Molecular Biology Reports

, Volume 38, Issue 5, pp 3235–3242 | Cite as

Protection by pyruvate against glutamate neurotoxicity is mediated by astrocytes through a glutathione-dependent mechanism

  • Yifeng Miao
  • Yongming Qiu
  • Yuchang Lin
  • Zengli Miao
  • Jing Zhang
  • Xiaojie Lu
Article
First Online:
Received:
Accepted:

Abstract

Pyruvate, an endogenous metabolite of glycolysis, is an anti-toxicity agent. Recent studies have suggested possible roles for pyruvate in protecting CNS neurons from excitotoxic and metabolic insults. Utilizing cultures derived from embryonic rat cortex, the studies presented in this paper indicate that an astroglia-mediated mechanism is involved in the neuroprotective effects of pyruvate against glutamate toxicity. Glutamate-induced toxicity could be reversed by pyruvate in a mixed culture of cortex cells. Importantly, in pure neuronal cultures from the same tissue, pyruvate failed to protect against glutamate toxicity. Addition of astroglia to the pure neuronal cultures restores the ability of pyruvate to protect neurons from glutamate-induced toxicity. Our results further suggest that pyruvate can induce glia to up-regulate the synthesis of glutathione (GSH), an antioxidant that protects cells from toxins such as free radicals. Taken together, our data suggest that astroglia in mixed cultures are essential for mediating the effects of pyruvate, revealing a novel mechanism by which pyruvate, an important intermediate of tricarboxylic acid cycle in the body, may act to protect neurons from damage during insults such as brain ischemia.

Keywords

Pyruvate Glutamate toxicity Neuroprotection Glutathione Astrocytes 
This is a preview of subscription content, log in to check access.

Notes

Acknowledgments

This study was funded by grants from the Scientific Research Foundation of Nanjing Medical University (No. 2002-19) and the Shanghai Science and Technology Committee (No. 074107019).

