Advances in the understanding of the endogenous
cannabinoid system have led to several therapeutic indications for new classes of compounds that enhance cannabinergic responses.
Endocannabinoid levels are elevated during pathogenic conditions, and inhibitors of
endocannabinoid inactivation promote such on-demand responses. The
endocannabinoids anandamide and 2-arachidonoyl
glycerol have been implicated in protective signaling against excitotoxic episodes, including
seizures. To better understand modulatory pathways that can exploit such responses, we used the new generation compound
AM6701 that blocks both the
anandamide-deactivating
enzyme fatty acid amide hydrolase (FAAH) and the 2-arachidonoyl
glycerol-deactivating
enzyme monoacylglycerol lipase (MAGL) with equal potency. Also studied was the structural isomer AM6702 which is 44-fold more potent for inhibiting FAAH versus MAGL. When applied before and during
kainic acid (KA) exposure to cultured hippocampal slices,
AM6701 protected against the resulting excitotoxic events of
calpain-mediated cytoskeletal damage, loss of presynaptic and postsynaptic
proteins, and pyknotic changes in neurons. The equipotent inhibitor was more effective than its close relative AM6702 at protecting against the neurodegenerative cascade assessed in the slice model. In vivo,
AM6701 was also the more effective compound for reducing the severity of KA-induced
seizures and protecting against behavioral deficits linked to seizure damage. Corresponding with the behavioral improvements, cytoskeletal and synaptic protection was elicited by
AM6701, as found in the KA-treated hippocampal slice model. It is proposed that the influence of
AM6701 on FAAH and MAGL exerts a synergistic action on the
endocannabinoid system, thereby promoting the protective nature of cannabinergic signaling to offset excitotoxic
brain injury.