Skip to main content

Advertisement

SpringerLink
Log in

p38 MAPK Participates in the Mediation of GLT-1 Up-regulation During the Induction of Brain Ischemic Tolerance by Cerebral Ischemic Preconditioning

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Our previous study has proved that the up-regulation of glial glutamate transporter 1 (GLT-1) played an important role in the acquisition of brain ischemic tolerance after cerebral ischemic preconditioning (CIP) in rats. However, little is known about the mechanism involved in the up-regulation of GLT-1 in the process. The present study investigates whether p38 MAPK, ERK1/2, and/or JNK participates in the up-regulation of GLT-1 during the induction of brain ischemic tolerance by CIP. It was found that CIP significantly enhanced the expression of p-p38 MAPK without altering p-ERK1/2 and p-JNK expression in the CA1 hippocampus. Inhibition of p38 MAPK function by its selective inhibitor SB203580 or knockdown p38 MAPK expression by its antisense oligodeoxynucleotides (AS-ODNs) suppressed the induction of brain ischemic tolerance. Furthermore, p38 MAPK was activated earlier than the up-regulation of GLT-1 in the CA1 hippocampus after CIP. Meanwhile, the expression of p-p38 MAPK by astrocytes was increased, and p38 MAPK AS-ODNs dose-dependently inhibited the up-regulation of GLT-1 after CIP. Taken together, it could be concluded that p38 MAPK participates in the mediation of GLT-1 up-regulation during the induction of brain ischemic tolerance after CIP.

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
Fig. 6

Similar content being viewed by others

References

  1. Kirino T (2002) Ischemic tolerance. J Cereb Blood Flow Metab Off J Int Soc Cer Blood Flow Metab 22(11):1283–1296. doi:10.1097/00004647-200211000-0000

    Article  Google Scholar 

  2. TV N, Sangwan A, Sharma B, Majid A, Gk R (2015) Cerebral ischemic preconditioning: the road so far. Mol Neurobiol. doi:10.1007/s12035-015-9278-z

    Google Scholar 

  3. Rybnikova E, Glushchenko T, Tyulkova E, Baranova K, Samoilov M (2009) Mild hypobaric hypoxia preconditioning up-regulates expression of transcription factors c-Fos and NGFI-A in rat neocortex and hippocampus. Neurosci Res 65(4):360–366. doi:10.1016/j.neures.2009.08.013

    Article  CAS  PubMed  Google Scholar 

  4. Heurteaux C, Lauritzen I, Widmann C, Lazdunski M (1995) Essential role of adenosine, adenosine A1 receptors, and ATP-sensitive K+ channels in cerebral ischemic preconditioning. Proc Natl Acad Sci U S A 92(10):4666–4670

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Le LL, Li XY, Meng D, Liang QJ, Wang XH, Li N, Quan J, Xiang M et al (2013) Heme oxygenase-1 mediated memorial and revivable protective effect of ischemic preconditioning on brain injury. CNS Neurosci Ther 19(12):963–968. doi:10.1111/cns.12152

    Article  CAS  PubMed  Google Scholar 

  6. Nishino K, Nowak TS Jr (2004) Time course and cellular distribution of hsp27 and hsp72 stress protein expression in a quantitative gerbil model of ischemic injury and tolerance: thresholds for hsp72 induction and hilar lesioning in the context of ischemic preconditioning. J Cereb Blood Flow Metab Off J Int Soc Cer Blood Flow Metab 24(2):167–178. doi:10.1097/01.WCB.0000100853.67976.8B

    Article  CAS  Google Scholar 

  7. Tomimoto H, Takemoto O, Akiguchi I, Yanagihara T (1999) Immunoelectron microscopic study of c-Fos, c-Jun and heat shock protein after transient cerebral ischemia in gerbils. Acta Neuropathol 97(1):22–30

