Specific antagonism of excitotoxic action of 'uncommon' amino acids assayed in organotypic mouse cortical cultures

Stephen M. Ross, Mary Seelig, Peter Spencer

Research output: Contribution to journalArticle

132 Citations (Scopus)

Abstract

β-N-Methylamino-l-alanine (BMAA) and β-N-oxalylamino-l-alanine (BOAA) are chemically related excitant amino acids present in the seeds of Cycas circinalis and Lathyrus sativus, respectively. Consumption of these seeds has been linked to Guam amyotrophic lateral sclerosis (BMAA) and lathyrism (BOAA) (a form of primary lateral sclerosis). We report that the acute neuronotoxic actions of these amino acids are blocked selectively by specific glutamate receptor antagonists. Administration of BOAA and BMAA to neuratal mouse cortex explants (EC100 = 28 μM and 1.6 mM, respectively) rapidly induces postsynaptic vacuolation (PSV) and neuronal degeneration characterized by dark/shrunken (D/S) cells. BOAA-mediated neuronotoxic effects are attenuated in a concentration-dependent manner by cis-2,3-piperidine dicarboxylic acid (PDA), an antagonist of quisqualate (QA)-preferring and kainate (KA)-preferring glutamate receptors. PDA maximally protected against BOAA-induced PSV by 84% at 1 mM and D/S cells by 80% at 0.5 mM. BMAA-induced cellular changes were antagonized selectively in a concentration-dependent manner by 2-amino-7-phosphonoheptanoic acid (AP7), an N-methyl-d-aspartate (NMDA) glutamate-receptor antagonist. AP7 maximally protected against BMAA-induced induced PSV and D/S by 88% at 1.0 and 0.5 mM, respectively. These protective actions were selective and specific since AP7 failed to attenuate BOAA-induced alterations, and PDA was ineffective in ameliorating BMAA-induced changes. Other glutamate receptor antagonists (glutamic diethyl ester and streptomycin) failed to protect the explants from the destructive action of either toxin. Taken collectively, our data indicate that the acute neuronotoxic actions of BOAA and BMAA (or a metabolite) operate through different glutamate receptor species. BMAA, probably acting indirectly through a metabolite, exerts its action predominantly via the NMDA glutamate receptor, while BOAA acts at the QA and/or KA receptor.

Original languageEnglish (US)
Pages (from-to)120-127
Number of pages8
JournalBrain Research
Volume425
Issue number1
DOIs
StatePublished - Nov 3 1987
Externally publishedYes

Fingerprint

Alanine
Amino Acids
Excitatory Amino Acid Antagonists
Glutamate Receptors
Dicarboxylic Acids
2-amino-7-phosphonoheptanoic acid
Seeds
Cycas
Lathyrism
Guam
Lathyrus
Quisqualic Acid
Kainic Acid Receptors
Motor Neuron Disease
AMPA Receptors
Kainic Acid
Amyotrophic Lateral Sclerosis
Streptomycin
Esters

Keywords

  • (AP7)
  • (BMAA)
  • (BOAA)
  • (PDA)
  • 2-Amino-7-phosphonoheptanoic acid
  • cis-2,3-Piperidine dicarboxylic acid
  • Glutamate receptor antagonism
  • Organotypic tissue culture
  • β-N-Methylamino-l-alanine
  • β-N-Oxalylamino-l-alanine

ASJC Scopus subject areas

  • Developmental Biology
  • Molecular Biology
  • Clinical Neurology
  • Neuroscience(all)

Cite this

Specific antagonism of excitotoxic action of 'uncommon' amino acids assayed in organotypic mouse cortical cultures. / Ross, Stephen M.; Seelig, Mary; Spencer, Peter.

In: Brain Research, Vol. 425, No. 1, 03.11.1987, p. 120-127.

