The type 1 cannabinoid receptor positive allosteric modulators GAT591 and GAT593 reduce spike-and-wave discharges in Genetic Absence Epilepsy Rats from Strasbourg

IBRO Neuroscience Reports

Quentin Greba¹  John G. Howland²  Orhan Yilmaz²  Stuart M. Cain²  Dan L. McElroy³  Sumanta Garai³  Andrew J. Roebuck³  Robert B. Laprairie⁴  Asher L. Brandt⁴  Ganesh A. Thakur⁵  Terrance P. Snutch⁵ 

[1] School of Liberal Arts, Yukon University, Whitehorse, YT Y1A 5K4, Canada;College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada;Department of Anatomy, Physiology, and Pharmacology, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada;Department of Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, United States;Michael Smith Laboratories and Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC V6T 1Z4, Canada;

关键词: Endocannabinoid system;    Childhood absence epilepsy;    GAERS;    Type 1 cannabinoid receptor;    Positive allosteric modulator;    Electroencephalogram;   

DOI  :  

来源: DOAJ

【 摘 要 】

Childhood absence epilepsy (CAE) is a non-convulsive seizure disorder primarily in children characterized by absence seizures. Absence seizures consist of 2.5–5 Hz spike-and-wave discharges (SWDs) detectable using electroencephalography (EEG). Current drug treatments are only partially effective and adverse side effects have spurred research into alternative treatment approaches. Recent research shows that positive allosteric modulation of the type-1 cannabinoid receptor (CB1R) reduces the frequency and duration of SWDs in Genetic Absence Epilepsy Rats from Strasbourg (GAERS), a model that recapitulates the SWDs in CAE. Here, we tested additional CB1R ago-PAMs, GAT591 and GAT593, for their potential in alleviating SWD activity in GAERS. In vitro experiments confirm that GAT591 and GAT593 exhibit increased potency and selectivity in cell cultures and behave as CB1R allosteric agonists and PAMs. To assess drug effects on SWDs, bilateral electrodes were surgically implanted in the somatosensory cortices of male GAERS and EEGs recorded for 4 h following systemic administration of GAT591 or GAT593 (1.0, 3.0 and 10.0 mg/kg). Both GAT591 and GAT593 dose-dependently reduced total SWD duration during the recording period. The greatest effect on SWD activity was observed at 10.0 mg/kg doses, with GAT591 and GAT593 reducing seizure duration by 36% and 34% respectively. Taken together, these results support the continued investigation of CB1R PAMs as a potential therapeutic to alleviate SWDs in absence epilepsy.

【 授权许可】

Unknown