Suppression of cortical spreading depression in migraine prophylaxis

Authors

  • Cenk Ayata MD,

    1. Stroke and Neurovascular Regulation Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA
    2. Stroke Service and Neuroscience Intensive Care Unit, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA
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    • C.A. and H.J. contributed equally to this study.

  • Hongwei Jin PhD,

    1. Stroke and Neurovascular Regulation Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA
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    • C.A. and H.J. contributed equally to this study.

  • Chiho Kudo DDS, PhD,

    1. Stroke and Neurovascular Regulation Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA
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  • Turgay Dalkara MD, PhD,

    1. Department of Neurology, Faculty of Medicine, Hacettepe University, Ankara, Turkey
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  • Michael A. Moskowitz MD

    Corresponding author
    1. Stroke and Neurovascular Regulation Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA
    • Stroke and Neurovascular Regulation, Massachusetts General Hospital, 149 13th Street, Room 6403, Charlestown, MA 02129
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Abstract

Objective

Topiramate, valproate, propranolol, amitriptyline, and methysergide have been widely prescribed for migraine prophylaxis, but their mechanism or site of action is uncertain. Cortical spreading depression (CSD) has been implicated in migraine and as a headache trigger and can be evoked in experimental animals by electrical or chemical stimulation. We hypothesized that migraine prophylactic agents suppress CSD as a common mechanism of action.

Methods

Rats were treated either acutely or chronically over weeks and months, with one of the above migraine prophylactic drugs, vehicle, or D-propranolol, a clinically ineffective drug. The impact of treatment was determined on the frequency of evoked CSDs after topical potassium application or on the incremental cathodal stimulation threshold to evoke CSD.

Results

Chronic daily administration of migraine prophylactic drugs dose-dependently suppressed CSD frequency by 40 to 80% and increased the cathodal stimulation threshold, whereas acute treatment was ineffective. Longer treatment durations produced stronger CSD suppression. Chronic D-propranolol treatment did not differ from saline control.

Interpretation

Our data suggest that CSD provides a common therapeutic target for widely prescribed migraine prophylactic drugs. Assessing CSD threshold may prove useful for developing new prophylactic drugs and improving upon existing ones. Ann Neurol 2006

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