Abstract
Prolonged exposure of cultured cortical neurons to the residue 25-35 fragment of beta-amyloid protein, in the presence of dizocilpine, an antagonist of the N-methyl-D-aspartate receptor, and of 6,7-dinitroquinoxaline-2,3-dione, an antagonist of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate receptors, resulted in the expression of the proapoptotic protein Bax and neuronal death. Beta-amyloid protein(25-35)-induced neuronal death was substantially attenuated by the sigma1 receptor agonist 2-(4-morpholinethyl)1-phenylcyclohexanecarboxylate. The neuroprotective action of 2-(4-morpholinethyl)1-phenylcyclohexanecarboxylate was mimicked by the sigma1 ligand methyl (1S,2R)-2-[1-adamantyl(methyl)amino]methyl-1-phenylcyclopropanecarboxylate and was antagonized by the sigma1 receptor antagonist N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)-phenyl]-ethylamine monohydrochloride. These results suggest that sigma1 receptor agonists might function as neuroprotectant agents in Alzheimer's disease.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Amyloid beta-Peptides / antagonists & inhibitors
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Amyloid beta-Peptides / toxicity*
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Animals
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Anisoles / pharmacology
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Blotting, Western / methods
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Cell Count / methods
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Cell Survival / drug effects
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Cells, Cultured
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Cerebral Cortex / cytology
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Dose-Response Relationship, Drug
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Drug Interactions
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Embryo, Mammalian
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Excitatory Amino Acid Antagonists / pharmacology
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Morpholines / pharmacology*
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Neurons / cytology
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Neurons / drug effects*
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Neuroprotective Agents / pharmacology*
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Peptide Fragments / antagonists & inhibitors
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Peptide Fragments / toxicity*
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Propylamines / pharmacology
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Rats
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Receptors, sigma / agonists*
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Receptors, sigma / antagonists & inhibitors
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Sigma-1 Receptor
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bcl-2-Associated X Protein
Substances
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Amyloid beta-Peptides
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Anisoles
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Bax protein, rat
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Excitatory Amino Acid Antagonists
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Morpholines
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Neuroprotective Agents
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Peptide Fragments
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Propylamines
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Proto-Oncogene Proteins c-bcl-2
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Receptors, sigma
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amyloid beta-protein (25-35)
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bcl-2-Associated X Protein
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2-(4-morpholino)ethyl-1-phenylcyclohexane-1-carboxylate
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N,N-dipropyl-2-(4-methoxy-3-(2-phenylethoxy)phenyl)ethylamine monohydrochloride