Non-NMDA receptor-mediated neurotoxicity in cortical culture

Jae Young Koh, Mark P. Goldberg, Dean M. Hartley, Dennis W. Choi

Research output: Contribution to journalArticle

255 Citations (Scopus)

Abstract

The neurotoxicity of 3 non-NMDA glutamate receptor agonists-kainate, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)quisqualate - was investigated quantitatively in dissociated murine cortical cultures. Five minute exposure to 500 μM kainate, but not AMPA, produced widespread acute neuronal swelling. Kainate-induced swelling was resistant to 2-amino-5-phosphonovalerate (APV) or replacement of extracellular sodium with choline but attenuated by either kynurenate or low concentrations of quisqualate. Unlike NMDA agonists, kainate or AMPA did not produce much late neuronal loss after a 5 min exposure. In contrast, 5 min exposure to 500 MM quisqualate produced both acute neuronal swelling and widespread late neuronal degeneration. This acute swelling was blocked by APV or by replacement of extracellular sodium by choline, consistent with mediation by NMDA receptors; we speculate that high concentrations of quisqualate may directly activate NMDA receptors or induce the release of endogenous glutamate. Quisqualate-induced late neuronal degeneration may be due to another unexpected process: cellular quisqualate uptake and delayed release, converting brief addition into prolonged exposure. Hours after thorough washout of exogenously added quisqualate, micromolar concentrations could be detected in the bathing medium by high performance liquid chromatography. With lengthy exposure (20-24 hr), all 3 non-NMDA agonists were potent neurotoxins, able to destroy neurons with EC50's of about 20 μM for kainate, 4 μM for AMPA, and 1 μM for quisqualate. Kynurenate and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), but not APV or L-glutamate diethyl ester, were effective in attenuating the neuronal degeneration induced by these agonists. CNQX was about 3 times more selective than kynurenate against kainate-induced neuronal injury, but CNQX was still nearly equipotent with APV against NMDA-induced injury. Gamma-D-glutamylaminomethyl sulfonate exhibited partial antagonist specificity for AMPA-induced toxicity.

Original languageEnglish (US)
Pages (from-to)693-705
Number of pages13
JournalJournal of Neuroscience
Volume10
Issue number2
StatePublished - 1990

Fingerprint

Quisqualic Acid
Kainic Acid
alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
2-Amino-5-phosphonovalerate
Kynurenic Acid
6-Cyano-7-nitroquinoxaline-2,3-dione
N-Methylaspartate
Choline
N-Methyl-D-Aspartate Receptors
Glutamic Acid
Sodium
Excitatory Amino Acid Agonists
Wounds and Injuries
Neurotoxins
Glutamate Receptors
Esters
High Pressure Liquid Chromatography
Neurons

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Koh, J. Y., Goldberg, M. P., Hartley, D. M., & Choi, D. W. (1990). Non-NMDA receptor-mediated neurotoxicity in cortical culture. Journal of Neuroscience, 10(2), 693-705.

Non-NMDA receptor-mediated neurotoxicity in cortical culture. / Koh, Jae Young; Goldberg, Mark P.; Hartley, Dean M.; Choi, Dennis W.

In: Journal of Neuroscience, Vol. 10, No. 2, 1990, p. 693-705.

Research output: Contribution to journalArticle

Koh, JY, Goldberg, MP, Hartley, DM & Choi, DW 1990, 'Non-NMDA receptor-mediated neurotoxicity in cortical culture', Journal of Neuroscience, vol. 10, no. 2, pp. 693-705.
Koh, Jae Young ; Goldberg, Mark P. ; Hartley, Dean M. ; Choi, Dennis W. / Non-NMDA receptor-mediated neurotoxicity in cortical culture. In: Journal of Neuroscience. 1990 ; Vol. 10, No. 2. pp. 693-705.
@article{df1b0348fe024f0f8f14e36d9ef74799,
title = "Non-NMDA receptor-mediated neurotoxicity in cortical culture",
abstract = "The neurotoxicity of 3 non-NMDA glutamate receptor agonists-kainate, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)quisqualate - was investigated quantitatively in dissociated murine cortical cultures. Five minute exposure to 500 μM kainate, but not AMPA, produced widespread acute neuronal swelling. Kainate-induced swelling was resistant to 2-amino-5-phosphonovalerate (APV) or replacement of extracellular sodium with choline but attenuated by either kynurenate or low concentrations of quisqualate. Unlike NMDA agonists, kainate or AMPA did not produce much late neuronal loss after a 5 min exposure. In contrast, 5 min exposure to 500 MM quisqualate produced both acute neuronal swelling and widespread late neuronal degeneration. This acute swelling was blocked by APV or by replacement of extracellular sodium by choline, consistent with mediation by NMDA receptors; we speculate that high concentrations of quisqualate may directly activate NMDA receptors or induce the release of endogenous glutamate. Quisqualate-induced late neuronal degeneration may be due to another unexpected process: cellular quisqualate uptake and delayed release, converting brief addition into prolonged exposure. Hours after thorough washout of exogenously added quisqualate, micromolar concentrations could be detected in the bathing medium by high performance liquid chromatography. With lengthy exposure (20-24 hr), all 3 non-NMDA agonists were potent neurotoxins, able to destroy neurons with EC50's of about 20 μM for kainate, 4 μM for AMPA, and 1 μM for quisqualate. Kynurenate and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), but not APV or L-glutamate diethyl ester, were effective in attenuating the neuronal degeneration induced by these agonists. CNQX was about 3 times more selective than kynurenate against kainate-induced neuronal injury, but CNQX was still nearly equipotent with APV against NMDA-induced injury. Gamma-D-glutamylaminomethyl sulfonate exhibited partial antagonist specificity for AMPA-induced toxicity.",
author = "Koh, {Jae Young} and Goldberg, {Mark P.} and Hartley, {Dean M.} and Choi, {Dennis W.}",
year = "1990",
language = "English (US)",
volume = "10",
pages = "693--705",
journal = "Journal of Neuroscience",
issn = "0270-6474",
publisher = "Society for Neuroscience",
number = "2",

