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

Stephen M. Ross, Mary Seelig, Peter S. Spencer

Research output: Contribution to journalArticle

132 Scopus citations

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

Keywords

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

ASJC Scopus subject areas

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

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