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Intermittent Hypoxia Preconditioning-Induced Epileptic Tolerance by Upregulation of Monocarboxylate Transporter 4 Expression in Rat Hippocampal Astrocytes

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Abstract

Noxious stimuli applied at doses close to but below the threshold of cell injury induce adaptive responses that provide a defense against additional stress. Epileptic preconditioning protects neurons against status epilepticus and ischemia; however, it is not known if the converse is true. During hypoxia/ischemia (H/I), lactate released from astrocytes is taken up by neurons and is stored for energy, a process mediated by monocarboxylate transporter 4 (MCT4) in astroglia. The present study investigated whether H/I preconditioning can provide protection to neurons against epilepsy through upregulation of MCT4 expression in astrocytes in vitro and in vivo. An oxygen/glucose deprivation protocol was used in primary astrocyte cultures, while rats were subjected to an intermittent hypoxia preconditioning (IHP) paradigm followed by lithium-pilocarpine-induced epilepsy as well as lactate transportation inhibitor injection, with a subsequent evaluation of protein expression as well as behavior. H/I induced an upregulation of MCT4 expression, while an IHP time course of 5 days provided the greatest protection against epileptic seizures, which was most apparent by 3 days after IHP. However, lactate transport function disturbances can block the protective effect induced by IHP. These findings provide a potential basis for the clinical treatment of epilepsy.

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References

  1. Fisher RS, van Emde Boas W, Blume W, Elger C, Genton P, Lee P, Engel J Jr (2005) Epileptic seizures and epilepsy. Definitions proposed by the International League against Epilepsy (ILAE) and the International Bureau for Epilepsy (IBE). Epilepsia 46:470–472

    Article  PubMed  Google Scholar 

  2. Janoff A (1964) Alterations in lysosomes (intracellular enzymes) during shock; effects of preconditioning (tolerance) and protective drugs. Int Anesthesiol Clin 2:251–269

    Article  PubMed  CAS  Google Scholar 

  3. Kirino T (2002) Ischemic tolerance. J Cereb Blood Flow Metab 22:1283–1296

    Article  PubMed  Google Scholar 

  4. Plamondon H, Blondeau N, Heurteaux C, Lazdunski M (1999) Mutually protective actions of kainic acid epileptic preconditioning and sublethal global ischemia on hippocampal neuronal death: involvement of adenosine A1 receptors and KATP channels. J Cereb Blood Flow Metab 19:1296–1308

    Article  PubMed  CAS  Google Scholar 

  5. Cloix JF, Ardourel MY, Hévor T (2008) Glycogen metabolism and brain pathologies. Cent Nerv Syst Agents Med Chem 8:187–197

    Article  CAS  Google Scholar 

  6. Brown AM, Baltan Tekkok S, Ransom BR (2004) Energy transfer from astrocytes to axons: the role of CNS glycogen. Neurochem Int 45:529–536

    Article  PubMed  CAS  Google Scholar 

  7. Pellerin L (2003) Lactate as a pivotal element in neuron-glia metabolic cooperation. Neurochem Int 43:331–338

    Article  PubMed  CAS  Google Scholar 

  8. Greene AE, Todorova MM, Seyfried TN (2003) Perspectives on the metabolic management of epilepsy through dietary reduction of glucose and elevation of ketone bodies. J Neurochem 86:529–537

    Article  PubMed  CAS  Google Scholar 

  9. Li X, Yokono K, Okada Y (2000) Phosphofructokinase, a glycolytic regulatory enzyme has a crucial role for maintenance of synaptic activity in guinea pig hippocampal slices. Neurosci Lett 294:81–84

    Article  PubMed  CAS  Google Scholar 

  10. Vielhaber S, Von Oertzen JH, Kudin AF, Schoenfeld A, Menzel C, Biersack HJ, Kral T, Elger CE, Kunz WS (2003) Correlation of hippocampal glucose oxidation capacity and interictal FDG-PET in temporal lobe epilepsy. Epilepsia 44:193–199

    Article  PubMed  CAS  Google Scholar 

  11. Pierre K, Pellerin L (2005) Monocarboxylate transporters in the central nervous system: distribution, regulation and function. J Neurochem 94:1–14

    Article  PubMed  CAS  Google Scholar 

  12. Simpson IA, Carruthers A, Vannucci SJ (2007) Supply and demand in cerebral energy metabolism: the role of nutrient transporters. J Cereb Blood Flow Metab 27:1766–1791

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  13. Halestrap AP, Meredith D (2004) The SLC16 gene family-from monocarboxylate transporters (MCTs) to aromatic amino acid transporters and beyond. Pflugers Arch 447:619–628

