Enhancement of Endocannabinoid Signaling by Dual MAGL/ABHD6 Inhibition Reduces Neurodegeneration and Neuro-Inflammation Following AMPA-Mediated Excitotoxicity
4 affiliations
- 1Department of Basic Science, School of Medicine, University of Crete, 71003 Heraklion, Greece
- 2Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology, 70013 Heraklion, Greece
- 3Department of Neurology, School of Medicine, University of Ioannina, 45110 Ioannina, Greece
- 4Center for Drug Discovery, Departments of Chemistry and Chemical Biology and Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, USA
Abstract
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.
Related
- Selective autophagy inhibition alleviates oxidative stress-associated neurodegeneration in an AD+CCH model
- Cholesteryl ester transfer protein (CETP) inhibition and high-density lipoprotein particle composition: consequences for atherogenesis and neurodegeneration
- Adipose tissue as a systemic modulator of brain aging: mechanistic links between metabolism, inflammation and neurodegeneration
- Multipronged enhancement of CART cell activity against ROR1 neoantigen by inhibition of H3K27 methyltransferase EZH2
- Endoplasmic Reticulum Autophagy Enhancement Alleviates Synaptic Plasticity Dysfunction and Ameliorates Cognitive Impairment in SAE Mice by Relieving STING‐Associated Inhibition of PKM2 Activity
BibTeX
@article{spyridakos2026enhancement,
title = {{Enhancement of Endocannabinoid Signaling by Dual MAGL/ABHD6 Inhibition Reduces Neurodegeneration and Neuro-Inflammation Following AMPA-Mediated Excitotoxicity}},
author = {Dimitris Spyridakos and Ioannis Zyganitidis and Sofia Petsangouraki and Chrystalla Konstantinou and Alexandros Tsimpolis and Sygkliti-Henrietta Pelidou and Kostas Theodorakis and Michael Malamas and Domna Karagogeos},
journal = {Biomolecules},
year = {2026},
month = oct,
doi = {10.3390/biom16101496},
url = {https://www.mdpi.com/2218-273X/16/10/1496},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Enhancement of Endocannabinoid Signaling by Dual MAGL/ABHD6 Inhibition Reduces Neurodegeneration and Neuro-Inflammation Following AMPA-Mediated Excitotoxicity
AU - Dimitris Spyridakos
AU - Ioannis Zyganitidis
AU - Sofia Petsangouraki
AU - Chrystalla Konstantinou
AU - Alexandros Tsimpolis
AU - Sygkliti-Henrietta Pelidou
AU - Kostas Theodorakis
AU - Michael Malamas
AU - Domna Karagogeos
PY - 2026
DA - 2026/10/01
JO - Biomolecules
DO - 10.3390/biom16101496
UR - https://www.mdpi.com/2218-273X/16/10/1496
AB - 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.
SN - 2218-273X
ER -