Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 114, Issue 9, Pages 2401-2406Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1614447114
Keywords
familial hemiplegic migraine type 1; migraine; diffusion-weighted MRI; voltage-gated calcium channel; gabapentinoids
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Funding
- Brain Canada Multi Investigator Research Initiative Grant
- Genome BC
- Michael Smith Foundation for Health Research
- Koerner Foundation
- Pfizer Neuropathic Pain Award
- Canadian Institutes of Health Research (CIHR) [10677]
- Canadian Research Chair (CRC) in Biotechnology and Genomics-Neurobiology
- BC Epilepsy Society
- CRC in Neuroscience
- CIHR [148397, 8545, 115121, TCE-117869]
- Fondation Leducq
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Migraine is characterized by severe headaches that can be preceded by an aura likely caused by cortical spreading depression (SD). The antiepileptic pregabalin (Lyrica) shows clinical promise for migraine therapy, although its efficacy and mechanism of action are unclear. As detected by diffusion-weighted MRI (DW-MRI) in wildtype (WT) mice, the acute systemic administration of pregabalin increased the threshold for SD initiation in vivo. In familial hemiplegic migraine type 1 mutant mice expressing human mutations (R192Q and S218L) in the Ca(V)2.1 (P/Q-type) calcium channel subunit, pregabalin slowed the speed of SD propagation in vivo. Acute systemic administration of pregabalin in vivo also selectively prevented the migration of SD into subcortical striatal and hippocampal regions in the R192Q strain that exhibits a milder phenotype and gain of Ca(V)2.1 channel function. At the cellular level, pregabalin inhibited glutamatergic synaptic transmission differentially in WT, R192Q, and S218L mice. The study describes a DW-MRI analysis method for tracking the progression of SD and provides support and a mechanism of action for pregabalin as a possible effective therapy in the treatment of migraine.
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