    Article  PubMed  CAS  Google Scholar 

  14. Lauritzen F, de Lanerolle NC, Lee TS, Spencer DD, Kim JH, Bergersen LH, Eid T (2011) Monocarboxylate transporter 1 is deficient on microvessels in the human epileptogenic hippocampus. Neurobiol Dis 41:577–584

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  15. Lauritzen F, Heuser K, de Lanerolle NC, Lee TS, Spencer DD, Kim JH, Gjedde A, Eid T, Bergersen LH (2012) Redistribution of monocarboxylate transporter 2 on the surface of astrocytes in the human epileptogenic hippocampus. Glia 60:1172–1181

    Article  PubMed  PubMed Central  Google Scholar 

  16. Ullah MS, Davies AJ, Halestrap AP (2006) The plasma membrane lactate transporter MCT4, but not MCT1, is up-regulated by hypoxia through a HIF-1alpha-dependent mechanism. J Biol Chem 281:9030–9037

    Article  PubMed  CAS  Google Scholar 

  17. Sen E, Basu A, Willing LB, Uliasz TF, Myrkalo JL, Vannucci SJ, Hewett SJ, Levison SW (2011) Pre-conditioning induces the precocious differentiation of neonatal astrocytes to enhance their neuroprotective properties. ASN neuro 3:e00062

    Article  PubMed  PubMed Central  Google Scholar 

  18. Nakagawa S, Deli MA, Kawaguchi H, Shimizudani T, Shimono T, Kittel A, Tanaka K, Niwa M (2009) A new blood-brain barrier model using primary rat brain endothelial cells, pericytes and astrocytes. Neurochem Int 54:253–263

    Article  PubMed  CAS  Google Scholar 

  19. Beetsch JW, Olson JE (1993) Taurine transport in rat astrocytes adapted to hyperosmotic conditions. Brain Res 613:10–15

    Article  PubMed  CAS  Google Scholar 

  20. Montana V, Ni Y, Sunjara V, Hua X, Parpura V (2004) Vesicular glutamate transporter-dependent glutamate release from astrocytes. J Neurosci 24:2633–2642

    Article  PubMed  CAS  Google Scholar 

  21. Huang XJ, Zhang WP, Li CT, Shi WZ, Fang SH, Lu YB, Chen Z, Wei EQ (2008) Activation of CysLT receptors induces astrocyte proliferation and death after oxygen–glucose deprivation. Glia 56:27–37

    Article  PubMed  Google Scholar 

  22. Williams RJ, Maus M, Stella N, Glowinski J, Premont J (1996) Reduced glucose metabolism enhances the glutamate-evoked release of arachidonic acid from striatal neurons. Neuroscience 74:461–468

    Article  PubMed  CAS  Google Scholar 

  23. Schneider U, Poole RC, Halestrap AP, Grafe P (1993) Lactate-proton co-transport and its contribution to interstitial acidification during hypoxia in isolated rat. Neuroscience 53:1153–1162

    Article  PubMed  CAS  Google Scholar 

  24. Barnard JP, Reynafarje B, Pedersen PL (1993) Glucose catabolism in African trypanosomes. Evidence that the terminal step is catalyzed by a pyruvate transporter capable of facilitating uptake of toxic analogs. J Biol Chem 268:3654–3661

    PubMed  CAS  Google Scholar 

  25. Medina-Ceja L, Cordero-Romero A, Morales-Villagrán A (2008) Antiepileptic effect of carbenoxolone on seizures induced by 4-aminopyridine: a study in the rat hippocampus and entorhinal cortex. Brain Res 1187:74–81

    Article  PubMed  CAS  Google Scholar 

  26. Medina-Ceja L, Sandoval-García F, Morales-Villagrán A, López-Pérez SJ (2012) Rapid compensatory changes in the expression of EAAT-3 and GAT-1 transporters during seizures in cells of the CA1 and dentate gyrus. J Biomed Sci 19:78

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  27. Gao CJ, Niu L, Ren PC, Wang W, Zhu C, Li YQ, Chai W, Sun XD (2012) Hypoxic preconditioning attenuates global cerebral ischemic injury following asphyxial cardiac arrest through regulation of delta opioid receptor system. Neuroscience 202:352–362

    Article  PubMed  CAS  Google Scholar 

  28. Noshita N, Sugawara T, Hayashi T, Lewen A, Omar G, Chan PH (2002) Copper/zincsuperoxide dismutase attenuates neuronal cell death by preventing extracellular signal-regulated kinase activation after transient focal cerebral ischemia in mice. J Neurosci 22:7923–7930

    PubMed  CAS  Google Scholar 

  29. Saito A, Hayashi T, Okuno S, Ferrand-Drake M, Chan PH (2003) Overexpression of copper/zinc superoxide dismutase in transgenic mice protects against neuronal cell death after transient focal ischemia by blocking activation of the Bad cell death signaling pathway. J Neurosci 23:1710–1718

