neurodegenerative disorder. However, the mechanism of glutamate-induced injury remains elusive. Gastrodin, a major active component of the traditional herbal agent Gastrodia elata (GE) Blume, has been recognized as a potential neuroprotective drug. In the current study, a classical injury model based on glutamate-induced cell death of rat pheochromocytoma (PC12) cells was used to investigate the neuroprotective effect of gastrodin, and its potential mechanisms involved. In this paper, the presence of gastrodin inhibits glutamate-induced oxidative stress as measured by the formation of reactive oxygen species (ROS), the level of malondialdehyde (MDA), mitochondrial membrane potential (MMP), and superoxide dismutase (SOD); gastrodin also prevents glutamate-induced [Ca2+]i influx, blocks the activation of the calmodulin-dependent kinase II (CaMKII) and the apoptosis signaling-regulating kinase-1 (ASK-1), inhibits phosphorylation of p38 mitogen-activated kinase (MAPK). Additionally, gastrodin blocked the expression of p53 phosphorylation, caspase-3 and cytochrome C, reduced bax/bcl-2 ratio induced by glutamate in PC12 cells. All these findings indicate that gastrodin protects PC12 cells from the apoptosis induced by glutamate through a new mechanism of the CaMKII/ASK-1/p38 MAPK/p53-signaling pathway.

Keywords

Gastrodin Glutamate Apoptosis Calmodulin-dependent kinase II (CaMKII) Apoptosis signaling-regulating kinase-1 (ASK-1) 

Notes

Conflict of interest

The authors declare that there are no conflicts of interest.

