Suppression of cortical spreading depression in migraine prophylaxis

Ann Neurol. 2006 Apr;59(4):652-61. doi: 10.1002/ana.20778.


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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cortical Spreading Depression / drug effects
  • Cortical Spreading Depression / physiology*
  • Cortical Spreading Depression / radiation effects
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Drug Interactions
  • Electric Stimulation / adverse effects
  • Male
  • Migraine Disorders / etiology
  • Migraine Disorders / physiopathology*
  • Migraine Disorders / prevention & control*
  • Neuroprotective Agents / administration & dosage*
  • Physical Examination / methods
  • Potassium / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Time Factors


  • Neuroprotective Agents
  • Potassium