    PubMed  CAS  Google Scholar 

  30. Medina-Ceja L, Sandoval-García F, Pardo-Peña K (2011) Effect of early glutamate exposure on EAAT-3 and GAT-1 protein expression in cells of the dentate gyrus and CA1 region of the adult rat hippocampus. Arch Med Res 42:433–438

    Article  PubMed  CAS  Google Scholar 

  31. Turski L, Ikonomidou C, Turski WA, Bortolotto ZA, Cavalheiro EA (1989) Review: cholinergic mechanisms and epileptogenesis. The seizures induced by pilocarpine: a novel model of intractable epilepsy. Synapse 3:154–171

    Article  PubMed  CAS  Google Scholar 

  32. Zemke D, Smith JL, Reeves MJ, Majid A (2004) Ischemia and ischemic tolerance in the brain: an overview. Neurotoxicology 25:895–904

    Article  PubMed  CAS  Google Scholar 

  33. Dirnagl U, Meisel A (2008) Endogenous neuroprotection: mito-chondria as gateways to cerebral preconditioning? Neuropharmacology 55:334–344

    Article  PubMed  CAS  Google Scholar 

  34. Schaller B, Graf R (2002) Cerebral ischemic preconditioning. An experimental phenomenon or a clinical important entity of stroke prevention? J Neurol 249:1503–1511

    Article  PubMed  CAS  Google Scholar 

  35. Dirnagl U, Simon RP, Hallenbeck JM (2003) Ischemic tolerance and endogenous neuroprotection. Trends Neurosci 26:248–254

    Article  PubMed  CAS  Google Scholar 

  36. Pellerin L, Bonvento G, Chatton J, Pierre K, Magistretti PJ (2002) Role of neuron-glia interactions in brain energy metabolism: implications for neurodegenerative disorders. Diabetes Nutr Metab 15:268–273

    PubMed  CAS  Google Scholar 

  37. Magistretti PJ (2006) Neuron-glia metabolic coupling and plasticity. J Exp Biol 209:2304–2311

    Article  PubMed  CAS  Google Scholar 

  38. Nedergaard M, Dirnagl U (2005) Role of glial cells in cerebral ischemia. Glia 50:281–286

    Article  PubMed  Google Scholar 

  39. Rosenberg PA, Aizenman E (1989) Hundred-fold increase in neuronal vulnerability to glutamate toxicity in astrocyte-poor cultures of rat cerebral cortex. Neurosci Lett 103:162–168

    Article  PubMed  CAS  Google Scholar 

  40. Wilson JX (1997) Antioxidant defense of the brain: a role for astrocytes. Can J Physiol Pharmacol 75:1149–1163

    Article  PubMed  CAS  Google Scholar 

  41. Dringen R, Gutterer JM, Hirrlinger J (2000) Glutathione metabolism in brain metabolic interaction between astrocytes and neurons in the defense against reactive oxygen species. Eur J Biochem 267:4912–4916

    Article  PubMed  CAS  Google Scholar 

  42. Wender R, Brown AM, Fern R, Swanson RA, Farrell K, Ransom BR (2000) Astrocytic glycogen influences axon function and survival during glucose deprivation in central white matter. J Neurosci 20:6804–6810

    PubMed  CAS  Google Scholar 

  43. Anderson CM, Swanson RA (2000) Astrocyte glutamate transport: review of properties, regulation, and physiological functions. Glia 32:1–14

    Article  PubMed  CAS  Google Scholar 

  44. Voutsinos-Porche B, Bonvento G, Tanaka K, Steiner P, Welker E, Chatton JY, Magistretti PJ, Pellerin L (2003) Glial glutamate transporters mediate a functional metabolic crosstalk between neurons and astrocytes in the mouse developing cortex. Neuron 37:275–286

    Article  PubMed  CAS  Google Scholar 

  45. Gong SJ, Chen LY, Zhang M, Gong JX, Ma YX, Zhang JM, Wang YJ, Hu YY, Sun XC, Li WB, Zhang Y (2012) Intermittent hypobaric hypoxia preconditioning induced brain ischemic tolerance by up-regulating glial glutamate transporter-1 in rats. Neurochem Res 37:527–537

    Article  PubMed  CAS  Google Scholar 

  46. Domora´kova I, Mechı´rova E, Dankova M, Danielisova V, Burda J (2009) Effect of antioxidant treatment in global ischemia and ischemic postconditioning in the rat hippocampus. Cell Mol Neurobiol 29:37–44

