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

Spyridakos D.; Zyganitidis I.; Petsangouraki S.; Konstantinou C.; Tsimpolis A.; Pelidou S.; Theodorakis K.; Malamas M.; Karagogeos D. · Biomolecules · 2026

**Background & Methods** This 2026 review examined the effects of AM11920, a dual monoacylglycerol lipase (MAGL) and α/β-hydrolase domain-containing protein 6 (ABHD6) inhibitor, on AMPA receptor-mediated excitotoxicity. The study employed both in vivo mouse models of cortical excitotoxicity and in vitro primary cell cultures (microglia, neurons, and oligodendrocyte precursor cells) to evaluate neuroprotective and anti-inflammatory mechanisms. **Key Findings** • In vivo administration of AM11920 reduced microglial and astrocytic reactivity, attenuated neuronal loss, and increased mature oligodendrocyte density at lesion sites. Chronic administration did not alter cannabinoid receptor type 1 (CB1R) protein expression levels. • In vitro, AM11920 suppressed microglial activation by decreasing CD68 expression and reducing interleukin-6 (IL-6) production, while protecting primary neurons and oligodendrocyte precursor cells from AMPA-induced cell death through CB1R-dependent mechanisms. • The dual inhibitor enhanced 2-arachidonoylglycerol (2-AG) signaling by blocking its enzymatic degradation, thereby amplifying endocannabinoid system-mediated neuroprotection and immunomodulation. **Dosage & Administration** Intraperitoneal (i.p.) administration of AM11920 was used in vivo; specific dosing parameters were not reported in the abstract provided. **Safety & Adverse Effects** Not reported. The abstract does not detail adverse effects or safety outcomes from AM11920 administration in either in vivo or in vitro experiments. **Evidence Quality** This review article synthesizes findings from preclinical models rather than clinical trials, representing lower evidence hierarchy. Limitations include the use of animal models that may not fully translate to human pathophysiology, reliance on primary cell cultures that lack complex neural network interactions, and potential species-specific differences in endocannabinoid metabolism. The lack of reported dosing details and adverse effect monitoring limits clinical applicability assessment. However, the dual mechanistic approach (inhibiting both MAGL and ABHD6) and multi-tissue evaluation (neuronal, glial, oligodendroglial) strengthen the biological rationale. Further preclinical dose-response studies and toxicology data, followed by human clinical trials, would be necessary to establish therapeutic viability for excitotoxic neurological disorders.

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