Research output: Contribution to journalArticle

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abstract = "β-N-Methylamino-l-alanine (BMAA) and β-N-oxalylamino-l-alanine (BOAA) are chemically related excitant amino acids present in the seeds of Cycas circinalis and Lathyrus sativus, respectively. Consumption of these seeds has been linked to Guam amyotrophic lateral sclerosis (BMAA) and lathyrism (BOAA) (a form of primary lateral sclerosis). We report that the acute neuronotoxic actions of these amino acids are blocked selectively by specific glutamate receptor antagonists. Administration of BOAA and BMAA to neuratal mouse cortex explants (EC100 = 28 μM and 1.6 mM, respectively) rapidly induces postsynaptic vacuolation (PSV) and neuronal degeneration characterized by dark/shrunken (D/S) cells. BOAA-mediated neuronotoxic effects are attenuated in a concentration-dependent manner by cis-2,3-piperidine dicarboxylic acid (PDA), an antagonist of quisqualate (QA)-preferring and kainate (KA)-preferring glutamate receptors. PDA maximally protected against BOAA-induced PSV by 84{\%} at 1 mM and D/S cells by 80{\%} at 0.5 mM. BMAA-induced cellular changes were antagonized selectively in a concentration-dependent manner by 2-amino-7-phosphonoheptanoic acid (AP7), an N-methyl-d-aspartate (NMDA) glutamate-receptor antagonist. AP7 maximally protected against BMAA-induced induced PSV and D/S by 88{\%} at 1.0 and 0.5 mM, respectively. These protective actions were selective and specific since AP7 failed to attenuate BOAA-induced alterations, and PDA was ineffective in ameliorating BMAA-induced changes. Other glutamate receptor antagonists (glutamic diethyl ester and streptomycin) failed to protect the explants from the destructive action of either toxin. Taken collectively, our data indicate that the acute neuronotoxic actions of BOAA and BMAA (or a metabolite) operate through different glutamate receptor species. BMAA, probably acting indirectly through a metabolite, exerts its action predominantly via the NMDA glutamate receptor, while BOAA acts at the QA and/or KA receptor.",
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N2 - β-N-Methylamino-l-alanine (BMAA) and β-N-oxalylamino-l-alanine (BOAA) are chemically related excitant amino acids present in the seeds of Cycas circinalis and Lathyrus sativus, respectively. Consumption of these seeds has been linked to Guam amyotrophic lateral sclerosis (BMAA) and lathyrism (BOAA) (a form of primary lateral sclerosis). We report that the acute neuronotoxic actions of these amino acids are blocked selectively by specific glutamate receptor antagonists. Administration of BOAA and BMAA to neuratal mouse cortex explants (EC100 = 28 μM and 1.6 mM, respectively) rapidly induces postsynaptic vacuolation (PSV) and neuronal degeneration characterized by dark/shrunken (D/S) cells. BOAA-mediated neuronotoxic effects are attenuated in a concentration-dependent manner by cis-2,3-piperidine dicarboxylic acid (PDA), an antagonist of quisqualate (QA)-preferring and kainate (KA)-preferring glutamate receptors. PDA maximally protected against BOAA-induced PSV by 84% at 1 mM and D/S cells by 80% at 0.5 mM. BMAA-induced cellular changes were antagonized selectively in a concentration-dependent manner by 2-amino-7-phosphonoheptanoic acid (AP7), an N-methyl-d-aspartate (NMDA) glutamate-receptor antagonist. AP7 maximally protected against BMAA-induced induced PSV and D/S by 88% at 1.0 and 0.5 mM, respectively. These protective actions were selective and specific since AP7 failed to attenuate BOAA-induced alterations, and PDA was ineffective in ameliorating BMAA-induced changes. Other glutamate receptor antagonists (glutamic diethyl ester and streptomycin) failed to protect the explants from the destructive action of either toxin. Taken collectively, our data indicate that the acute neuronotoxic actions of BOAA and BMAA (or a metabolite) operate through different glutamate receptor species. BMAA, probably acting indirectly through a metabolite, exerts its action predominantly via the NMDA glutamate receptor, while BOAA acts at the QA and/or KA receptor.

AB - β-N-Methylamino-l-alanine (BMAA) and β-N-oxalylamino-l-alanine (BOAA) are chemically related excitant amino acids present in the seeds of Cycas circinalis and Lathyrus sativus, respectively. Consumption of these seeds has been linked to Guam amyotrophic lateral sclerosis (BMAA) and lathyrism (BOAA) (a form of primary lateral sclerosis). We report that the acute neuronotoxic actions of these amino acids are blocked selectively by specific glutamate receptor antagonists. Administration of BOAA and BMAA to neuratal mouse cortex explants (EC100 = 28 μM and 1.6 mM, respectively) rapidly induces postsynaptic vacuolation (PSV) and neuronal degeneration characterized by dark/shrunken (D/S) cells. BOAA-mediated neuronotoxic effects are attenuated in a concentration-dependent manner by cis-2,3-piperidine dicarboxylic acid (PDA), an antagonist of quisqualate (QA)-preferring and kainate (KA)-preferring glutamate receptors. PDA maximally protected against BOAA-induced PSV by 84% at 1 mM and D/S cells by 80% at 0.5 mM. BMAA-induced cellular changes were antagonized selectively in a concentration-dependent manner by 2-amino-7-phosphonoheptanoic acid (AP7), an N-methyl-d-aspartate (NMDA) glutamate-receptor antagonist. AP7 maximally protected against BMAA-induced induced PSV and D/S by 88% at 1.0 and 0.5 mM, respectively. These protective actions were selective and specific since AP7 failed to attenuate BOAA-induced alterations, and PDA was ineffective in ameliorating BMAA-induced changes. Other glutamate receptor antagonists (glutamic diethyl ester and streptomycin) failed to protect the explants from the destructive action of either toxin. Taken collectively, our data indicate that the acute neuronotoxic actions of BOAA and BMAA (or a metabolite) operate through different glutamate receptor species. BMAA, probably acting indirectly through a metabolite, exerts its action predominantly via the NMDA glutamate receptor, while BOAA acts at the QA and/or KA receptor.

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KW - β-N-Oxalylamino-l-alanine

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