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The glutamate transport inhibitor L-trans-pyrrolidine-2,4-dicarboxylate indirectly evokes NMDA receptor mediated neurotoxicity in rat cortical cultures.

Publication ,  Journal Article
Blitzblau, R; Gupta, S; Djali, S; Robinson, MB; Rosenberg, PA
Published in: Eur J Neurosci
September 1996

Because of the well-documented importance of glutamate uptake in protecting neurons against glutamate toxicity, we were interested in testing the effects of L-trans-pyrrolidine-2,4-dicarboxylate (PDC) on rat cortical cultures. This compound is a substrate for glutamate transporters and is a potent glutamate transport inhibitor that does not interact significantly with glutamate receptors. Using a 30 min exposure, and assessing neuronal survival after 20-24 h, PDC was neurotoxic in conventional astrocyte-rich cortical cultures, with an EC50 in these cultures of 320 +/- 157 microM. In astrocyte-poor cultures, an EC50 for PDC of 50 +/- 5 microM was determined. The neurotoxicity of PDC in both astrocyte-rich and astrocyte-poor cultures was blocked by the NMDA antagonist MK-801, but not by the non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). We tested the possibility that the neurotoxicity of PDC might be due to release of excitatory amino acids using several approaches. After pre-loading cells with the non-metabolizable analogue of glutamate, [3H]-D-aspartate, first we demonstrated that PDC caused significant efflux of [3H]-D-aspartate. This effect of PDC was dependent upon extracellular sodium. In contrast with glutamate neurotoxicity, PDC neurotoxicity was inhibited by removal of extracellular sodium. In the presence of 1 mM PDC, sodium caused neurotoxicity with an EC50 of 18 +/- 7.6 mM. Tetrodotoxin had no effect on either PDC neurotoxicity or on PDC-evoked [3H]-D-aspartate release. PDC-evoked release of [3H]-D-aspartate was demonstrable in astrocyte cultures with no neurons present. PDC also evoked release of endogenous glutamate. Finally, the neurotoxicity of PDC was blocked by coincubation with glutamate-pyruvate transaminase plus pyruvate to degrade extracellular glutamate. These results demonstrate the neurotoxicity of PDC, and suggest that the mechanism of this toxicity is the glutamate transporter-dependent accumulation of glutamate in the extracellular space.

Duke Scholars

Published In

Eur J Neurosci

DOI

ISSN

0953-816X

Publication Date

September 1996

Volume

8

Issue

9

Start / End Page

1840 / 1852

Location

France

Related Subject Headings

  • Stereoisomerism
  • Receptors, N-Methyl-D-Aspartate
  • Rats, Sprague-Dawley
  • Rats
  • Pyrrolidines
  • Neurotoxins
  • Neurology & Neurosurgery
  • Excitatory Amino Acid Agonists
  • Dicarboxylic Acids
  • Cerebral Cortex
 

Citation

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MLA
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Blitzblau, R., Gupta, S., Djali, S., Robinson, M. B., & Rosenberg, P. A. (1996). The glutamate transport inhibitor L-trans-pyrrolidine-2,4-dicarboxylate indirectly evokes NMDA receptor mediated neurotoxicity in rat cortical cultures. Eur J Neurosci, 8(9), 1840–1852. https://doi.org/10.1111/j.1460-9568.1996.tb01328.x
Blitzblau, R., S. Gupta, S. Djali, M. B. Robinson, and P. A. Rosenberg. “The glutamate transport inhibitor L-trans-pyrrolidine-2,4-dicarboxylate indirectly evokes NMDA receptor mediated neurotoxicity in rat cortical cultures.Eur J Neurosci 8, no. 9 (September 1996): 1840–52. https://doi.org/10.1111/j.1460-9568.1996.tb01328.x.
Blitzblau, R., et al. “The glutamate transport inhibitor L-trans-pyrrolidine-2,4-dicarboxylate indirectly evokes NMDA receptor mediated neurotoxicity in rat cortical cultures.Eur J Neurosci, vol. 8, no. 9, Sept. 1996, pp. 1840–52. Pubmed, doi:10.1111/j.1460-9568.1996.tb01328.x.
Journal cover image

Published In

Eur J Neurosci

DOI

ISSN

0953-816X

Publication Date

September 1996

Volume

8

Issue

9

Start / End Page

1840 / 1852

Location

France

Related Subject Headings

  • Stereoisomerism
  • Receptors, N-Methyl-D-Aspartate
  • Rats, Sprague-Dawley
  • Rats
  • Pyrrolidines
  • Neurotoxins
  • Neurology & Neurosurgery
  • Excitatory Amino Acid Agonists
  • Dicarboxylic Acids
  • Cerebral Cortex