Pharmacological blockade of 2-AG degradation ameliorates clinical, neuroinflammatory and synaptic alterations in experimental autoimmune encephalomyelitis

The endocannabinoid system (ECS) is critically involved in the pathophysiology of Multiple Sclerosis (MS), a neuroinflammatory and neurodegenerative disease of the central nervous system (CNS). Over the past decade, researchers have extensively studied the neuroprotective and anti-inflammatory effec...

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Published in:Neuropharmacology 2024-07, Vol.252, p.109940-109940, Article 109940
Main Authors: Guadalupi, Livia, Mandolesi, Georgia, Vanni, Valentina, Balletta, Sara, Caioli, Silvia, Pavlovic, Anto, De Vito, Francesca, Fresegna, Diego, Sanna, Krizia, Vitiello, Laura, Nencini, Monica, Tartacca, Alice, Mariani, Fabrizio, Rovella, Valentina, Schippling, Sven, Ruf, Iris, Collin, Ludovic, Centonze, Diego, Musella, Alessandra
Format: Article
Language:English
Subjects:
Animals
Arachidonic Acids - metabolism
Arachidonic Acids - pharmacology
Encephalomyelitis, Autoimmune, Experimental - drug therapy
Encephalomyelitis, Autoimmune, Experimental - metabolism
Encephalomyelitis, Autoimmune, Experimental - pathology
Endocannabinoid
Endocannabinoids - metabolism
Excitotoxicity
Female
Glycerides - metabolism
Mice
Mice, Inbred C57BL
Microglia
Microglia - drug effects
Microglia - metabolism
Monoacylglycerol lipase (MAGL)
Monoacylglycerol Lipases - antagonists & inhibitors
Monoacylglycerol Lipases - metabolism
Multiple sclerosis (MS)
Neuroinflammation
Neuroinflammatory Diseases - drug therapy
Neuroinflammatory Diseases - metabolism
Synapses - drug effects
Synapses - metabolism
Synapses - pathology
Synaptic transmission
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Summary:The endocannabinoid system (ECS) is critically involved in the pathophysiology of Multiple Sclerosis (MS), a neuroinflammatory and neurodegenerative disease of the central nervous system (CNS). Over the past decade, researchers have extensively studied the neuroprotective and anti-inflammatory effects of the ECS. Inhibiting the degradation of the endocannabinoid 2-arachidonoylglycerol (2-AG) has emerged as a promising strategy to mitigate brain damage in MS. In this study, we investigated the effects of a novel reversible MAGL inhibitor (MAGLi 432) on C57/BL6 female mice with experimental autoimmune encephalomyelitis (EAE), a model of MS. We assessed its implications on motor disability, neuroinflammation, and synaptic dysfunction. Systemic in vivo treatment with MAGLi 432 resulted in a less severe EAE disease, accompanied by increased 2-AG levels and decreased levels of arachidonic acid (AA) and prostaglandins (PGs) in the brain. Additionally, MAGLi 432 reduced both astrogliosis and microgliosis, as evidenced by decreased microglia/macrophage density and a less reactive morphology. Flow cytometry analysis further revealed fewer infiltrating CD45+ and CD3+ cells in the brains of MAGLi 432-treated EAE mice. Finally, MAGLi treatment counteracted the striatal synaptic hyperexcitability promoted by EAE neuroinflammation. In conclusion, MAGL inhibition significantly ameliorated EAE clinical disability and striatal inflammatory synaptopathy through potent anti-inflammatory effects. These findings provide new mechanistic insights into the neuroprotective role of the ECS during neuroinflammation and highlight the therapeutic potential of MAGLi-based drugs in mitigating MS-related inflammatory and neurodegenerative brain damage. [Display omitted] •Intraperitoneal treatment with MAGLi 432 (inhibitor of 2-AG degradation) induces the increase of 2-AG levels into the brain.•In vivo treatment with MAGLi 432 ameliorates the clinical score and the synaptic hyperexcitability typical of EAE.•MAGLi 432 ameliorates striatal inflammation and attenuates the infiltration of CD45+ and CD3+ cells in the brain of EAE mice.
ISSN:0028-3908
1873-7064
DOI:10.1016/j.neuropharm.2024.109940