References

  1. 1.
    Magistretti PJ, Pellerin L, Rothman DL, Shulman RG (1999) Energy on demand. Science 283:496–497PubMedCrossRefGoogle Scholar
  2. 2.
    Coyle JT, Puttfarcken P (1993) Oxidative stress, glutamate, and neurodegenerative disorders. Science 262:689–695PubMedCrossRefGoogle Scholar
  3. 3.
    Lipton SA, Rosenberg PA (1994) Excitatory amino acids as a final common pathway for neurologic disorders. N Engl J Med 330:613–622PubMedCrossRefGoogle Scholar
  4. 4.
    Urushitani M, Nakamizo T, Inoue R et al (2001) N-methyl-d-aspartate receptor-mediated mitochondrial Ca(2+) overload in acute excitotoxic motor neuron death: a mechanism distinct from chronic neurotoxicity after Ca(2+) influx. J Neurosci Res 63:377–387PubMedCrossRefGoogle Scholar
  5. 5.
    Matthews CC, Zielke HR, Wollack JB, Fishman PS (2000) Enzymatic degradation protects neurons from glutamate excitotoxicity. J Neurochem 75:1045–1052PubMedCrossRefGoogle Scholar
  6. 6.
    Sanelli T, Strong MJ (2007) Loss of nitric oxide-mediated down-regulation of NMDA receptors in neurofilament aggregate-bearing motor neurons in vitro: implications for motor neuron disease. Free Radic Bio Med 42:143–151CrossRefGoogle Scholar
  7. 7.
    Sanganahalli BG, Joshi PG, Joshi NB (2005) Xanthine oxidase, nitric oxide synthase and phospholipase A2 produce reactive oxygen species via mitochondria. Brain Res 1037:200–203PubMedCrossRefGoogle Scholar
  8. 8.
    Eftmova T, Deucher A, Kuroki T, Ohba M, Eckert RL (2002) Novel protein kinase C isoforms regulate human keratinocyte differentiation by activating a p38 delta mitogen-activated protein kinase cascade that targets CCAAT/enhancer-binding protein alpha. J Bio Chem 277:31753–31760CrossRefGoogle Scholar
  9. 9.
    Ginsberg MD (2009) Current status of neuroprotection for cerebral ischemia. Synoptic overview. Stroke 40:111–114CrossRefGoogle Scholar
  10. 10.
    Trendelenburg G, Dirnagl U (2005) Neuroprotective role of astrocytes in cerebral ischemia: focus on ischemic preconditioning. Glia 50:307–320PubMedCrossRefGoogle Scholar
  11. 11.
    Desagher S, Glowinski J, Premont J (1997) Pyruvate protects neurons against hydrogen peroxide-induced toxicity. J Neurosci 17:9060–9067PubMedGoogle Scholar
  12. 12.
    Lee JY, Kim YH, Koh JY (2001) Protection by pyruvate against transient forebrain ischemia in rats. J Neurosci 21:RC171PubMedGoogle Scholar
  13. 13.
    Olstad E, Olsen GM, Qu H, Sonnewald U (2007) Pyruvate recycling in cultured neurons from cerebellum. J Neurosci Res 85:3318–3325PubMedCrossRefGoogle Scholar
  14. 14.
    Alves PM, Nunes R, Zhang CH et al (2000) Metabolism of 3-C-13-malate in primary cultures of mouse astrocytes. Dev Neurosci 22:456–462PubMedCrossRefGoogle Scholar
  15. 15.
    Waagepetersen HS, Qu H, Hertz L, Sonnewald U, Schousboe A (2002) Demonstration of pyruvate recycling in primary cultures of neocortical astrocytes but not in neurons. Neurochem Res 27:1431–1437PubMedCrossRefGoogle Scholar
  16. 16.
    Frenzel J, Richter J, Eschrich K (2005) Pyruvate protects glucose-deprived miffler cells from nitric oxide-induced oxidative stress by radical scavenging. Glia 52:276–288PubMedCrossRefGoogle Scholar
  17. 17.
    Kala G, Hertz L (2005) Ammonia effects on pyruvate/lactate production in astrocytes—interaction with glutamate. Neurochem Int 47:4–12PubMedCrossRefGoogle Scholar
  18. 18.
    McCarthy KD, Devellis J (1980) Preparation of separate astroglial and oligodendrogial cell-cultures from rat cerebral tissue. J Cell Biol 85:890–902PubMedCrossRefGoogle Scholar
  19. 19.
    Goodwin GW, Kuntz MJ, Paxton R, Harris RA (1987) Enzymatic determination of the branched-chain alpha-keto acids. Ana Biochem 162:536–539CrossRefGoogle Scholar
  20. 20.
    White MJ, DiCaprio MJ, Greenberg DA (1996) Assessment of neuronal viability with Alamar blue in cortical and granule cell cultures. J Neurosci Meth 70:195–200CrossRefGoogle Scholar
  21. 21.
    Wang XF, Cynader MS (2001) Pyruvate released by astrocytes protects neurons from copper-catalyzed cysteine neurotoxicity. J Neurosci 21:3322–3331PubMedGoogle Scholar
  22. 22.
    Wang XF, Cynader MS (1999) Effects of astrocytes on neuronal attachment and survival shown in a serum-free co-culture system. Brain Res Protoc 4:209–216CrossRefGoogle Scholar
  23. 23.
    Nakamichi N, Kambe Y, Oikawa H et al (2005) Protection by exogenous pyruvate through a mechanism related to monocarboxylate transporters against cell death induced by hydrogen peroxide in cultured rat cortical neurons. J Neurochem 93:84–93PubMedCrossRefGoogle Scholar
  24. 24.
    Lobner D, Canzoniero LM, Manzerra P et al (2000) Zinc-induced neuronal death in cortical neurons. Cell Mol Biol 46:797–806PubMedGoogle Scholar
  25. 25.
    Maus M, Marin P, Israel M, Glowinski J, Premont J (1999) Pyruvate and lactate protect striatal neurons against N-methyl-d-aspartate-induced neurotoxicity. Eur J Neurosci 11:3215–3224PubMedCrossRefGoogle Scholar
  26. 26.
    Regan RF, Guo Y (1999) Extracellular reduced glutathione increases neuronal vulnerability to combined chemical hypoxia and glucose deprivation. Brain Res 817:145–150PubMedCrossRefGoogle Scholar
  27. 27.
    Ramírez BG, Rodrigues TB, Violante IR et al (2007) Kinetic properties of the redox switch/redox coupling mechanism as determined in primary cultures of cortical neurons and astrocytes from at brain. J Neurosci Res 85(15):3244–3253PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2010

Authors and Affiliations

  • Yifeng Miao
    • 1
    • 2
  • Yongming Qiu
    • 2
  • Yuchang Lin
    • 1
  • Zengli Miao
    • 1
  • Jing Zhang
    • 1
  • Xiaojie Lu
    • 1
  1. 1.Neuroscience Center, Wuxi No. 2 People’s HospitalNanjing Medical UniversityWuxiChina
  2. 2.Department of Neurosurgery, Ren Ji HospitalShanghai Jiao Tong University, School of MedicineShanghaiChina

Personalised recommendations