σ Receptor ligands attenuate N-methyl-d-aspartate cytotoxicity in dopaminergic neurons of mesencephalic slice cultures
| Autor: | Seiichiro Shimazu, Akinori Akaike, Chikako Takenaka, Toshiaki Kume, Shuji Kaneko, Michiko Tomita, Hiroshi Katsuki |
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| Rok vydání: | 2000 |
| Předmět: |
Agonist
medicine.medical_specialty N-Methylaspartate Tyrosine 3-Monooxygenase Cell Survival medicine.drug_class Dopamine Sigma receptor Excitotoxicity Biology Ligands medicine.disease_cause Neuroprotection chemistry.chemical_compound Organ Culture Techniques Phenazocine Mesencephalon Internal medicine Excitatory Amino Acid Agonists medicine Ifenprodil Animals Receptors sigma Rats Wistar Receptor Phencyclidine Neurons Pharmacology Propylamines Immunohistochemistry Rats Endocrinology Animals Newborn nervous system chemistry NMDA receptor medicine.drug |
| Zdroj: | European Journal of Pharmacology. 388:139-146 |
| ISSN: | 0014-2999 |
| DOI: | 10.1016/s0014-2999(99)00852-3 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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