Anticonvulsant activity of pregabalin in the maximal electroshock-induced seizure assay in α2δ1 (R217A) and α2δ2 (R279A) mouse mutants.
Pregabalin has been shown to have anticonvulsant, analgesic, and anxiolytic activity in animal models. Pregabalin binds with high affinity to the α2δ1 and α2δ2 subunits of voltage-gated calcium channels. In order to better understand the relative contribution that binding to either the α2δ1 or α2δ2 subunits confers on the anticonvulsant activity of pregabalin, we characterized the anticonvulsant activity of pregabalin in different wild-type (WT) and mutant mouse strains. Two targeted mouse mutants have been made in which either the α2δ1 subunit was mutated (arginine-to-alanine mutation at amino acid 217; R217A) or the α2δ2 subunit was mutated (arginine-to-alanine mutation at amino acid 279; R279A). These mutations in α2δ1 or α2δ2 render the subunits relatively insensitive to pregabalin binding. The anticonvulsant activity of pregabalin was assessed in these different mouse lines using the maximal electroshock-induced seizure (MES) model. Pregabalin reduced the percentage of seizures and increased the latency to seizure in the MES model in two parental mouse strains used to construct the mutants. Pregabalin also reduced the percentage of seizures and increased latency to seizure similarly in the α2δ2 (R279A) and WT littermate control mice. In contrast, pregabalin's anticonvulsant efficacy was significantly reduced in α2δ1 (R217A) mutants compared with WT littermate control mice. Phenytoin showed anticonvulsant activity across all WT and mutant mice. These data show that the anticonvulsant activity of pregabalin in the MES model requires binding to the α2δ1 subunit.
Pfizer Inc., Groton, CT, USA.
Susan
S
Lotarski
Melior Discovery, Exton, PA, USA.
Heather
H
Hain
Melior Discovery, Exton, PA, USA.
Jason
J
Peterson
Melior Discovery, Exton, PA, USA.
Stacey
S
Galvin
Melior Discovery, Exton, PA, USA.
Bryan
B
Strenkowski
Pfizer Inc., Groton, CT, USA.
Sean
S
Donevan
Pfizer Inc., Groton, CT, USA. Electronic address: jofford@umich.edu.
James
J
Offord
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004597:Electroshock; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020125:Mutation, Missense; D010672:Phenytoin / Q000494:pharmacology; D000069583:Pregabalin; D012640:Seizures / Q000188:drug therapy* / Q000503:physiopathology*; D013045:Species Specificity; D013997:Time Factors; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives* / Q000494:pharmacology
D000927:Anticonvulsants; C512066:CACNA2D1 protein, mouse; C486058:Cacna2d2 protein, mouse; D015220:Calcium Channels; D000069583:Pregabalin; D005680:gamma-Aminobutyric Acid; D010672:Phenytoin
Genetically modified mice; Maximal electroshock; Pregabalin; α(2)δ subunit mutation