Selective blockade of the hydrolysis of the endocannabinoid 2-arachidonoylglycerol impairs learning and memory performance while producing antinociceptive activity in rodents
Year: 2015
Type: article
Abstract: Monoacylglycerol lipase (MAGL) represents a primary degradation enzyme of the endogenous cannabinoid (eCB), 2-arachidonoyglycerol (2-AG). This study reports a potent covalent MAGL inhibitor, SAR127303. The compound behaves as a selective and competitive inhibitor of mouse and human MAGL, which potently elevates hippocampal levels of 2-AG in mice. In vivo, SAR127303 produces antinociceptive effects in assays of inflammatory and visceral pain. In addition, the drug alters learning performance in several assays related to episodic, working and spatial memory. Moreover, long term potentiation (LTP) of CA1 synaptic transmission and acetylcholine release in the hippocampus, two hallmarks of memory function, are both decreased by SAR127303. Although inactive in acute seizure tests, repeated administration of SAR127303 delays the acquisition and decreases kindled seizures in mice, indicating that the drug slows down epileptogenesis, a finding deserving further investigation to evaluate the potential of MAGL inhibitors as antiepileptics. However, the observation that 2-AG hydrolysis blockade alters learning and memory performance, suggests that such drugs may have limited value as therapeutic agents.
Source: Scientific Reports
DOI: 10.1038/srep07642
Authors: Guy Griebel, Philippe Pichat, Sandra Beeské, Thibaud Leroy, Nicolas Redon, Agnès Jacquet, Dominique Françon, Lionel Bert, Luc Even, Mati Lopez-Grancha, Tatiana Tolstykh, Fangxian Sun, Qunyan Yu, Scott Brittain, Heike Arlt, Timothy He, Bailin Zhang, Dmitri Wiederschain, Thomas Bertrand, Jacques Houtmann, Alexey Rak, François Vallée, Nadine Michot, Franck Augé, Véronique Menet, Olivier E. Bergis, Pascal George, Patrick Avenet, Vincent Mikol, Michel Didier, Johanna Escoubet
Institution: Sanofi (France)
Language: English
Subfield: Pharmacology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,690
OpenAlex ID: W2017486246