title: Energy-related neurotoxicity at the NMDA receptor: a possible role in Alzheimer's disease and related disorders.
abstract: Using rat cerebellar granule cells in primary culture as our model system, we have shown that excitatory amino acids (EAAs) become neurotoxic via the NMDA (N-methyl-D-aspartate) receptor when neuronal energy levels are compromised. Omission of glucose, exclusion of oxygen, or inclusion of inhibitors of oxidative phosphorylation or of Na+/K+-ATPases enables NMDA receptor agonists to express their neurotoxic potential. Both competitive and noncompetitive NMDA receptor antagonists are potent blockers of EAA neurotoxicity, with MK-801 fully effective at 20 nM. We interpret these results as indicating that glucose metabolism, ATP production, and functioning ion pumps are necessary to generate a resting potential sufficient to maintain the voltage-dependent Mg++ block of the NMDA receptor channel; relief of the block enables EAAs to act persistently at the NMDA receptor causing an excessive ion influx which leads to neuronal death by a mechanism not yet understood. These findings are discussed in the context of the potential role for NMDA receptor-mediated neurotoxicity in Alzheimer's disease and related disorders.
authors: Laboratory of Molecular Biology NINDS, NIH, Bethesda, MD 20892.
authors: R C
authors: RC
authors: Henneberry
authors: A
authors: A
authors: Novelli
authors: M A
authors: MA
authors: Vigano
authors: J A
authors: JA
authors: Reilly
authors: J A
authors: JA
authors: Cox
authors: P G
authors: PG
authors: Lysko
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005947:Glucose / Q000494:pharmacology; D005971:Glutamates / Q000378:metabolism / Q000633:toxicity*; D007473:Ion Channels / Q000378:metabolism; D008274:Magnesium / Q000502:physiology; D009474:Neurons / Q000378:metabolism*; D011773:Pyruvates / Q000494:pharmacology; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter / Q000378:metabolism*
chemical_list: D005971:Glutamates; D007473:Ion Channels; D011773:Pyruvates; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter; D008274:Magnesium; D005947:Glucose