    Article  CAS  PubMed  Google Scholar 

  8. Kawahara K, Kosugi T, Tanaka M, Nakajima T, Yamada T (2005) Reversed operation of glutamate transporter GLT-1 is crucial to the development of preconditioning-induced ischemic tolerance of neurons in neuron/astrocyte co-cultures. Glia 49(3):349–359. doi:10.1002/glia.20114

    Article  PubMed  Google Scholar 

  9. Krzyzanowska W, Pomierny B, Filip M, Pera J (2014) Glutamate transporters in brain ischemia: to modulate or not? Acta Pharmacol Sin 35(4):444–462. doi:10.1038/aps.2014.1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Rao VL, Dogan A, Todd KG, Bowen KK, Kim BT, Rothstein JD, Dempsey RJ (2001) Antisense knockdown of the glial glutamate transporter GLT-1, but not the neuronal glutamate transporter EAAC1, exacerbates transient focal cerebral ischemia-induced neuronal damage in rat brain. J Neurosc Off J Soc Neurosci 21(6):1876–1883

    CAS  Google Scholar 

  11. Zhang M, Li WB, Geng JX, Li QJ, Sun XC, Xian XH, Qi J, Li SQ (2007) The upregulation of glial glutamate transporter-1 participates in the induction of brain ischemic tolerance in rats. J Cereb Blood Flow Metab Off J Int Soc Cer Blood Flow Metab 27(7):1352–1368. doi:10.1038/sj.jcbfm.9600441

    Article  CAS  Google Scholar 

  12. Liu AJ, Hu YY, Li WB, Xu J, Zhang M (2011) Cerebral ischemic pre-conditioning enhances the binding characteristics and glutamate uptake of glial glutamate transporter-1 in hippocampal CA1 subfield of rats. J Neurochem 119(1):202–209. doi:10.1111/j.1471-4159.2011.07396.x

    Article  CAS  PubMed  Google Scholar 

  13. Liu YX, Zhang M, Liu LZ, Cui X, Hu YY, Li WB (2012) The role of glutamate transporter-1a in the induction of brain ischemic tolerance in rats. Glia 60(1):112–124. doi:10.1002/glia.21252

    Article  PubMed  Google Scholar 

  14. Geng JX, Cai JS, Zhang M, Li SQ, Sun XC, Xian XH, Hu YY, Li WB et al (2008) Antisense oligodeoxynucleotides of glial glutamate transporter-1 inhibits the neuro-protection of cerebral ischemic preconditioning in rats. Sheng li xue bao [Acta Phys Sin] 60(4):497–503

    CAS  Google Scholar 

  15. Seger R, Krebs EG (1995) The MAPK signaling cascade. FASEB J Off Publ Fed Am Soc Exp Biol 9(9):726–735

    CAS  Google Scholar 

  16. Hu BR, Liu CL, Park DJ (2000) Alteration of MAP kinase pathways after transient forebrain ischemia. J Cereb Blood Flow Metab Off J Int Soc Cereb Blood Flow Metab 20(7):1089–1095. doi:10.1097/00004647-200007000-00008

    Article  CAS  Google Scholar 

  17. New L, Han J (1998) The p38 MAP kinase pathway and its biological function. Trends Cardiovasc Med 8(5):220–228

    Article  CAS  PubMed  Google Scholar 

  18. Weston CR, Davis RJ (2007) The JNK signal transduction pathway. Curr Opin Cell Biol 19(2):142–149. doi:10.1016/j.ceb.2007.02.001

    Article  CAS  PubMed  Google Scholar 

  19. Lee JM, Kim KR, Im H, Kim YH (2015) Zinc preconditioning protects against neuronal apoptosis through the mitogen-activated protein kinase-mediated induction of heat shock protein 70. Biochem Biophys Res Commun 459(2):220–226. doi:10.1016/j.bbrc.2015.02.068

