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• W2114063072 abstract "Spreading depression (SD) has long been associated with the underlying pathophysiology of migraine. Evidence that the <i>N</i>-methyl-d-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, (1<i>S</i>,2<i>S</i>)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol (CP-101,606) and (±)-(<i>R</i>*,<i>S</i>*)-α-(4-hydroxyphenyl)-β-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 O₂ (pO₂) 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 pCO₂,pO₂, 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." @default.
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• W2114063072 date "2007-01-31" @default.
• W2114063072 modified "2023-10-14" @default.
• W2114063072 title "Effects of Pan- and Subtype-Selective <i>N</i>-Methyl-d-aspartate Receptor Antagonists on Cortical Spreading Depression in the Rat: Therapeutic Potential for Migraine" @default.
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• W2114063072 doi "https://doi.org/10.1124/jpet.106.117101" @default.
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