ABSTRACT
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.
Subject(s)
Anticonvulsants/pharmacology , Calcium Channels/metabolism , Seizures/drug therapy , Seizures/physiopathology , gamma-Aminobutyric Acid/analogs & derivatives , Animals , Calcium Channels/genetics , Disease Models, Animal , Dose-Response Relationship, Drug , Electroshock , Mice, 129 Strain , Mice, Inbred C57BL , Mice, Transgenic , Mutation, Missense , Phenytoin/pharmacology , Pregabalin , Species Specificity , Time Factors , gamma-Aminobutyric Acid/pharmacologyABSTRACT
Many noted clinicians and educators led the development of nurse anesthesia as a profession during the first half of the 20th century. Betty E. Lank, CRNA, a nurse anesthetist at Children's Hospital Boston, Massachusetts, for 34 years, devoted her professional life to the delivery and advancement of pediatric anesthesia. She is credited with many contributions including the first use of cyclopropane for infant anesthesia, developing pediatric-sized anesthesia masks and ventilation bags, and instituting standards for specialized postanesthesia recovery areas. Lank recorded her anesthesia experiences in various nursing publications and shared her knowledge with colleagues at professional meetings. Her accomplishments make her a notable figure in the early history of pediatric anesthesia, and her dedication helped forge the foundation for anesthesia at Children's Hospital Boston.