    Article  Google Scholar 

  47. Lin AMY, Chen CF, Ho TL (2002) Neuroprotective effect of intermittent hypoxia on iron-induced oxidative injury in rat brain. Exp Neurol 176:328–335

    Article  PubMed  CAS  Google Scholar 

  48. Andoh T, Lee SY, Chock B, Chiueh CC (2000) Preconditioning regulation of bcl-2 and p66shc by human NOS1 enhances tolerance to oxidative stress. FASEB J 14:44–46

    Google Scholar 

  49. Blondeau N, Widmann C, Lazdunski M, Heurteaux C (2001) Activation of the nuclear factor-kappaB is a key event in brain tolerance. J Neurosci 21:4668–4677

    PubMed  CAS  Google Scholar 

  50. Emerson MR, Samson FE, Pazdernik TL (2000) Effect of hypoxia preconditioning on expression of metallothinein-1,2 and heme oxygenase-1 before and after kainic acid-induced seizures. Cell Mol Biol 46:19–26

    Google Scholar 

  51. Barone FC, White RF, Spera PA, Ellison J, Currie RW, Wang X, Feuerstein GZ (1998) Ischemic preconditioning and brain tolerance: temporal histological and functional outcomes, protein synthesis requirement, and interleukin-1 receptor antagonist and early gene expression. Stroke 9:1937–1951

    Article  Google Scholar 

  52. Lauritzen F, Perez EL, Melillo ER, Roh JM, Zaveri HP, Lee TS, Wang Y, Bergersen LH, Eid T (2012) Altered expression of brain monocarboxylate transporter 1 in models of temporal lobe epilepsy. Neurobiol Dis 45:165–176

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  53. Rademakers SE, Lok J, van der Kogel AJ, Bussink J, Kaanders JH (2011) Metabolic markers in relation to hypoxia; staining patterns and colocalization of pimonidazole, HIF-1α, CAIX, LDH-5, GLUT-1, MCT1 and MCT4[J]. BMC Cancer 12:167

    Article  Google Scholar 

  54. Pérez de Heredia F, Wood IS, Trayhurn P (2010) Hypoxia stimulates lactate release and modulates monocarboxylate transporter (MCT1, MCT2, and MCT4) expression in human adipocytes. Pflugers Arch 459:509–518

    Article  PubMed  Google Scholar 

  55. Sharp FR, Bernaudin M (2004) HIF1 and oxygen sensing in the brain. Nat Rev Neurosci 5:437–448

    Article  PubMed  CAS  Google Scholar 

  56. Wang GL, Semenza GL (1995) Purification and characterization of hypoxiainducible factor 1. J Biol Chem 270:1230–1237

    Article  PubMed  CAS  Google Scholar 

  57. Semenza GL, Jiang BH, Leung SW, Passantino R, Concordet JP, Maire P, Giallongo A (1996) Hypoxia response elements in aldolase A, enolase 1, and lactate dehydrogenase A gene promoters contain essential binding sites for hypoxia-inducible factor-1. J Biol Chem 271:32529–32537

    Article  PubMed  CAS  Google Scholar 

  58. Bergersen L, Waerhaug O, Helm J, Thomas M, Laake P et al (2001) A novel postsynaptic density protein: the monocarboxylate transporter MCT2 is colocalized with delta-glutamate receptors in postsynaptic densities of parallel fiber-Purkinje cell synapses. Exp Brain Res 136:523–534

    Article  PubMed  CAS  Google Scholar 

  59. Deitmer JW (2000) Glial strategy for metabolic shuttling and neuronal function. BioEssays 22:747–752

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by the National Natural Science Foundation of China (Grant No. 81271433). The authors thank Dr. Haiyan Zhou for help with the astrocyte primary culture; Yi Li and Lei Tao for help with the epilepsy protocol; and Xiaorong Jin and Kai Jiao for their contributions to this work.

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Authors and Affiliations

  1. Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University, Xi’an, 710038, Shanxi Province, China

    Chen Gao, Chao Wang, Bei Liu, Hao Wu, Qianli Yang, Jungong Jin, Huanfa Li, Shan Dong, Guodong Gao & Hua Zhang

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  1. Chen Gao
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  2. Chao Wang
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  3. Bei Liu
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  4. Hao Wu
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Correspondence to Guodong Gao or Hua Zhang.

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Chen Gao, Chao Wang and Bei Liu have contributed equally to this work.

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Gao, C., Wang, C., Liu, B. et al. Intermittent Hypoxia Preconditioning-Induced Epileptic Tolerance by Upregulation of Monocarboxylate Transporter 4 Expression in Rat Hippocampal Astrocytes. Neurochem Res 39, 2160–2169 (2014). https://doi.org/10.1007/s11064-014-1411-2

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