title: In vivo imaging reveals that pregabalin inhibits cortical spreading depression and propagation to subcortical brain structures.
abstract: 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 wild-type (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 CaV2.1 (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 CaV2.1 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.
authors.affiliation: Michael Smith Laboratories, University of British Columbia, Vancouver, BC V6T 1Z4, Canada; scain@msl.ubc.ca snutch@msl.ubc.ca.|Djavad Mowafaghian Center for Brain Health, University of British Columbia, Vancouver, BC V6T 1Z4, Canada.
authors.forename: Stuart M
authors.initials: SM
authors.lastname: Cain
authors.affiliation: UBC MRI Research Centre, University of British Columbia, Vancouver, BC V6T 1Z4, Canada.
authors.forename: Barry
authors.initials: B
authors.lastname: Bohnet
authors.affiliation: Djavad Mowafaghian Center for Brain Health, University of British Columbia, Vancouver, BC V6T 1Z4, Canada.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: LeDue
authors.affiliation: UBC MRI Research Centre, University of British Columbia, Vancouver, BC V6T 1Z4, Canada.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Yung
authors.affiliation: Michael Smith Laboratories, University of British Columbia, Vancouver, BC V6T 1Z4, Canada.|Djavad Mowafaghian Center for Brain Health, University of British Columbia, Vancouver, BC V6T 1Z4, Canada.
authors.forename: Esperanza
authors.initials: E
authors.lastname: Garcia
authors.affiliation: Michael Smith Laboratories, University of British Columbia, Vancouver, BC V6T 1Z4, Canada.|Djavad Mowafaghian Center for Brain Health, University of British Columbia, Vancouver, BC V6T 1Z4, Canada.
authors.forename: John R
authors.initials: JR
authors.lastname: Tyson
authors.affiliation: Michael Smith Laboratories, University of British Columbia, Vancouver, BC V6T 1Z4, Canada.|Djavad Mowafaghian Center for Brain Health, University of British Columbia, Vancouver, BC V6T 1Z4, Canada.
authors.forename: Sascha R A
authors.initials: SR
authors.lastname: Alles
authors.affiliation: Djavad Mowafaghian Center for Brain Health, University of British Columbia, Vancouver, BC V6T 1Z4, Canada.
authors.forename: Huili
authors.initials: H
authors.lastname: Han
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.|Department of Neurology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
authors.forename: Arn M J M
authors.initials: AM
authors.lastname: van den Maagdenberg
authors.affiliation: UBC MRI Research Centre, University of British Columbia, Vancouver, BC V6T 1Z4, Canada.
authors.forename: Piotr
authors.initials: P
authors.lastname: Kozlowski
authors.affiliation: Djavad Mowafaghian Center for Brain Health, University of British Columbia, Vancouver, BC V6T 1Z4, Canada.
authors.forename: Brian A
authors.initials: BA
authors.lastname: MacVicar
authors.affiliation: Michael Smith Laboratories, University of British Columbia, Vancouver, BC V6T 1Z4, Canada; scain@msl.ubc.ca snutch@msl.ubc.ca.|Djavad Mowafaghian Center for Brain Health, University of British Columbia, Vancouver, BC V6T 1Z4, Canada.
authors.forename: Terrance P
authors.initials: TP
authors.lastname: Snutch
mesh_terms: D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020864:Calcium Channels, N-Type / Q000235:genetics* / Q000378:metabolism; D002524:Cerebellar Ataxia / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D013181:Cortical Spreading Depression / Q000187:drug effects*; D038524:Diffusion Magnetic Resonance Imaging; D004195:Disease Models, Animal; D015870:Gene Expression; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008881:Migraine Disorders / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D020325:Migraine with Aura / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000069583:Pregabalin / Q000494:pharmacology*; D009435:Synaptic Transmission
chemical_list: D000700:Analgesics; D002121:Calcium Channel Blockers; D020864:Calcium Channels, N-Type; D000069583:Pregabalin
keywords: diffusion-weighted MRI; familial hemiplegic migraine type 1; gabapentinoids; migraine; voltage-gated calcium channel