Enhancement of Endocannabinoid Signaling by Dual MAGL/ABHD6 Inhibition Reduces Neurodegeneration and Neuro-Inflammation Following AMPA-Mediated Excitotoxicity

Excitotoxicity mediated by the α-amino-3-hydroxy-5-methyl-4 isoxazolepropionic acid receptor (AMPAR) is a major contributor to neuronal degeneration and inflammation in various neurological disorders. The endocannabinoid system (ECS), specifically through the endocannabinoid 2-arachidonoylglycerol (2-AG), exerts neuroprotective and anti-inflammatory effects, but these actions are limited by enzymatic degradation of 2-AG by monoacylglycerol lipase (MAGL) and α/β-hydrolase domain-containing protein 6 (ABHD6). In the present study we investigated the effects of AM11920, a dual MAGL/ABHD6 inhibitor, in a mouse model of AMPA-induced cortical excitotoxicity and in primary cultures of microglia, neurons, and oligodendrocyte precursor cells (OPCs). Intraperitoneal administration (i.p.) of AM11920 reduced microglial and astrocytic reactivity, attenuated neuronal loss, and increased the density of mature oligodendrocytes at the lesion site in vivo. Importantly, chronic administration of AM11920 in vivo did not affect cannabinoid receptor type 1 (CB1R) protein expression. In vitro, AM11920 suppressed microglial activation by reducing CD68 expression and attenuated interleukin-6 (IL-6) expression, while also protecting primary neurons and OPCs from AMPA-induced cell death via a CB1R-dependent mechanism. Collectively, these findings demonstrate that enhancing 2-AG signaling through dual MAGL/ABHD6 blockade provides neuroprotective and immunomodulatory effects and represents a promising therapeutic strategy against excitotoxic-induced neurodegeneration.