SIGMA-RECEPTOR-MEDIATED NEUROPROTECTION AGAINST GLUTAMATE TOXICITY IN PRIMARY RAT NEURONAL CULTURES
SIGMA-RECEPTOR-MEDIATED NEUROPROTECTION AGAINST GLUTAMATE TOXICITY IN PRIMARY RAT NEURONAL CULTURES
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DOI：
10.1016/0006-8993(94)01294-r
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发表时间：
1995-02-06
期刊：
影响因子：
2.9
通讯作者：
TORTELLA, FC
中科院分区：
文献类型：
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作者：
DECOSTER, MA;KLETTE, KL;TORTELLA, FC
在成熟培养的大鼠皮层神经元中检查了假定的α受体在介导针对谷氨酸诱导的神经元损伤的神经保护中的作用。除选择性 sigma(1) 配体 (+)-3-PPP 外，所有测试的 sigma 配体均具有神经保护作用，可防止谷氨酸诱导的形态变化和 LDH 释放增加。它们的神经保护效力（和EC（50）值）的顺序如下：（+）-SKF 10,047（0.81μM）>（+）-环佐辛（2.3μM）>右美沙芬（3.1μM）=氟哌啶醇（3.7μM）>（+）-喷他佐辛（8.5μM）>DTG（42.7μM）=卡倍戊烷(46.3μM)。当校正相对 sigma 与 PCP 结合亲和力时，神经保护效力和 sigma(1) 位点亲和力之间似乎存在正相关。然而，神经保护效力和 sigma(2) 位点之间似乎没有显着相关性。重要的是，当在至少 5-30 倍其各自神经保护 EC(50) 值的浓度下单独测试时，所有 α 配体均不具有神经毒性。选择性 sigma(1) 配体 (+)-喷他佐辛的初步实验结果表明，sigma 介导的神经保护可能涉及谷氨酸诱导的钙流的缓冲。总的来说，这些体外实验的结果表明，σ配体具有神经保护作用，因此值得进一步探索作为中枢神经系统损伤和神经退行性疾病体内模型的潜在治疗剂。
The role of the putative a receptor in mediating neuroprotection against glutamate-induced neuronal injury was examined in mature cultured rat cortical neurons. With the exception of the selective sigma(1) ligand (+)-3-PPP, all of the sigma ligands tested were neuroprotective, preventing glutamate-induced morphological changes and increases in LDH release. Their rank order of neuroprotective potency (and EC(50) values) was as follows: (+)-SKF 10,047 (0.81 mu M)>(+)-cyclazocine (2.3 mu M)>dextromethorphan (3.1 mu M) = haloperidol (3.7 mu M)>(+)-pentazocine (8.5 mu M)>DTG (42.7 mu M) = carbetapentane (46.3 mu M). When corrected for relative sigma versus PCP binding affinity, it appears that a positive correlation exists between neuroprotective potency and sigma(1) site affinity. However, there does not appear to be a significant correlation between neuroprotective potency and the sigma(2) site. Critically, none of the a ligands were neurotoxic when tested alone at concentrations at least 5-30 times their respective neuroprotective EC(50) values. Results from preliminary experiments with the selective sigma(1) ligand (+)-pentazocine indicated that sigma-mediated neuroprotection may involve the buffering of glutamate-induced calcium flux. Collectively, the results of these in vitro experiments demonstrate that sigma ligands are neuroprotective and therefore deserve further exploration as potential therapeutic agents in in vivo models of CNS injury and neurodegenerative disorders.