title: sigma receptor ligands attenuate N-methyl-D-aspartate cytotoxicity in dopaminergic neurons of mesencephalic slice cultures.
abstract: We investigated the potential neuroprotective effects of several sigma receptor ligands in organotypic midbrain slice cultures as an excitotoxicity model system. When challenged with 100-microM N-methyl-D-aspartate (NMDA) for 24 h, dopaminergic neurons in midbrain slice cultures degenerated, and this was prevented by (5R, 10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,b]-cyclohepten-5, 10-imine (MK-801; 1-10 microM). Concomitant application of ifenprodil (1-10 microM) or haloperidol (1-10 microM), both of which are high-affinity sigma receptor ligands, significantly attenuated the neurotoxicity of 100 microM NMDA. The sigma(1) receptor-selective ligand (+)-N-allylnormetazocine ((+)-SKF 10047; 1-10 microM) was also effective in attenuating the toxicity of NMDA. The effect of R(-)-N-(3-phenyl-1-propyl)-1-phenyl-2-aminopropane hydrochloride ((-)-PPAP), a sigma receptor ligand with negligible affinity for the phencyclidine site of NMDA receptors, was also examined. (-)-PPAP (3-100 microM) caused a concentration-dependent reduction of NMDA cytotoxicity, with significant protection at concentrations of 30 and 100 microM. In contrast, (+)-SKF 10047 (10 microM) and (-)-PPAP (100 microM) showed no protective effects against cell death induced by the Ca(2+) ionophore ionomycin (1-3 microM). These results indicate that sigma receptor ligands attenuate the cytotoxic effects of NMDA on midbrain dopaminergic neurons, possibly via inhibition of NMDA receptor functions.
authors.affiliation: Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Shimazu
authors.forename: H
authors.initials: H
authors.lastname: Katsuki
authors.forename: C
authors.initials: C
authors.lastname: Takenaka
authors.forename: M
authors.initials: M
authors.lastname: Tomita
authors.forename: T
authors.initials: T
authors.lastname: Kume
authors.forename: S
authors.initials: S
authors.lastname: Kaneko
authors.forename: A
authors.initials: A
authors.lastname: Akaike
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002470:Cell Survival / Q000187:drug effects; D004298:Dopamine / Q000502:physiology*; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity*; D007150:Immunohistochemistry; D008024:Ligands; D008636:Mesencephalon / Q000166:cytology* / Q000187:drug effects; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors / Q000633:toxicity*; D009474:Neurons / Q000187:drug effects*; D009924:Organ Culture Techniques; D010620:Phenazocine / Q000031:analogs & derivatives / Q000494:pharmacology; D011437:Propylamines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D017480:Receptors, sigma / Q000187:drug effects*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D018690:Excitatory Amino Acid Agonists; D008024:Ligands; D011437:Propylamines; D017480:Receptors, sigma; C068473:N-(3-phenyl-n-propyl)-1-phenyl-2-aminopropane; D016202:N-Methylaspartate; C012134:SK&F 10047; D014446:Tyrosine 3-Monooxygenase; D010620:Phenazocine; D004298:Dopamine