Effects of pan- and subtype-selective N-methyl-D-aspartate receptor antagonists on cortical spreading depression in the rat:: Therapeutic potential for migraine
Effects of pan- and subtype-selective N-methyl-D-aspartate receptor antagonists on cortical spreading depression in the rat:: Therapeutic potential for migraine
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DOI：
10.1124/jpet.106.117101
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发表时间：
2007-05-01
影响因子：
3.5
通讯作者：
James, Michael F.
中科院分区：
文献类型：
--
作者：
Peeters, Magali;Gunthorpe, Martin J.;James, Michael F.
扩散性抑制（SD）长期以来一直与偏头痛的潜在病理生理学相关。N甲基D-天冬氨酸（NMDA）谷氨酸受体（NMDA-R）参与SD的产生和传播的证据本身已经超过15年。然而，迄今为止，还没有关于NMDA-R拮抗剂被开发用于偏头痛治疗的报道.在这项研究中，一种非竞争性的，泛-NMDA-R阻滞剂，美金刚，批准用于临床使用，和两种拮抗剂具有选择性的NMDA-R含有NR 2B亚单位，（1 S，2S）- 1-（4-羟基苯基）-2-（4-羟基-4-苯基哌啶基）1-丙醇（CP-101，606）和（+/-）-（R*，S*）-α-（4-羟基苯基）-β-甲基-4-（苯甲基）-1-哌啶丙醇（Ro 25- 6981），以评估其对大鼠SD的保护作用。异氟醚麻醉下，d. C.在不同的皮质部位同时记录电位和相关的皮质血流量和O-2分压（pO（2））。药物（1、3和10 mg/ kg i.第页）在KCl应用于脑表面之前1小时或30分钟给予。核心温度和动脉pCO（2）、pO（2）和pH值测量结果证实了生理稳定性。KCl诱导7.7 ± 1.8（平均值± S. D.）SD事件，d。C.振幅为14.9 +/- 2.8 mV。美金刚和CP-101，606在与治疗用途相关的剂量下剂量依赖性地降低SD事件数量（分别至2.0 +/-1.8和2.3 +/-2.9）和SD幅度。Ro 25- 6981还显着减少SD事件，但效果较差（至4.5 +/- 1.6），且不影响振幅。这些结果表明，含NR 2B的NMDA受体是SD的关键介质，因此，美金刚和NR 2B选择性拮抗剂可能是用于治疗偏头痛和其他SD相关病症的有用的新治疗剂（例如，例如，在一个实施例中，中风和脑损伤）。慢性治疗而非急性治疗是否可以提高其疗效仍有待确定。
Spreading depression ( SD) has long been associated with the underlying pathophysiology of migraine. Evidence that the NmethylD- aspartate ( NMDA) glutamate receptor ( NMDA- R) is implicated in the generation and propagation of SD has itself been available for more than 15 years. However, to date, there are no reports of NMDA- R antagonists being developed for migraine therapy. In this study, an uncompetitive, pan- NMDA- R blocker, memantine, approved for clinical use, and two antagonists with selectivity for NMDA- R containing the NR2B subunit, ( 1S, 2S)- 1-( 4- hydroxyphenyl)- 2-( 4- hydroxy- 4- phenylpiperidino)1- propanol ( CP- 101,606) and (+/-)-( R*, S*)-alpha-(4- hydroxyphenyl)-beta methyl- 4-( phenylmethyl)- 1- piperidine propanol ( Ro 25- 6981), were investigated to assess their protective effects against SD in the rat. Under isoflurane anesthesia, d. c. potential and the related cortical blood flow and partial pressure of O-2 ( pO(2)) were recorded simultaneously at separate cortical sites. Drugs ( 1, 3, and 10 mg/ kg i. p.) were given 1 h or 30 min before KCl application to the brain surface. Core temperature and arterial pCO(2), pO(2), and pH measurements confirmed physiological stability. KCl induced 7.7 +/- 1.8 ( mean +/- S. D.) SD events with d. c. amplitude of 14.9 +/- 2.8 mV. Memantine and CP- 101,606 dose- dependently decreased SD event number ( to 2.0 +/- 1.8 and 2.3 +/- 2.9, respectively) and SD amplitude at doses relevant for therapeutic use. Ro 25- 6981 also decreased SD events significantly, but less effectively ( to 4.5 +/- 1.6), without affecting amplitude. These results indicate that NR2B- containing NMDA receptors are key mediators of SD, and as such, memantine- and NR2B- selective antagonists may be useful new therapeutic agents for the treatment of migraine and other SD- related disorders ( e. g., stroke and brain injury). Whether chronic, rather than acute, treatment may improve their efficacy remains to be determined.