Activation of sigma1 receptor subtype leads to neuroprotection in the rat primary neuronal cultures.
The mechanisms of sigma (sigma) receptor ligands-induced neuroprotective effects are controversial because both sigma receptors and phencyclidine (PCP) binding sites of the N-methyl-D-aspartate (NMDA) receptor channel complex have been reported to contribute to these neuroprotective effects. Thus, to clarify the role of sigma receptor in the neuroprotective effects, we examined the effects of 1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine dihydrochloride (SA4503), a novel sigma1 receptor agonist with negligible affinity for the NMDA/PCP receptor channel complex, on the hypoxia/hypoglycemia- and exogenously applied NMDA-induced neurotoxicity in the rat primary neuronal cultures. A selective sigma1 receptor agonist, SA4503, significantly suppressed the hypoxia/hypoglycemia-induced neurotoxicity in the cultures, whereas this agonist failed to inhibit the NMDA-induced neurotoxicity. Similarly, (+)-pentazocine ((+)-PTZ), a prototype sigma1 receptor agonist, inhibited the hypoxia/hypoglycemia-induced neurotoxicity, whilst it did not affect the NMDA-induced toxicity in the cultures. These neuroprotective effects of SA4503 and (+)-PTZ were partially blocked by N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]ethylamine monohydrochloride (NE-100), a putative sigma1 receptor antagonist. These results suggest that the sigma1 receptor subtype plays an important role in the sigma receptor ligands-induced neuroprotective effects via the regulation of excitatory amino acids (EAAs) release from the presynaptic sites.
Nakazawa
M
M
Central Research Laboratories, Santen Pharmaceutical Co., Ltd, Higashiyodogawa, Osaka, Japan.
Matsuno
K
K
Mita
S
S
D000818:Animals; D000840:Anisoles / Q000378:metabolism; D002478:Cells, Cultured; D008024:Ligands; D009474:Neurons / Q000378:metabolism*; D018697:Nootropic Agents / Q000494:pharmacology; D010423:Pentazocine / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D011437:Propylamines / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017480:Receptors, sigma / Q000378:metabolism*
D000840:Anisoles; D008024:Ligands; D018697:Nootropic Agents; D010879:Piperazines; D011437:Propylamines; D017480:Receptors, sigma; C101491:sigma1-binding protein, rat; C083832:N,N-dipropyl-2-(4-methoxy-3-(2-phenylethoxy)phenyl)ethylamine monohydrochloride; C101789:SA 4503; D010423:Pentazocine