}

TY - JOUR

T1 - Non-NMDA receptor-mediated neurotoxicity in cortical culture

AU - Koh, Jae Young

AU - Goldberg, Mark P.

AU - Hartley, Dean M.

AU - Choi, Dennis W.

PY - 1990

Y1 - 1990

N2 - The neurotoxicity of 3 non-NMDA glutamate receptor agonists-kainate, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)quisqualate - was investigated quantitatively in dissociated murine cortical cultures. Five minute exposure to 500 μM kainate, but not AMPA, produced widespread acute neuronal swelling. Kainate-induced swelling was resistant to 2-amino-5-phosphonovalerate (APV) or replacement of extracellular sodium with choline but attenuated by either kynurenate or low concentrations of quisqualate. Unlike NMDA agonists, kainate or AMPA did not produce much late neuronal loss after a 5 min exposure. In contrast, 5 min exposure to 500 MM quisqualate produced both acute neuronal swelling and widespread late neuronal degeneration. This acute swelling was blocked by APV or by replacement of extracellular sodium by choline, consistent with mediation by NMDA receptors; we speculate that high concentrations of quisqualate may directly activate NMDA receptors or induce the release of endogenous glutamate. Quisqualate-induced late neuronal degeneration may be due to another unexpected process: cellular quisqualate uptake and delayed release, converting brief addition into prolonged exposure. Hours after thorough washout of exogenously added quisqualate, micromolar concentrations could be detected in the bathing medium by high performance liquid chromatography. With lengthy exposure (20-24 hr), all 3 non-NMDA agonists were potent neurotoxins, able to destroy neurons with EC50's of about 20 μM for kainate, 4 μM for AMPA, and 1 μM for quisqualate. Kynurenate and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), but not APV or L-glutamate diethyl ester, were effective in attenuating the neuronal degeneration induced by these agonists. CNQX was about 3 times more selective than kynurenate against kainate-induced neuronal injury, but CNQX was still nearly equipotent with APV against NMDA-induced injury. Gamma-D-glutamylaminomethyl sulfonate exhibited partial antagonist specificity for AMPA-induced toxicity.

AB - The neurotoxicity of 3 non-NMDA glutamate receptor agonists-kainate, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)quisqualate - was investigated quantitatively in dissociated murine cortical cultures. Five minute exposure to 500 μM kainate, but not AMPA, produced widespread acute neuronal swelling. Kainate-induced swelling was resistant to 2-amino-5-phosphonovalerate (APV) or replacement of extracellular sodium with choline but attenuated by either kynurenate or low concentrations of quisqualate. Unlike NMDA agonists, kainate or AMPA did not produce much late neuronal loss after a 5 min exposure. In contrast, 5 min exposure to 500 MM quisqualate produced both acute neuronal swelling and widespread late neuronal degeneration. This acute swelling was blocked by APV or by replacement of extracellular sodium by choline, consistent with mediation by NMDA receptors; we speculate that high concentrations of quisqualate may directly activate NMDA receptors or induce the release of endogenous glutamate. Quisqualate-induced late neuronal degeneration may be due to another unexpected process: cellular quisqualate uptake and delayed release, converting brief addition into prolonged exposure. Hours after thorough washout of exogenously added quisqualate, micromolar concentrations could be detected in the bathing medium by high performance liquid chromatography. With lengthy exposure (20-24 hr), all 3 non-NMDA agonists were potent neurotoxins, able to destroy neurons with EC50's of about 20 μM for kainate, 4 μM for AMPA, and 1 μM for quisqualate. Kynurenate and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), but not APV or L-glutamate diethyl ester, were effective in attenuating the neuronal degeneration induced by these agonists. CNQX was about 3 times more selective than kynurenate against kainate-induced neuronal injury, but CNQX was still nearly equipotent with APV against NMDA-induced injury. Gamma-D-glutamylaminomethyl sulfonate exhibited partial antagonist specificity for AMPA-induced toxicity.

UR - http://www.scopus.com/inward/record.url?scp=0025341925&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0025341925&partnerID=8YFLogxK

M3 - Article

C2 - 2406381

AN - SCOPUS:0025341925

VL - 10

SP - 693

EP - 705

JO - Journal of Neuroscience

JF - Journal of Neuroscience

SN - 0270-6474

IS - 2

ER -