Skip to main content
Brain Pathology logoLink to Brain Pathology
. 2006 Apr 5;12(4):475–481. doi: 10.1111/j.1750-3639.2002.tb00465.x

Astrocyte Modulation of Neurotoxic Injury

Michael Aschner 1,, Ursula Sonnewald 2, Kim H Tan 3
PMCID: PMC8095941  PMID: 12408234

Abstract

Astrocytes produce trophic factors, regulate neurotransmitter and ion concentrations, and remove toxins and debris from the extracellular space of the CNS, maintaining an extracellular milieu that is optimally suited for neuronal function. Consequently, astrocytic functional impairments, as well as physiological reactions of astrocytes to injury have the potential to induce and/or exacerbate neuronal dysfunction. This mini‐review showcases contemporary evidence provoking reformulation of concepts of the inter‐dependence between astrocytes and neurons and advances several mechanisms used by astrocytes in potentiating or nullifying the final pathway of neuropathologic injury. Though clearly possessing an array of protective systems and upregulating a large number of protective molecules in response to xenobiotic exposure, recent evidence also invokes astrocytes in secondary amplification of cell injury in multiple neurodegenerative disorders.

Full Text

The Full Text of this article is available as a PDF (46.9 KB).

References

  • 1. Albrecht J (1998) Roles of neuroactive amino acids in ammonia neurotoxicity. J Neurosci Res 51:133–138. [DOI] [PubMed] [Google Scholar]
  • 2. Alvarez‐Maubecin V, Garcia‐Hernandez F, Williams JT, Van Bockstaele EJ (2000) Functional coupling between neurons and glia. J Neurosci 20:4091–4098. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3. Bezzi P, Volterra A (2001) A neuron‐glia signaling network in the active brain. Curr Opinion Neurobiol 11:387–394. [DOI] [PubMed] [Google Scholar]
  • 4. Bradford HF (1995) Glutamate, GABA and epilepsy. Prog Neurobiol 47:477–511. [DOI] [PubMed] [Google Scholar]
  • 5. Brenner M, Johnson AB, Boespflug‐Tanguy O, Rodriguez D, Goldman JE, Messing A (2001) Mutations in GFAP, encoding glial fibrillary acidic protein, are associated with Alexander disease. Nature Genet 27:117–120. [DOI] [PubMed] [Google Scholar]
  • 6. Butterworth RF, Tonon M‐C, Désy L, Giguère J‐F, Vaudry H, Pelletier G (1991) Increased brain content of the endogenous benzodiazepine receptor ligand, octadecaneuropeptide (ODN), following portacaval anastomosis in the rat. Neuropeptides 12:119–125. [DOI] [PubMed] [Google Scholar]
  • 7. Chen Y, Vartiainen NE, Ying W, Chan PH, Koistinaho J, Swanson RA (2001) Astrocytes protect neurons from nitric oxide toxicity by a glutathione‐dependent mechanism. J Neurochem 77:1601–1610. [DOI] [PubMed] [Google Scholar]
  • 8. Cholet N, Pellerin L, Welker E, Lacombe P, Seylaz J, Magistretti P, Bonvento G (2001) Local injection of anti‐sense oligonucleotides targeted to the glial glutamate transporter GLAST decreases the metabolic response to somatosensory activation. J Cereb Blood Flow Metab 21:404–412. [DOI] [PubMed] [Google Scholar]
  • 9. De Vito WJ, Xhaja K, Stone S (2000) Prenatal alcohol exposure increases TNFα‐induced cytotoxicity in primary astrocytes. Alcohol 21:63–71. [DOI] [PubMed] [Google Scholar]
  • 10. Di Monte DA, Schipper HM, Hetts S, Langston JW (1995) Iron‐mediated bioactivation of 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) in glial cultures. Glia 15:203–206. [DOI] [PubMed] [Google Scholar]
  • 11. Dringen R, Pfeiffer B, Hamprecht B (1999) Synthesis of the antioxidant glutathione in neurons: supply by astrocytes of CysGly as precursor for neuronal glutathione. J Neurosci 19:562–569. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12. Fraser DD, Mudrick‐Donnon LA, MacVicar BA (1994) Astrocytic GABA receptors. Glia 11:83–93. [DOI] [PubMed] [Google Scholar]
  • 13. Froes MM, Correia AH, Garcia‐Abreu J, Spray DC, Campos de Carvalho AC, Neto MV (1999) Gap‐junctional coupling between neurons and astrocytes in primary central nervous system cultures. Proc Natl Acad Sci U S A 96:7541–7546. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14. Giguère JF, Hamel E, Butterworth RF (1992) Increased densities of binding sites for the “peripheral‐type” benzodiazepine receptor ligand 3H‐PK 11195 in rat brain following portacaval anastomosis. Brain Res 585:295–298. [DOI] [PubMed] [Google Scholar]
