Neuroprotective effects of sigma-1 receptor agonists against beta-amyloid-induced toxicity.
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.
Marrazzo
Agostino
A
Department of Pharmaceutical Sciences, University of Catania 2I.B.B., CNR-Catania, Catania, Italy.
Caraci
Filippo
F
Salinaro
Elisa Trovato
ET
Su
Tsung-Ping
TP
Copani
Agata
A
Ronsisvalle
Giuseppe
G
D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000633:toxicity*; D000818:Animals; D000840:Anisoles / Q000494:pharmacology; D015153:Blotting, Western / Q000379:methods; D002452:Cell Count / Q000379:methods; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004622:Embryo, Mammalian; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D009025:Morpholines / Q000494:pharmacology*; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000633:toxicity*; D011437:Propylamines / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D017480:Receptors, sigma / Q000819:agonists* / Q000037:antagonists & inhibitors; D051028:bcl-2-Associated X Protein; D000097605:Sigma-1 Receptor
D016229:Amyloid beta-Peptides; D000840:Anisoles; D018691:Excitatory Amino Acid Antagonists; D009025:Morpholines; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D011437:Propylamines; D019253:Proto-Oncogene Proteins c-bcl-2; D017480:Receptors, sigma; D051028:bcl-2-Associated X Protein; D000097605:Sigma-1 Receptor; C494828:Bax protein, rat; C074636:amyloid beta-protein (25-35); C071738:2-(4-morpholino)ethyl-1-phenylcyclohexane-1-carboxylate; C083832:N,N-dipropyl-2-(4-methoxy-3-(2-phenylethoxy)phenyl)ethylamine monohydrochloride