Effects of Pan- and Subtype-SelectiveN-Methyl-d-aspartate Receptor Antagonists on Cortical Spreading Depression in the Rat: Therapeutic Potential for Migraine

Abstract

Spreading depression (SD) has long been associated with the underlying pathophysiology of migraine. Evidence that the Nmethyl-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, (1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol (CP-101,606) and (Ϯ)-(R*,S*)-␣-(4-hydroxyphenyl)-␤-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 Ϯ 1.8 (mean Ϯ S.D.) SD events with d.c. amplitude of 14.9 Ϯ 2.8 mV.Memantine and CP-101,606 dose-dependently decreased SD event number (to 2.0 Ϯ 1.8 and 2.3 Ϯ 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 Ϯ 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.Spreading depression (SD) is a slowly (2-6 mm/min) propagating wave of transiently increased cerebral blood flow, suppressed cortical activity, and loss of membrane potential accompanied by major metabolic disturbance (for review, see Smith et al., 2006). SD can be induced in the brains of all animal species investigated, including human, using a variety of mechanical and chemical methods. Typically, in the anesthetized rat, the brain is surgically exposed using a small craniotomy, and SD is evoked by topical administration of KCl. SD can be detected via a reduction in d.c. amplitude using electrodes placed on the brain surface distant from the SD induction site. Associated changes in extracellular ion concentrations and cerebral blood flow can also be detected with appropriate probes. Changes in cerebral tissue water, This study was supported by Marie Curie Industry Host Fellowship QLG5-CT-2001-60018 and the Fonds Spécial de Recherche de l'Université Catholique de Louvain, Belgium) (to M.P.).

Memantine for prevention of migraine: a retrospective study of 60 cases

“…Memantine, like other NMDA antagonists, has been found to modulate CSD [5]. It is therefore possible that memantine could reduce episodic increases in cortical excitability underlying migraine.…”

Current and prospective pharmacological targets in relation to antimigraine action

“…In agreement with this hypothesis, the infusion of Mg 2+ provided sustained headache relief (Bigal et al 2002), and oral Mg 2+ has been demonstrated to be an effective prophylactic in menstrual migraine (Facchinetti et al 1991). Thus, glutamate receptor modulators seem to be of benefit in migraine treatment; indeed, the NMDA receptor antagonist memantine and the NR2B subunit containing antagonist, CP-101,606, decreased spreading depression (Peeters et al 2007), a potentially important factor in migraine pathophysiology. However, stronger basic and clinical evidence for the delineation of their exact role in the pathogenesis of migraine, as well as their cardiovascular safety, is awaited with great interest.…”

Role of different voltage-gated Ca2+channels in cortical spreading depression: Specific requirement of P/Q-type Ca2+channels

“…23 Moreover, multiple CSDs induced in vivo by continuous K + microdialysis or topical application of a KCl cristal are strongly reduced in frequency but not completely suppressed by P/Q-type (or N-type) Ca 2+ channel blockers 24 and by NMDA antagonists (that also reduce their amplitude and duration). 25,26 The Ca 2+ channel blockers do not affect CSD induced by pinprick in vivo. 24,27 Thus, even limiting our discussion to the methods that are used to elicit CSD in normally metabolizing cortical tissues (because the pharmacological profile of hypoxia and/or ouabain-induced CSD is again different), it is clear that different methods lead to different pharmacological profiles regarding the role of NMDA receptors and Ca 2+ influx through P/Qtype Ca 2+ channels in CSD induction and propagation.…”