Neuroprotective effects of sigma-1 receptor agonists against beta-amyloid-induced toxicity

Neuroreport. 2005 Aug 1;16(11):1223-6. doi: 10.1097/00001756-200508010-00018.

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

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid beta-Peptides / antagonists & inhibitors
  • Amyloid beta-Peptides / toxicity*
  • Animals
  • Anisoles / pharmacology
  • Blotting, Western / methods
  • Cell Count / methods
  • Cell Survival / drug effects
  • Cells, Cultured
  • Cerebral Cortex / cytology
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Embryo, Mammalian
  • Excitatory Amino Acid Antagonists / pharmacology
  • Morpholines / pharmacology*
  • Neurons / cytology
  • Neurons / drug effects*
  • Neuroprotective Agents / pharmacology*
  • Peptide Fragments / antagonists & inhibitors
  • Peptide Fragments / toxicity*
  • Propylamines / pharmacology
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Rats
  • Receptors, sigma / agonists*
  • Receptors, sigma / antagonists & inhibitors
  • bcl-2-Associated X Protein

Substances

  • Amyloid beta-Peptides
  • Anisoles
  • Bax protein, rat
  • Excitatory Amino Acid Antagonists
  • Morpholines
  • Neuroprotective Agents
  • Peptide Fragments
  • Propylamines
  • Proto-Oncogene Proteins c-bcl-2
  • Receptors, sigma
  • amyloid beta-protein (25-35)
  • bcl-2-Associated X Protein
  • sigma-1 receptor
  • 2-(4-morpholino)ethyl-1-phenylcyclohexane-1-carboxylate
  • N,N-dipropyl-2-(4-methoxy-3-(2-phenylethoxy)phenyl)ethylamine monohydrochloride