Acid-sensing ion channel 1: A novel therapeutic target for migraine with aura

Centre for Neuroregeneration, University of Edinburgh, Edinburgh, United Kingdom.
Annals of Neurology (Impact Factor: 9.98). 10/2012; 72(4):559-63. DOI: 10.1002/ana.23653
Source: PubMed


Migraine with aura is a severe debilitating neurological disorder with few relatively specific therapeutic options.
We used amiloride, a blocker of epithelial sodium channels, to evaluate its pharmacological potential and explored the biology of a potential mechanism of action in well-established experimental models.
Amiloride was shown to block cortical spreading depression, the experimental correlate of aura, and inhibited trigeminal activation in in vivo migraine models, via an acid-sensing ion channel 1 mechanism. Remarkably, amiloride then demonstrated good clinical efficacy in a small open-labeled pilot study of patients, reducing aura and headache symptoms in 4 of 7 patients with otherwise intractable aura.
The observations here identify an entirely novel treatment strategy for migraine. ANN NEUROL 2012;72:559-563.

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Available from: Philip R Holland, Oct 01, 2015
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    • "Is NDPH a group of conditions that just happen to all start daily from onset and have little else in common including no shared underlying pathogenesis or is there some distinct cortical change that causes a daily headache from onset in all patients with NDPH although the mechanism by which this cortical phenomena is triggered may be different for individual patients (post-infectious, post-surgical for example)? If NDPH is a distinct all-encompassing syndrome like migraine then we need to define sub-forms that may have specific effective treatments such has been noted for migraine with aura for example [2]. The end result of this will be improved patient satisfaction. "
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    ABSTRACT: At present new daily persistent headache is just a group of conditions that are connected based on the temporal profile of their mode of onset. If new daily persistent headache is a true distinct syndrome like migraine then we need to start to define subtypes that have specific effective treatments such has been noted for migraine sub-forms. We present what we believe is the first recognized subtype of new daily persistent headache that which starts with a thunderclap headache onset. A patient presented with a 13 month history of a daily headache from onset which initiated as a thunderclap headache along with persistent acalculia. All neuroimaging studies for secondary causes were negative. Nimodipine rapidly and completely alleviated her headache and associated neurologic symptoms. We propose that this subtype of new daily persistent headache is caused by a very rapid increase in CSF tumor necrosis factor alpha levels leading to cerebral artery vasospasm with a subsequent thunderclap headache, then continuous or near continuous cerebral artery vasospasm leading to a persistent daily headache. Nimodipine which not only inhibits cerebral artery vasospasm but also tumor necrosis factor alpha production appears to be a specific treatment for this distinct subtype of new daily persistent headache.
    The Journal of Headache and Pain 12/2013; 14(1):100. DOI:10.1186/1129-2377-14-100 · 2.80 Impact Factor
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    • "A recent open-labeled pilot study on the Na+/H+ exchanger amiloride showed that it was clinically effective by reducing aura and headache symptoms in 4 of 7 patients with intractable MwA. Preclinical findings from the same study suggested that the drug blocks CSD and inhibits trigeminal activation in in vivo migraine models, via the acid-sensing ion channel (ASIC)1 mechanism [182]. This mechanism could be a novel therapeutic target for MwA. "
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    ABSTRACT: Spreading depression (SD) is a slowly propagating wave of neuronal and glial depolarization lasting a few minutes, that can develop within the cerebral cortex or other brain areas after electrical, mechanical or chemical depolarizing stimulations. Cortical SD (CSD) is considered the neurophysiological correlate of migraine aura. It is characterized by massive increases in both extracellular K+ and glutamate, as well as rises in intracellular Na+ and Ca2+. These ionic shifts produce slow direct current (DC) potential shifts that can be recorded extracellularly. Moreover, CSD is associated with changes in cortical parenchymal blood flow. CSD has been shown to be a common therapeutic target for currently prescribed migraine prophylactic drugs. Yet, no effects have been observed for the antiepileptic drugs carbamazepine and oxcarbazepine, consistent with their lack of efficacy on migraine. Some molecules of interest for migraine have been tested for their effect on CSD. Specifically, blocking CSD may play an enabling role for novel benzopyran derivative tonabersat in preventing migraine with aura. Additionally, calcitonin gene-related peptide (CGRP) antagonists have been recently reported to inhibit CSD, suggesting the contribution of CGRP receptor activation to the initiation and maintenance of CSD not only at the classic vascular sites, but also at a central neuronal level. Understanding what may be lying behind this contribution, would add further insights into the mechanisms of actions for “gepants”, which may be pivotal for the effectiveness of these drugs as anti-migraine agents. CSD models are useful tools for testing current and novel prophylactic drugs, providing knowledge on mechanisms of action relevant for migraine.
    The Journal of Headache and Pain 07/2013; 14(1):62. DOI:10.1186/1129-2377-14-62 · 2.80 Impact Factor
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    • "Lastly, it may be that prolonged dosing is required for an effect [10]. This is not the case for topiramate when used at a clinical dose [11] nor with recently identified effects on ASIC channels [12]. This may highlight the extent of what we are yet to learn about CSD. "
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    ABSTRACT: Background Migraine with aura is a complex neurological disorder modeled in animals by cortical spreading depression. It is less usual to find complete animal models for the disease so any opportunity to test a human effect back at the bench is welcome. Findings We report the case of a 24 year old woman who developed new onset episodic migraine with visual aura shortly after treatment initiation with the If ion channel blocker ivabradine for frequency control in hypertrophic cardiomyopathy. We studied whether ivabradine could alter cortical spreading depression in a suitable animal model. Sixteen rats received either ivabradine or saline, and the number of depolarization shifts and blood flow changes induced by cortical spreading depression were measured in both groups. No significant differences between the ivabradine and saline group were detected. Conclusions Ivabradine is an interesting substance since it is known to produce migraine-like phosphenes frequently and the patient we report developed de novo migraine with aura. However, we were unable to demonstrate that the drug influences the susceptibility of the brain to cortical spreading depression with acute administration. The combined data show the relationship of migraine aura to cortical spreading depression may have some nuances yet to be identified.
    The Journal of Headache and Pain 05/2013; 14(1):45. DOI:10.1186/1129-2377-14-45 · 2.80 Impact Factor
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