    Article  CAS  PubMed  Google Scholar 

  20. Nishimura M, Sugino T, Nozaki K, Takagi Y, Hattori I, Hayashi J, Hashimoto N, Moriguchi T et al (2003) Activation of p38 kinase in the gerbil hippocampus showing ischemic tolerance. J Cereb Blood Flow Metab Off J Int Soc Cer Blood Flow Metab 23(9):1052–1059. doi:10.1097/01.WCB.0000084251.20114.65

    Article  CAS  Google Scholar 

  21. Sun XC, Xian XH, Li WB, Li L, Yan CZ, Li QJ, Zhang M (2010) Activation of p38 MAPK participates in brain ischemic tolerance induced by limb ischemic preconditioning by up-regulating HSP 70. Exp Neurol 224(2):347–355. doi:10.1016/j.expneurol.2010.04.009

    Article  CAS  PubMed  Google Scholar 

  22. Chen JH, Kuo HC, Lee KF, Tsai TH (2015) Global proteomic analysis of brain tissues in transient ischemia brain damage in rats. Int J Mol Sci 16(6):11873–11891. doi:10.3390/ijms160611873

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Kovalska M, Kovalska L, Pavlikova M, Janickova M, Mikuskova K, Adamkov M, Kaplan P, Tatarkova Z et al (2012) Intracellular signaling MAPK pathway after cerebral ischemia-reperfusion injury. Neurochem Res 37(7):1568–1577. doi:10.1007/s11064-012-0752-y

    Article  CAS  PubMed  Google Scholar 

  24. Stanciu M, Wang Y, Kentor R, Burke N, Watkins S, Kress G, Reynolds I, Klann E et al (2000) Persistent activation of ERK contributes to glutamate-induced oxidative toxicity in a neuronal cell line and primary cortical neuron cultures. J Biol Chem 275(16):12200–12206

    Article  CAS  PubMed  Google Scholar 

  25. Wang LW, Tu YF, Huang CC, Ho CJ (2012) JNK signaling is the shared pathway linking neuroinflammation, blood–brain barrier disruption, and oligodendroglial apoptosis in the white matter injury of the immature brain. J Neuroinflammation 9:175. doi:10.1186/1742-2094-9-175

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Matos M, Augusto E, Oliveira CR, Agostinho P (2008) Amyloid-beta peptide decreases glutamate uptake in cultured astrocytes: involvement of oxidative stress and mitogen-activated protein kinase cascades. Neuroscience 156(4):898–910. doi:10.1016/j.neuroscience.2008.08.022

    Article  CAS  PubMed  Google Scholar 

  27. Pulsinelli WA, Brierley JB (1979) A new model of bilateral hemispheric ischemia in the unanesthetized rat. Stroke a J Cereb Circ 10(3):267–272

    Article  CAS  Google Scholar 

  28. Paxinos G, Watson C (1998) The rat brain in stereotaxic coordinates. Academic Press, New York

    Google Scholar 

  29. Ren PLZ, Ma YX, Hu CX (2005) Relationship between the protein expression of p38MAPK and proliferation of VSMC in rat. Chin J Cardiovasc Med 10(3):170–172

    Google Scholar 

  30. Kato H, Liu Y, Araki T, Kogure K (1991) Temporal profile of the effects of pretreatment with brief cerebral ischemia on the neuronal damage following secondary ischemic insult in the gerbil: cumulative damage and protective effects. Brain Res 553(2):238–242

    Article  CAS  PubMed  Google Scholar 

  31. Kitagawa K, Matsumoto M, Tagaya M, Hata R, Ueda H, Niinobe M, Handa N, Fukunaga R et al (1990) Ischemic tolerance. phenomenon found in the brain. Brain Res 528:21–24

    Article  CAS  PubMed  Google Scholar 

  32. Chen JC, Hsu-Chou H, Lu JL, Chiang YC, Huang HM, Wang HL, Wu T, Liao JJ et al (2005) Down-regulation of the glial glutamate transporter GLT-1 in rat hippocampus and striatum and its modulation by a group III metabotropic glutamate receptor antagonist following transient global forebrain ischemia. Neuropharmacology 49(5):703–714. doi:10.1016/j.neuropharm.2005.05.002

