LY293558, a Novel AMPA/GluR5 Antagonist, is Efficacious and Well-Tolerated in Acute Migraine

Abstract

Glutamatergic hyperactivity is implicated migraine pathogenesis. Also, LY293558, an alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate (KA) receptor antagonist, is effective in preclinical models of migraine. We therefore tested LY293558 in acute migraine. We conducted a randomized, triple-blind, parallel-group, double-dummy, multicentre trial of 1.2 mg/kg intravenous (IV) LY293558, 6 mg subcutaneous (SC) sumatriptan, or placebo in the treatment of acute migraine. The primary efficacy variable was the headache response rate, i.e. headache score improvement from moderate/severe at baseline to mild/none at 2 h. Of 45 enrolled patients, 44 patients (20M:24F; mean age +/- SD = 40 +/- 9 years) completed the study. Response rates were 69% for LY293558 (P = 0.017 vs. placebo), 86% for sumatriptan (P < 0.01 vs. placebo) and 25% for placebo. LY293558 and sumatriptan were superior to placebo (P < 0.01 for all comparisons) on all other measures of improvement in pain and migraine associated symptoms. Fifteen percent of patients who took LY293558 reported adverse events (AEs) (n = 2; one mild, one severe). Fifty-three percent of patients who took sumatriptan (n = 8; seven mild, one moderate) and 31% of those who received placebo reported AEs (n = 5; four mild, one severe). The efficacy and safety results of LY293558 in this small migraine proof of concept trial, together with supportive preclinical data, provide evidence for a potential role of nonvasoactive AMPA/KA antagonists in treating migraine. Larger trials are needed to further test the hypothesis.

Current and prospective pharmacological targets in relation to antimigraine action

“…The effects of glutamate on brain excitability are mediated via the ionotropic NMDA, AMPA, and kainate receptors, as well as the metabotropic glutamate receptor (Sang et al 2004). Glutamate-like immunoreactivity has been seen in the dental pulp neurons that project to the trigeminal nucleus caudalis (TNC) in the rat (Clements et al 1991).…”

“…As glutamate receptors are co-localized in neurons in the trigeminal ganglion with 5-HT 1B , 5-HT 1D , and 5-HT 1F receptors, 5-HT 1 autoreceptors may presynaptically inhibit the release of glutamate (Ma 2001). Since glutamate may be involved in the cortical hyperexcitability typical of migraine (Goadsby 2005), the above ionotropic glutamate receptors are being studied as potential antimigraine targets (Sang et al 2004).…”

“…Indeed, the mixed AMPA/kainate receptor antagonist LY293558 has been shown to be effective in the acute treatment of migraine (Sang et al 2004). Also lamotrigine, a sodium channel blocker with antiglutamatergic actions, seemed highly effective in reducing migraine aura and migraine attacks in a controlled open study (Lampl et al 2005).…”

Update on future headache treatments

“…Two other iGluR types are a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors and kinate receptors. Tezampanel,LY293558, a mixed AMPA/kainate receptor antagonist has been demonstrated in early studies to be effective in the acute treatment of migraine and is well tolerated [60]. Phase III studies for acute migraine treatment are planned.…”

Kainate receptor trafficking

“…KARs have been implicated in a wide range of clinically important conditions including pain, 59 anxiety, 60 schizophrenia, 61 acute migraine, 62 autism, 63,64 Huntington's, ischemia 65,66 and epilepsy. [67][68][69][70] While of undoubted importance, discussion of these findings is beyond the scope of this review; however, the interested reader is referred to a number of recent reviews covering this subject.…”