title: Effect of SA4503, a novel sigma1 receptor agonist, against glutamate neurotoxicity in cultured rat retinal neurons.
abstract: We examined the effects of sigma1 receptor agonists against glutamate-induced neurotoxicity in cultured retinal neurons. Primary cultures obtained from fetal rat retinas (16-19 d gestation) were used. The neurotoxic effect of glutamate was quantitatively assessed using the trypan blue exclusion method. A brief exposure of retinal cultures to glutamate (500 microM) led to delayed neuronal cell death. The glutamate-induced neurotoxicity was inhibited by (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo-[a,b]-cyclohepten-5 ,10-imine hydrogen maleate (MK-801). The sigma1 receptor agonists, 1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)-piperazine dihydrochloride (SA4503) and (+)-pentazocine at a concentration range of 0.1 approximately 100 microM reduced the glutamate-induced neurotoxicity in a dose-dependent manner. In addition, the neuroprotective effects of both SA4503 and (+)-pentazocine were antagonized by co-treatment with N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]ethylamine monohydrochloride (NE-100), a putative sigma1 receptor antagonist. These findings suggest that sigma1 receptor agonists protect retinal cells against glutamate-induced neurotoxicity.
authors.affiliation: Discovery Research Division, Santen Pharmaceutical Co., Ltd., Osaka, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Senda
authors.forename: S
authors.initials: S
authors.lastname: Mita
authors.forename: K
authors.initials: K
authors.lastname: Kaneda
authors.forename: M
authors.initials: M
authors.lastname: Kikuchi
authors.forename: A
authors.initials: A
authors.lastname: Akaike
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D018756:GABA Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000633:toxicity*; D009474:Neurons / Q000187:drug effects*; D010423:Pentazocine / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology*; D051381:Rats; D017480:Receptors, sigma / Q000819:agonists*; D012160:Retina / Q000166:cytology* / Q000187:drug effects
chemical_list: D000701:Analgesics, Opioid; D018691:Excitatory Amino Acid Antagonists; D018756:GABA Antagonists; D010879:Piperazines; D017480:Receptors, sigma; D018698:Glutamic Acid; D016291:Dizocilpine Maleate; C101789:SA 4503; D010423:Pentazocine