Antagonism of NMDA receptors by sigma receptor ligands attenuates chemical ischemia-induced neuronal death in vitro.
We investigated the effects of sigma receptor ligands on neuronal death induced by chemical ischemia using primary cultures of rat cerebral cortical neurons. The induction of chemical ischemia by sodium azide and 2-deoxy-D-glucose led to delayed neuronal death in a time- and concentration-dependent manner, as determined by trypan blue exclusion. The neurotoxicity was inhibited by N-methyl-D-aspartate (NMDA) receptor antagonists, indicating the involvement of glutamate. The sigma receptor ligands (+)-N-allylnormetazocine ((+)-SKF10,047) and haloperidol, but not carbetapentane and R(+)-3-(3-hydroxyphenyl)-N-propylpiperidine ((+)-3-PPP), prevented chemical ischemia-induced neurotoxicity in a concentration-dependent manner. The protective effects of (+)-SKF10,047 and haloperidol were not affected by the sigma receptor antagonists. (+)-SKF10,047 and haloperidol, but not carbetapentane and (+)-3PPP, inhibited the glutamate-induced increase in intracellular Ca(2+), and the inhibitory effects were not attenuated by sigma receptor antagonists. These results suggest that direct interaction with NMDA receptors but not sigma receptors is crucial to the neuroprotective effects of sigma receptor ligands with affinity for NMDA receptors.
Kume
Toshiaki
T
Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-Shimoadachi-cho Sakyo-ku, Kyoto 606-8501, Japan.
Nishikawa
Hiroyuki
H
Taguchi
Ryota
R
Hashino
Asami
A
Katsuki
Hiroshi
H
Kaneko
Shuji
S
Minami
Masabumi
M
Satoh
Masamichi
M
Akaike
Akinori
A
D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology; D015687:Cell Hypoxia; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex; D003517:Cyclopentanes / Q000494:pharmacology; D003847:Deoxyglucose / Q000008:administration & dosage; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005333:Fetus; D005947:Glucose / Q000494:pharmacology; D005971:Glutamates / Q000378:metabolism / Q000494:pharmacology; D006220:Haloperidol / Q000494:pharmacology; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010620:Phenazocine / Q000031:analogs & derivatives* / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D017480:Receptors, sigma / Q000819:agonists*; D019810:Sodium Azide / Q000008:administration & dosage
D003517:Cyclopentanes; D018691:Excitatory Amino Acid Antagonists; D005971:Glutamates; D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate; D017480:Receptors, sigma; C018861:carbetapentane; D016291:Dizocilpine Maleate; C012134:SK&F 10047; D015763:2-Amino-5-phosphonovalerate; D019810:Sodium Azide; D003847:Deoxyglucose; C026539:preclamol; D005947:Glucose; D010620:Phenazocine; D006220:Haloperidol; D002118:Calcium