2007年9月
Cleft-type cyclophanes confer neuroprotection against excitatory neurotoxicity in vitro and in vivo through inhibition of NMDA receptors
NEUROPHARMACOLOGY
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- 巻
- 53
- 号
- 4
- 開始ページ
- 515
- 終了ページ
- 523
- 記述言語
- 英語
- 掲載種別
- 研究論文(学術雑誌)
- DOI
- 10.1016/j.neuropharm.2007.06.013
- 出版者・発行元
- PERGAMON-ELSEVIER SCIENCE LTD
The cleft-type cyclophanes (ACCn, DNCn and TsDCn) were found to strongly inhibit macroscopic currents at heteromeric NMDA receptors (NR1/NR2) but not AMPA receptors expressed in Xenopus oocytes at voltage-clamp recording. The inhibition by cleft-type cyclophanes was voltage-dependent, because the inhibition was larger at - 100 mV than at -20 mV. Mutations at NR1 N650, located in the vestibule of the channel pore, reduced the inhibition by DNCn and TsDCn, suggesting that the residue (N650) interacts with these cleft-type cyclophanes. Cell toxicity of TsDCn on SH-SY5Y cells was slightly weaker than that of memantine. The neuroprotective effects of cleft-type cyclophanes against cell damage caused by NMDA were investigated in cultured rat hippocampal neurons. Addition of 10 mu M DNCn or TsDCn into the medium ablated the neurotoxicity induced by NMDA, and a similar effect was also observed with memantine. The neuroprotective effects of cleft-type cyclophanes were then assayed on NMDA-induced seizures in mice. Intracerebroventricular injection of TsDCn (5 mg/mouse) decreased the seizure induced by intraperitoneal injection of NMDA (115 mg/kg) in mice. The results demonstrate that these cleft-type cyclophanes interact directly with the extracellular mouth of the NMDA channel pore and exhibit neuroprotective effects on NMDA-induced excitatory toxicity in primary cultured neurons and mice. (C) 2007 Elsevier Ltd. All rights reserved.
- リンク情報
- ID情報
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- DOI : 10.1016/j.neuropharm.2007.06.013
- ISSN : 0028-3908
- Web of Science ID : WOS:000250103300006