  • 15. Heales SJ, Bolanos JP, Stewart VC, Brookes PS, Land JM, Clark JB (1999) Nitric oxide, mitochondria and neurological disease. Biochim Biophys Acta 1410:215–228. [DOI] [PubMed] [Google Scholar]
  • 16. Håberg A, Qu H, Saether O, Unsgard G, Haraldseth O, Sonnewald U (2001) Differences in neurotransmitter synthesis and intermediary metabolism between glutamatergic and GABAergic neurons during 4hours of middle cerebral artery occlusion in the rat: the role of astrocytes in neuronal survival. J Cereb Blood Flow Metab 21:1451–63. [DOI] [PubMed] [Google Scholar]
  • 17. John GR, Scemes E, Suadicani SO, Liu JSH, Charles PC, Lee SC, Spray DC, Brosnan CF (1999) IL‐1 _ differentially regulates calcium wave propagation between primary human fetal astrocytes via pathways involving P2 receptors and gap junction channels. Proc Natl Acad Sci U S A 96:11613–11618. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18. Langston JW, Ballard P, Tetrud JW, Irwin I (1982) Chronic parkinsonism in humans due to a product of Meperidineanalog synthesis. Science 219:979–980. [DOI] [PubMed] [Google Scholar]
  • 19. Lin JH, Weigel H, Cotrina ML, Liu S, Bueno E, Hansen AJ, Hansen TW, Goldman S, Nedergaard M (1998) Gap‐junction‐mediated propagation and amplification of cell injury. Nature Neurosci 1:494–500. [DOI] [PubMed] [Google Scholar]
  • 20. Muller B, Qu H, Garseth M, White LR, Aasly J, Sonnewald U (2000) Amino acid neurotransmitter metabolism in neurones and glia following kainate injection in rats. Neurosci Lett 279:169–72. [DOI] [PubMed] [Google Scholar]
  • 21. Murphy TH, Yu J, Ng R, Johnson DA, Shen H, Honey CR, Johnson JA (2001) Preferential expression of antioxidant response element mediated gene expression in astrocytes. J Neurochem 76:1670–1678. [DOI] [PubMed] [Google Scholar]
  • 22. Norenberg MD (1995) Hepatic encephalopathy In: Neuroglia, Kettenmann H, Ransom BR (eds.), pp. 950–963, Oxford University Press, New York . [Google Scholar]
  • 23. Qu H, Eloqayli H, Müller B, Aasly J, Sonnewald (2002) Glial Neuronal Interactions Following Kainate Injection in Rats Studied by MR Spectroscopy. Neurochem Int in press. [DOI] [PubMed] [Google Scholar]
  • 24. Rio C, Rieff HI, Qi P, Khurana TS, Corfas G (1997) Neuregulin and erbB receptors play a critical role in neuronal migration. Neuron 19:39–50. [DOI] [PubMed] [Google Scholar]
  • 25. Sagara J, Miura K, Bannai S (1993) Maintenance of neuronal glutathione by glial cells. J Neurochem 61:1672–1676. [DOI] [PubMed] [Google Scholar]
  • 26. Shanker G, Allen JW, Mutkus LA, Aschner M (2001) The uptake of cysteine in cultured primary astrocytes and neurons. Brain Res 902:156–163. [DOI] [PubMed] [Google Scholar]
  • 27. Smeyne M, Goloubeva O, Smeyne RJ (2001) Strain‐dependent susceptibility to MPTP and MPP(+)‐induced parkinsonism is determined by glia. Glia 34:73–80. [PubMed] [Google Scholar]
  • 28. Sonnewald U, Therrien G, Butterworth RF (1996) Portacaval anastomosis results in altered neuron—astrocytic metabolic trafficking of amino acids: evidence from 13C‐NMR studies. J Neurochem 67:1711–7. [DOI] [PubMed] [Google Scholar]
  • 29. Tsacopoulos M, Magistretti PJ (1996) Metabolic coupling between glia and neurons. J Neurosci 16):877–885. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30. Ulliam EM, Sapperstein SK, Christopherson KS, Barres BA (2001) Control of synapse number by glia. Science 291:657–661. [DOI] [PubMed] [Google Scholar]
  • 31. Vesce S, Bezzi P, Volterra A (1999) The active role of astrocytes in synaptic transmission. Cell Mol Life Sci 56:991–1000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32. Waagepetersen HS, Bakken IJ, Larsson OM, Sonnewald U, Schousboe A (1998) Comparison of lactate and glucose metabolism in cultured neocortical neurons and astrocytes using 13C‐NMR spectroscopy. Dev Neurosci 20:310–20. [DOI] [PubMed] [Google Scholar]
  • 33. Wang XF, Cynader MS (2000) Astrocytes provide cysteine to neurons by releasing glutathione. J Neurochem 74:1434–442. [DOI] [PubMed] [Google Scholar]
  • 34. Wang XF, Cynader MS (2001) Pyruvate released by astrocytes protects neurons from copper‐catalyzed cysteine neurotoxicity. J Neurosci 21:3322–3331. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35. Zhou BG, Norenberg MD (1999) Ammonia downregulates GLAST mRNA glutamate transporter in rat astrocyte cultures. Neurosci Lett 276:145–148s. [DOI] [PubMed] [Google Scholar]

Articles from Brain Pathology are provided here courtesy of Wiley

RESOURCES