References

  1. An H, Kim IS, Koppula S et al (2010) Protective effects of Gastrodia elata Blume on MPP+-induced cytotoxicity in human dopaminergic SH-SY5Y cells. J Ethnopharmacol 130:290–298CrossRefPubMedGoogle Scholar
  2. Arundine M, Tymianski M (2003) Molecular mechanisms of calcium-dependent neurodegeneration in excitotoxicity. Cell Calcium 34:524–537CrossRefGoogle Scholar
  3. Azadmehr A, Oghyanous KA, Hajiaghaee R (2013) Antioxidant and neuroprotective effects of scrophularia striata extract against oxidative stress-induced neurotoxicity. Cell Mol Neurobiol 33:1135–1141CrossRefPubMedGoogle Scholar
  4. Birben E, Sahiner UM, Sackesen C et al (2012) Oxidative stress and antioxidant defense. World Allergy Organ J 5:9–19CrossRefPubMedCentralPubMedGoogle Scholar
  5. Boronkai A, Bellyei S, Szigeti A et al (2009) Potentiation of paclitaxel-induced apoptosis by galectin-13 overexpression via activation of Ask-1-p38-MAPkinase and JNK/SAPK pathways and suppression of Akt and ERK1/2 activation in U-937 human macrophagecells. Eur J Cell Biol 88:753–763CrossRefPubMedGoogle Scholar
  6. CalìT Ottolini D, Brini M (2011) Mitochondria, calcium, and endoplasmic reticulum stress in Parkinson’s disease. BioFactors 37:228–240CrossRefGoogle Scholar
  7. Chae S, Lee AY, Lee H-W et al (2008) Three phenolic glycosides from Gastrodia elata. J Appl Biol Chem 51:61–65CrossRefGoogle Scholar
  8. Chen W, Li X, Jia LQ (2013) Neuroprotective activities of catalpol against CaMKII-dependent apoptosis induced by LPS in PC12 cells. Br J Pharmacol 169:1140–1152CrossRefPubMedGoogle Scholar
  9. Cheng YF, Zhu GQ, Wang M (2009) Involvement of ubiquitin proteasome system in protective mechanisms of Puerarin to MPP+-elicited apoptosis. Neurosci Res 63:52–58CrossRefPubMedGoogle Scholar
  10. Christophe M, Nicolas S (2006) Mitochondria: a target for neuroprotective interventions in cerebral ischemia–reperfusion. Curr Pharm Des 12:739–757CrossRefPubMedGoogle Scholar
  11. Coyle JT, Puttfarcken P (1993) Oxidative stress, glutamate, and neurodegenerative disorders. Science 262:689–695CrossRefPubMedGoogle Scholar
  12. Gross A, McDonnell JM, Korsmeyer SJ (1999) BCL-2 family members and the mitochondria in apoptosis. Genes Dev 13:1899–1911CrossRefPubMedGoogle Scholar
  13. Hirata Y, Yamamoto H, Atta MSM et al (2011) Chloroquine inhibits glutamate-induced death of a neuronal cell line by reducing reactive oxygen species through sigma-1 receptor. J Neurochem 119:839–847CrossRefPubMedGoogle Scholar
  14. Jiang GZ, Li JC (2014) Protective effects of ginsenoside Rg1 against colistin sulfate-induced neurotoxicity in PC12 cells. Cell Mol Neurobiol 34:167–172Google Scholar
  15. Kim SJ, Ju JW, Oh CD et al (2002) ERK-1/2 and p38 kinase oppositely regulate nitric oxide-induced apoptosis of chondrocytes in association with p53, caspase-3, and differentiation status. J Biol Chem 277:1332–1339CrossRefPubMedGoogle Scholar
  16. Kim IS, Choi D-K, Jung HJ (2011) Neuroprotective effects of vanillyl alcohol in Gastrodia elata Blume through suppression of oxidative stress and anti-apoptotic activity in toxin-induced dopaminergic MN9D cells. Molecules 16:5349–5361CrossRefPubMedGoogle Scholar
  17. Kim BW, Koppula S, Kim JW et al (2012) Modulation of LPS-stimulated neuroinflammation in BV-2 microglia by Gastrodia elata: 4-hydroxybenzyl alcohol is the bioactive candidate. J Ethnopharmacol 139:549–557CrossRefPubMedGoogle Scholar
  18. Kumar H, Kim IS, More SV et al (2013) Gastrodin protects apoptotic dopaminergic neurons in a toxin-induced Parkinson’s disease model. Evid Based Complement Altern Med 2013:514095CrossRefGoogle Scholar
  19. Lau A, Tymianski M (2010) Glutamate receptors, neurotoxicity and neurodegeneration. Pflugers Arch Eur J Physiol 460:525–542CrossRefGoogle Scholar
  20. Li N, Liu B, Dluzen DE et al (2007) Protective effects of ginsenoside Rg2 against glutamate-induced neurotoxicity in PC12 cells. J Ethnopharmacol 111:458–463CrossRefPubMedGoogle Scholar
  21. Li G, Ma R, Huang C (2008) Protective effect of erythropoietin on b-amyloid-induced PC12 cell death through antioxidant mechanisms. Neurosci Lett 442:143–147CrossRefPubMedGoogle Scholar
  22. Liu Y, Templeton DM (2007) Cadmium activates CaMK-II and initiates CaMK-II- dependent apoptosis in mesangial cells. FEBS Lett 581:1481–1486CrossRefPubMedGoogle Scholar
  23. Ma S, Liu H, Jiao H et al (2012) Neuroprotective effect of ginkgolide K on glutamate-induced cytotoxicity in PC 12 cells via inhibition of ROS generation and Ca2+ influx. Neurotoxicology 33:59–69CrossRefPubMedGoogle Scholar
  24. Means AR, Dedman JR (1980) Calmodulin—an intracellular calcium receptor. Nature 285:73–77CrossRefPubMedGoogle Scholar
  25. Nagai H, Noguchi T, Takeda K et al (2007) Pathophysiological roles of ASK1-MAP kinase signaling pathways. J Biochem Mol Biol 40:1–6CrossRefPubMedGoogle Scholar
  26. Ojemann LM, Nelson WL, Shin DS et al (2006) Tian ma, an ancient Chinese herb, offers new options for the treatment of epilepsy and other conditions. Epilepsy Behav 8:376–383CrossRefPubMedGoogle Scholar
