Effects of pan- and subtype-selective N-methyl-D-aspartate receptor antagonists on cortical spreading depression in the rat:: Therapeutic potential for migraine

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.