A Potential New Therapeutic Target for Migraine?

Abstract & Commentary

By Dara Jamieson, MD, Associate Professor of Clinical Neurology, Weill Cornell Medical College. Dr. Jamieson reports she is a retained consultant for Boehringer Ingelheim and Bayer, and is on the speakers bureau for Boehringer Ingelheim.

Synopsis: A novel target for suppression of cortical spreading depression shows promise in rodent models and in patients with medically refractory migraine with aura.

Source: Holland PR, et al. Acid-sensing ion channel 1: A novel therapeutic target for migraine with aura. Ann Neurol 2012;72:559-563.

Approximately 20-30% of patients with migraine headaches report a heralding aura, a focal neurological disturbance thought to be an expression of cortical spreading depression (CSD) caused by a depolarization wave that propagates slowly in the occipital lobe at velocity of 2-5 mm/min, followed by a spontaneous return to normal function. CSD results in a failure of cortical ion homeostasis and the release of a variety of agents, including H+, K+, and arachidonic acid (AA). Both H+ and AA are known to potentiate acid-sensing ion channels (ASICs), which may facilitate the propagation of the spreading depression. Inhibition of CSD by ASIC blockade potentially could halt the aura and prevent the subsequent migraine headache pain. Amiloride blocks the widely expressed epithelial sodium channels (ENaCs)/degenerin gene family, which includes the ASICs. The ASICs represent proton-gated channels that are able to flux Na+ and Ca++ and are encoded by genes linked to seizure termination and neuroprotection. Pharmacological blockade or transgenic deletion of the ASICs has been shown to be neuroprotective in multiple models of neurological disease, with potential extrapolation to models of migraine. The authors propose that blockade of the amiloride-sensitive ENaCs could be a novel beneficial treatment option for migraine, particularly for patients with aura.

Cortical needle prick (NP) or K+ was used to induce CSD in male Sprague Dawley rats and male age-matched wild-type and ASIC1 knockout mice. Administration of amiloride (10 mg/kg) 15 minutes prior to NP significantly inhibited the number of NP-induced CSDs (six of eight) in rats when compared to vehicle, but failed to inhibit the number of K+-induced CSDs. A specific ASIC blocker demonstrated significant efficacy, blocking five of six NP-induced CSDs in the rat model. Double the dose of amiloride significantly inhibited the propagation of NP-induced CSDs in wild-type mice (six of nine) when compared to knockout mice (one of eight). Humans (five females and two males) with medically refractory migraine with prolonged aura were offered amiloride. Amiloride substantially reduced both frequency of aura and headache severity in four of seven patients receiving 10-20 mg/day, followed for between 6 and 24 months. The only reported adverse effects were mild hyperkalemia and polyuria.


The authors note that the proposed mechanisms of action of amiloride for the treatment of migraine fit with the trigeminovascular mechanism of the disorder. Stimulation of dural vessels activates the trigeminal nerve, transmitting information to the trigeminal nucleus caudalis (TNC) via the trigeminal ganglion. Second-order neurons originating in the brainstem TNC then convey this information to higher brain structures, including the contralateral thalamus and cortex. Multiple regions — including the cingu-late cortex, hypothalamus, and periaqueductal gray matter — send descending modulating projections to the TNC. The ability of amiloride to block NP-induced CSDs and to show efficacy in rat and knockout mice models of trigeminovascular activation suggests multiple relevant sites of action. Amiloride blocks NP-induced CSD, which has been shown to increase c-fos in the TNC. Amiloride inhibits the neurogenic, dural, calcitonin gene-related peptide (CGRP)-mediated vasodilation, likely by inhibiting CGRP release, indicating a trigeminal primary afferent action. Amiloride also further modulates trigeminal nociceptive transmission by inhibiting TNC neuronal responses to cortical arterial stimulation. Amiloride’s anti-CSD actions are likely, at least in part, due to actions on the ASIC1 subunit and that ASIC1 may play a crucial role in CSD induction. Amiloride failed to inhibit K+-induced CSDs, which may indicate differences between experimental CSD induction models or, less likely, caution about the substance’s efficacy.

The ASIC1 subunit of acid-sensing ion channels may offer a new therapeutic target in migraine with aura, warranting the development of specifically targeted compounds. Amiloride reduced not only the frequency of aura, but decreased severity of pain, suggesting a possible beneficial effect in migraine without aura. The hope is that the investigation of this novel target will lead to randomized, placebo-controlled trials of patients with migraine, both with and without aura. Promising, trigeminovascular mechanism-derived targets that have failed to show efficacy (e.g., substance P antagonists) or safety (e.g., CGRP antagonists) teach us to temper initial enthusiasm. However, what many migraine sufferers consider to be one of the greatest medical discoveries of the 20th century, the triptans, was based on elucidation of another trigeminovascular mechanism derived target, the 5-HT receptor. Let us hope that blockage of this novel target, the acid-sensing ion channel, eventually will achieve the same success.