  27. Olanow CW, Tatton WG (1999) Etiology and pathogenesis of Parkinson’s disease. Annu Rev Neurosci 22:123–144CrossRefPubMedGoogle Scholar
  28. Orrenius S, Zhivotovsky B, Nicotera P (2003) Regulation of cell death: the calcium–apoptosis link. Nat Rev Mol Cell Biol 4:552–565CrossRefPubMedGoogle Scholar
  29. Peng TI, Jou MJ (2010) Oxidative stress caused by mitochondrial calcium overload. Ann N Y Acad Sci 1201:183–188CrossRefPubMedGoogle Scholar
  30. Rokhlin OW, Taghiyev AF, Bayer KU (2007) Calcium/calmodulin-dependent kinase II plays an important role in prostate cancer cell survival. Cancer Biol Ther 6:732–742CrossRefPubMedGoogle Scholar
  31. Salas MA, Valverde CA, Sánchez G et al (2010) The signaling pathway of CaMKII-mediated apoptosis and necrosis in the ischemia/reperfusion injury. J Mol Cell Cardiol 48:1298–1306CrossRefPubMedCentralPubMedGoogle Scholar
  32. Satpute RM, Kashyap RS, Deopujari JY (2009) Protection of PC12 cells from chemical ischemia induced oxidative stress by Fagonia arabica. Food Chem Toxicol 47:2689–2695CrossRefPubMedGoogle Scholar
  33. Sheldon AL, Robinson MB (2007) The role of glutamate transporters in neurodegenerative diseases and potential opportunities for intervention. Neurochem Int 51:333–355CrossRefPubMedCentralPubMedGoogle Scholar
  34. Shu C, Chen C, Zhang DP et al (2012) Gastrodin protects against cardiac hypertrophy and fibrosis. Mol Cell Biochem 359:9–16CrossRefPubMedGoogle Scholar
  35. Soga M, Matsuzawa A, Ichijo H (2012) Oxidative stress-induced diseases via the ASK1 signaling pathway. Int J Cell Biol 2012:439587CrossRefPubMedCentralPubMedGoogle Scholar
  36. Takeda K, Matsuzawa A, Nishitoh H (2004) Involvement of ASK1 in Ca2+-induced p38 MAP kinase activation. EMBO Rep 5:161–166CrossRefPubMedCentralPubMedGoogle Scholar
  37. Tan JW, Tham CL, Israf DA et al (2013) Neuroprotective effects of biochanin a against glutamate-induced cytotoxicity in PC12 cells via apoptosis inhibition. Neurochem Res 38:512–518CrossRefPubMedGoogle Scholar
  38. Thompson LM (2008) Neurodegeneration: a question of balance. Nature 452:707–708CrossRefPubMedGoogle Scholar
  39. Uberti D, Grilli M, Memo M (2000) Induction of p53 in the glutamate-induced cell death program. Amino Acids 19:253–261CrossRefPubMedGoogle Scholar
  40. Wakamatsu TH, Dogru M, Tsubota K (2008) Tearful relations: oxidative stress, inflammation and eye diseases. Arq Bras Oftalmol 71:72–79CrossRefPubMedGoogle Scholar
  41. Wang X, Zhu G, Yang S et al (2011) Paeonol prevents excitotoxicity in rat pheochromocytoma PC12 cells via down-regulation of ERK activation and inhibition of apoptosis. Planta Med 77:1695–1701CrossRefPubMedGoogle Scholar
  42. Wu H, Jiang G, Li Q (2012) Protection of gastrodin on PC12 cell injury induced by glutamate via inhibition of cell apoptosis. Chin J Clin Pharmacol Ther 17:1361–1367Google Scholar
  43. Xiao X, Liu J, Hu J et al (2008) Protective effects of protopine on hydrogen peroxide-induced oxidative injury of PC12 cells via Ca(2+) antagonism and antioxidant mechanisms. Eur J Pharmacol 591:21–27CrossRefPubMedGoogle Scholar
  44. Xu X, Lu Y, Bie X (2007) Protective effects of gastrodin on hypoxia-induced toxicity in primary cultures of rat cortical neurons. Planta Med 73:650–654CrossRefPubMedGoogle Scholar
  45. Yang XD, Zhu J, Yang R et al (2007) Phenolic constituents from the rhizomes of Gastrodia elata. Nat Prod Res 21:180–186CrossRefPubMedGoogle Scholar
  46. Yang X, Wang Y, Luo J et al (2011) Protective effects of YC-1 against glutamate induced PC12 cell apoptosis. Cell Mol Neurobiol 31:303–311CrossRefPubMedGoogle Scholar
  47. Yong W, Xing TR, Wang S et al (2009) Protective effects of gastrodin on lead-induced synaptic plasticity deficits in rat hippocampus. Planta Med 75:1112–1117CrossRefPubMedGoogle Scholar
  48. Yu X, Li X, Jiang G et al (2013) Isradipine prevents rotenone-induced intracellular calcium rise that accelerates senescence in human neuroblastoma SH-SY5Y cells. Neuroscience 246:243–253CrossRefPubMedGoogle Scholar
  49. Zeng X, Zhang S, Zhang L et al (2006) A study of the neuroprotective effect of the phenolic glucoside gastrodin during cerebral ischemia in vivo and in vitro. Planta Med 72:1359–1365CrossRefPubMedGoogle Scholar
  50. Zhang C, Du F, Shi M et al (2012) Ginsenoside Rd protects neurons against glutamate-induced excitotoxicity by inhibiting ca(2+) influx. Cell Mol Neurobiol 32:121–128CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Genling Jiang
    • 1
  • Haiyun Wu
    • 1
  • Yuqin Hu
    • 2
  • Jun Li
    • 1
  • Qinling Li
    • 1
    • 3
  1. 1.Key Laboratory of Xin’an Medicine, Ministry of Education, Anhui Province Key Laboratory of R&D of Chinese MedicineAnhui University of Chinese MedicineHefeiChina
  2. 2.Department of Clinical CollegeAnhui Medical UniversityHefeiChina
  3. 3.Anqing Medical and Pharmaceutical CollegeAnqingChina

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