Inhibition by 2-Methoxy-4-ethylphenol of Ca2+ Influx Through Acquired and Native N-Methyl-D-aspartate-Receptor Channels
Inhibition by 2-Methoxy-4-ethylphenol of Ca2+ Influx Through Acquired and Native N-Methyl-D-aspartate-Receptor Channels
复制标题
DOI：
10.1254/jphs.09294fp
复制
发表时间：
2010-03-01
影响因子：
3.5
通讯作者：
Yoneda, Yukio
中科院分区：
文献类型：
--
作者：
Fukumori, Ryo;Nakamichi, Noritaka;Yoneda, Yukio
评价了防腐木杂酚油成分2-甲氧基-4-乙基苯酚（2 M4 EP）的药理学性质，该成分被证明对N-甲基-D-天冬氨酸（NMDA）的神经毒性具有保护作用，以调节通过获得性和天然NMDA受体（NMDAR）通道的Ca 2+内流。NMDA可显著增加NR 2A或NR 2B亚基与必需NR 1亚基共转染的HEK 293细胞内游离Ca ~（2+）水平。进一步加入地佐环平可抑制NMDA引起的两种获得性NMDAR通道细胞内Ca ~（2+）水平的升高，而2 M4 EP和NR 2B亚基选择性拮抗剂ifenprodil对表达NR 1/NR 2B亚基的HEK 293细胞内NMDA引起的Ca ~（2+）水平升高的抑制作用比NR 1/NR 2A亚基的细胞更有效。2 M4 EP可明显抑制NMDA引起的海马神经元内Ca ~（2+）浓度升高。短暂暴露于NMDA导致细胞活力在培养的海马神经元24小时后急剧下降，而2 M4 EP显着防止NMDA的细胞活力的损失。同样，2 M4 EP对NR 1/NR 2B亚基的HEK 293细胞的保护作用比NR 1/NR 2A亚基的更有效。这些结果表明，2 M4 EP可能通过抑制由NR 1/NR 2A亚基而不是NR 1/NR 2B亚基组成的NMDAR通道的Ca ~（2+）内流来保护神经元免受兴奋性毒性。
Pharmacological properties were evaluated for the antidiarrheic wood creosote ingredient 2-methoxy-4-ethylphenol (2M4EP), which was shown to be protective against neurotoxicity of N-methyl-D-aspartate (NMDA), to modulate Ca2+ influx across acquired and native NMDA receptor (NMDAR) channels. NMDA markedly increased intracellular free Ca2+ levels in HEK293 cells transfected with the expression vector of either NR2A or NR2B subunit together with the essential NR1 subunit vector. Further addition of dizocilpine inhibited the increase by NMDA in intracellular Ca2+ levels in both types of acquired NMDAR channels, while 2M4EP and the NR2B-subunit selective antagonist ifenprodil were more effective in inhibiting the increase by NMDA in HEK293 cells expressing NR1/NR2B subunits than in those with NR1/NR2A subunits. 2M4EP significantly prevented the increased intracellular Ca2+ levels by NMDA in cultured rat hippocampal neurons. Brief exposure to NMDA led to a drastic decrease in cellular viability 24 h later in cultured hippocampal neurons, while 2M4EP significantly prevented the loss of cellular vitality by NMDA. Similarly, 2M4EP more efficiently protected HEK293 cells with NR1/NR2B subunits than those with NR1/NR2A subunits. These results suggest that 2M4EP may protect neurons from excitotoxicity through inhibition of Ca2+ influx across NMDAR channels composed of NR1/NR2B, rather than NR1/NR2A, subunits.