Biomaterial Database

Differential action of NMDA antagonists on cholinergic neurotoxicity produced by N-methyl-D-aspartate and quinolinic acid. 1996

A C Pawley, and S Flesher, and R J Boegman, and R J Beninger, and K H Jhamandas

Department of Pharmacology and Toxicology, Queen's University, Kingston, Ontario, Canada.

1. Injections of N-methyl-D-aspartate (NMDA) and quinolinic acid (Quin), agonists that activate NMDA receptors, into the rat nucleus basalis magnocellularis (nbM) produced a dose-related decrease in cholineacetyltransferase (ChAT) activity in the cerebral cortex and amygdala 7 days after injection. 2. In order to examine the possibility that NMDA and Quin activate different sub-types of NMDA receptors to produce central cholinergic neurotoxicity, the sensitivity of these agonists to the action of three different NMDA receptor antagonists, 2-amino-7-phosphonoheptanoate (AP-7), 7-chlorokynurenate and dizolcipine (MK801) was examined by injecting a fixed dose of NMDA (60 nmol) or Quin (120 nmol) in combination with different doses of the antagonists into the nbM. 3. Both AP-7 (0.6-15 nmol) and 7-chlorokynurenate (3.75-200 nmol), which block the NMDA receptor recognition site and glycine modulatory site respectively, produced a dose-related attenuation of the NMDA or Quin-induced decrease in ChAT activity in both the cortex and amygdala. Both antagonists showed a greater potency against the action of NMDA than against Quin. 4. MK801 (2-200 nmol), an NMDA receptor-linked channel blocker, attenuated the Quin and NMDA response only at a high dose. Unlike AP-7 and 7-chlorokynurenate, MK801 did not exhibit a consistent difference in its potency as an antagonist against NMDA and Quin. 5. The differential antagonist actions of AP-7 or 7-chlorokynurenate against NMDA and Quin-induced cholinergic neurotoxicity suggest that the excitotoxic actions of these two agonists are mediated via distinct NMDA receptor sub-types. The NMDA- and Quin-sensitive receptors appear to differ with respect to properties of the receptor recognition and glycine modulatory sites that are associated with these receptors.

UI	MeSH Term	Description	Entries
D007736	Kynurenic Acid	A broad-spectrum excitatory amino acid antagonist used as a research tool.	Kynurenate,Acid, Kynurenic
D008297	Male		Males
D001921	Brain	The part of CENTRAL NERVOUS SYSTEM that is contained within the skull (CRANIUM). Arising from the NEURAL TUBE, the embryonic brain is comprised of three major parts including PROSENCEPHALON (the forebrain); MESENCEPHALON (the midbrain); and RHOMBENCEPHALON (the hindbrain). The developed brain consists of CEREBRUM; CEREBELLUM; and other structures in the BRAIN STEM.	Encephalon
D002795	Choline O-Acetyltransferase	An enzyme that catalyzes the formation of acetylcholine from acetyl-CoA and choline. EC 2.3.1.6.	Choline Acetylase,Choline Acetyltransferase,Acetylase, Choline,Acetyltransferase, Choline,Choline O Acetyltransferase,O-Acetyltransferase, Choline
D004305	Dose-Response Relationship, Drug	The relationship between the dose of an administered drug and the response of the organism to the drug.	Dose Response Relationship, Drug,Dose-Response Relationships, Drug,Drug Dose-Response Relationship,Drug Dose-Response Relationships,Relationship, Drug Dose-Response,Relationships, Drug Dose-Response
D004336	Drug Antagonism	Phenomena and pharmaceutics of compounds that inhibit the function of agonists (DRUG AGONISM) and inverse agonists (DRUG INVERSE AGONISM) for a specific receptor. On their own, antagonists produce no effect by themselves to a receptor, and are said to have neither intrinsic activity nor efficacy.	Antagonism, Drug,Antagonisms, Drug,Drug Antagonisms
D000596	Amino Acids	Organic compounds that generally contain an amino (-NH2) and a carboxyl (-COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins.	Amino Acid,Acid, Amino,Acids, Amino
D000818	Animals	Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA.	Animal,Metazoa,Animalia
D015763	2-Amino-5-phosphonovalerate	The D-enantiomer is a potent and specific antagonist of NMDA glutamate receptors (RECEPTORS, N-METHYL-D-ASPARTATE). The L form is inactive at NMDA receptors but may affect the AP4 (2-amino-4-phosphonobutyrate; APB) excitatory amino acid receptors.	2-Amino-5-phosphonopentanoic Acid,2-Amino-5-phosphonovaleric Acid,2-APV,2-Amino-5-phosphonopentanoate,5-Phosphononorvaline,d-APV,dl-APV,2 Amino 5 phosphonopentanoate,2 Amino 5 phosphonopentanoic Acid,2 Amino 5 phosphonovalerate,2 Amino 5 phosphonovaleric Acid,5 Phosphononorvaline
D016194	Receptors, N-Methyl-D-Aspartate	A class of ionotropic glutamate receptors characterized by affinity for N-methyl-D-aspartate. NMDA receptors have an allosteric binding site for glycine which must be occupied for the channel to open efficiently and a site within the channel itself to which magnesium ions bind in a voltage-dependent manner. The positive voltage dependence of channel conductance and the high permeability of the conducting channel to calcium ions (as well as to monovalent cations) are important in excitotoxicity and neuronal plasticity.	N-Methyl-D-Aspartate Receptor,N-Methyl-D-Aspartate Receptors,NMDA Receptor,NMDA Receptor-Ionophore Complex,NMDA Receptors,Receptors, NMDA,N-Methylaspartate Receptors,Receptors, N-Methylaspartate,N Methyl D Aspartate Receptor,N Methyl D Aspartate Receptors,N Methylaspartate Receptors,NMDA Receptor Ionophore Complex,Receptor, N-Methyl-D-Aspartate,Receptor, NMDA,Receptors, N Methyl D Aspartate,Receptors, N Methylaspartate