    Article  CAS  PubMed  Google Scholar 

  33. Zhao L, Liu X, Liang J, Han S, Wang Y, Yin Y, Luo Y, Li J (2013) Phosphorylation of p38 MAPK mediates hypoxic preconditioning-induced neuroprotection against cerebral ischemic injury via mitochondria translocation of Bcl-xL in mice. Brain Res 1503:78–88. doi:10.1016/j.brainres.2013.01.051

    Article  CAS  PubMed  Google Scholar 

  34. Romera C, Hurtado O, Botella SH, Lizasoain I, Cardenas A, Fernandez-Tome P, Leza JC, Lorenzo P et al (2004) In vitro ischemic tolerance involves upregulation of glutamate transport partly mediated by the TACE/ADAM17-tumor necrosis factor-alpha pathway. J Neurosci Off J Soc Neurosci 24(6):1350–1357. doi:10.1523/JNEUROSCI.1596-03.2004

    Article  CAS  Google Scholar 

  35. Beller JA, Gurkoff GG, Berman RF, Lyeth BG (2011) Pharmacological enhancement of glutamate transport reduces excitotoxicity in vitro. Restor Neurol Neurosci 29(5):331–346. doi:10.3233/RNN-2011-603

    CAS  PubMed  Google Scholar 

  36. Cui C, Cui Y, Gao J, Sun L, Wang Y, Wang K, Li R, Tian Y et al (2014) Neuroprotective effect of ceftriaxone in a rat model of traumatic brain injury. Neurol Sci Off J Ital Neurol Soc Ital Soc Clin Neurophysiol 35(5):695–700. doi:10.1007/s10072-013-1585-4

    Google Scholar 

  37. Rothstein JD, Patel S, Regan MR, Haenggeli C, Huang YH, Bergles DE, Jin L, Dykes Hoberg M et al (2005) Beta-lactam antibiotics offer neuroprotection by increasing glutamate transporter expression. Nature 433(7021):73–77. doi:10.1038/nature03180

    Article  CAS  PubMed  Google Scholar 

  38. Weller ML, Stone IM, Goss A, Rau T, Rova C, Poulsen DJ (2008) Selective overexpression of excitatory amino acid transporter 2 (EAAT2) in astrocytes enhances neuroprotection from moderate but not severe hypoxia-ischemia. Neuroscience 155(4):1204–1211. doi:10.1016/j.neuroscience.2008.05.059

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Berger UV, DeSilva TM, Chen W, Rosenberg PA (2005) Cellular and subcellular mRNA localization of glutamate transporter isoforms GLT1a and GLT1b in rat brain by in situ hybridization. J Comp Neurol 492(1):78–89. doi:10.1002/cne.20737

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Pines G, Danbolt NC, Bjoras M, Zhang Y, Bendahan A, Eide L, Koepsell H, Storm-Mathisen J et al (1992) Cloning and expression of a rat brain l-glutamate transporter. Nature 360(6403):464–467. doi:10.1038/360464a0

    Article  CAS  PubMed  Google Scholar 

  41. Blanquet PR, Mariani J, Fournier B (2009) Temporal assessment of histone H3 phospho-acetylation and casein kinase 2 activation in dentate gyrus from ischemic rats. Brain Res 1302:10–20. doi:10.1016/j.brainres.2009.09.030

    Article  CAS  PubMed  Google Scholar 

  42. Lennmyr F, Ericsson A, Gerwins P, Ahlstrom H, Terent A (2003) Increased brain injury and vascular leakage after pretreatment with p38-inhibitor SB203580 in transient ischemia. Acta Neurol Scand 108(5):339–345

    Article  CAS  PubMed  Google Scholar 

  43. Ozawa H, Shioda S, Dohi K, Matsumoto H, Mizushima H, Zhou CJ, Funahashi H, Nakai Y et al (1999) Delayed neuronal cell death in the rat hippocampus is mediated by the mitogen-activated protein kinase signal transduction pathway. Neurosci Lett 262(1):57–60

    Article  CAS  PubMed  Google Scholar 

  44. Ghosh M, Yang Y, Rothstein JD, Robinson MB (2011) Nuclear factor-κB contributes to neuron-dependent induction of glutamate transporter-1 expression in astrocytes. J Neurosci 31(25):9159–9169

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Schulze-Osthoff K, Ferrari D, Riehemann K, Wesselborg S (1997) Regulation of NF-kappa B activation by MAP kinase cascades. Immunobiology 198(1–3):35–49

    Article  CAS  PubMed  Google Scholar 

  46. Alessandrini A, Namura S, Moskowitz MA, Bonventre JV (1999) MEK1 protein kinase inhibition protects against damage resulting from focal cerebral ischemia. Proc Natl Acad Sci U S A 96(22):12866–12869

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Gu Z, Jiang Q, Zhang G (2001) Extracellular signal-regulated kinase and c-Jun N-terminal protein kinase in ischemic tolerance. Neuroreport 12(16):3487–3491

    Article  CAS  PubMed  Google Scholar 

  48. Sawe N, Steinberg G, Zhao H (2008) Dual roles of the MAPK/ERK1/2 cell signaling pathway after stroke. J Neurosci Res 86(8):1659–1669. doi:10.1002/jnr.21604

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by the National Natural Science Foundation of China (no. 31271149 and no. 81271454), the Natural Science Foundation of Hebei Province (no. H2015206492), and the Foundation for high-level talented person of Hebei Province (no. A201400544).

Author information

Author notes

    Authors and Affiliations

    1. Department of Pathophysiology, Hebei Medical University, 361 Zhongshan East Road, Shijiazhuang, 050017, People’s Republic of China

      Min Zhang, Jian-Xue Gong, Jia-Lei Wang, Meng-Yang Jiang, Yu-Yan Hu, Jie Qi, Ling-Yan Zhang, Hang Zhao, Xin Cui, Xiao-Hui Xian & Wen-Bin Li

    2. Department of Science and Technology, The Second Hospital of Hebei Medical University, 215 Heping West Road, Shijiazhuang, 050000, People’s Republic of China

      Li Li

    3. Aging and Cognition Neuroscience Laboratory of Hebei Province, 89 Donggang Road, Shijiazhuang, 050031, People’s Republic of China

      Wen-Bin Li

    Authors
    1. Min Zhang
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Jian-Xue Gong
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Jia-Lei Wang
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Meng-Yang Jiang
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Li Li
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Yu-Yan Hu
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Jie Qi
      View author publications

      You can also search for this author in PubMed Google Scholar

    8. Ling-Yan Zhang
      View author publications

      You can also search for this author in PubMed Google Scholar

    9. Hang Zhao
      View author publications

      You can also search for this author in PubMed Google Scholar

    10. Xin Cui
      View author publications

      You can also search for this author in PubMed Google Scholar

    11. Xiao-Hui Xian
      View author publications

      You can also search for this author in PubMed Google Scholar

    12. Wen-Bin Li
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to Wen-Bin Li.

    Ethics declarations

    Conflict of Interest

    None of my co-authors has a conflict of interest.

    Additional information

    Min Zhang and Jian-Xue Gong contributed equally to this work.

    Electronic Supplementary Material

    Below is the link to the electronic supplementary material.

    ESM 1

    (DOC 88 kb)

    ESM 2

    (DOC 112 kb)

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Zhang, M., Gong, JX., Wang, JL. et al. p38 MAPK Participates in the Mediation of GLT-1 Up-regulation During the Induction of Brain Ischemic Tolerance by Cerebral Ischemic Preconditioning. Mol Neurobiol 54, 58–71 (2017). https://doi.org/10.1007/s12035-015-9652-x

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s12035-015-9652-x

    Keywords

    Search

    Navigation