A Reversible and Selective Inhibitor of Monoacylglycerol Lipase Ameliorates Multiple Sclerosis

Hernández‐Torres, Gloria; Cipriano, Mariateresa; Hedén, Erika; Björklund, Emmelie; Canales, Ángeles; Zian, Debora; Feliú, Ana; Mecha, Miriam; Guaza, Carmen; Fowler, Christopher J.; Ortega‐Gutiérrez, Silvia; López‐Rodríguez, María L.

doi:10.1002/anie.201407807

Cited by 98 publications

(56 citation statements)

References 35 publications

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“…2013) and 1,3,4-oxadizol-3-ones (Käsnänen et al 2013) had shown MGL-inhibitor activity, but these classes generally showed also inhibition of other serine hydrolases like FAAH. Recently, a compound lacking reactive functionalities, CL6a (Tuccinardi et al 2014, Figure 4) has been described as a micromolar reversible inhibitor of MGL, addressing the catalytic pocket, similarly to what had been observed for the crystal structure with the non-covalent inhibitor ZYH (Figure 2), and a lipophilic ester (Hernandez-Torrs et al, 2014, Comp21 in Figure 4) has been shown to inhibit MGL with sub-micromolar potency.…”

Section: Mgl Inhibitorssupporting

confidence: 52%

Monoglyceride lipase: Structure and inhibitors

Scalvini

Piomelli

Mor

2016

Chemistry and Physics of Lipids

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Monoglyceride lipase (MGL), the main enzyme responsible for the hydrolytic deactivation of the endocannabinoid 2-arachidonoyl-sn-glycerol (2-AG), is an intracellular serine hydrolase that plays critical roles in many physiological and pathological processes, such as pain, inflammation, neuroprotection and cancer. The crystal structures of MGL that are currently available provide valuable information about how this enzyme might function and interact with site-directed small-molecule inhibitors. On the other hand, its conformational equilibria and the contribution of regulatory cysteine residues present within the substrate-binding pocket or on protein surface remain open issues. Several classes of MGL inhibitors have been developed, from early reversible ones, such as URB602 and pristimerin, to carbamoylating agents that react with the catalytic serine, such as JZL184 and more recent O-hexafluoroisopropyl carbamates. Other inhibitors that modulate MGL activity by interacting with conserved regulatory cysteines act through mechanisms that deserve to be more thoroughly investigated.

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Section: Mgl Inhibitorssupporting

confidence: 52%

Monoglyceride lipase: Structure and inhibitors

Scalvini

Piomelli

Mor

2016

Chemistry and Physics of Lipids

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“…In addition, 2-AG treatment also increased axonal ramification and, as observed for axonal elongation, this increase was prevented when neurons were pre-incubated for 1 h with the CB1R antagonists (Figure 1F). Moreover, we tested the effect of increasing endogenous levels of 2-AG by using UCM-03025, a monoacylglycerol lipase (MAGL) inhibitor that prevents 2-AG degradation (Hernández-Torres et al, 2014). Similar to what occurred when neurons were treated with 2-AG, MAGL inhibition also promoted axonal elongation (467.54 ± 25.35 μm for UCM 1 μM vs. 324.15 ± 14.42 μm in control neurons, Kruskal-Wallis, Dunn’s multiple comparisons test, p < 0.0001, Figure 1G).…”

Section: Resultsmentioning

confidence: 99%

“…UCM-03025 was a gift from María Luz Lopez Rodriguez laboratory (Complutense University, Madrid; Hernández-Torres et al, 2014). CB1R interference RNA and scrambled RNA plasmids (Origene) were a kind gift of Dr. Ismael Galve-Ropert (Universidad Complutense, Madrid) and were previously validated (Diaz-Alonso et al, 2012).…”

Section: Methodsmentioning

confidence: 99%

Cannabinoid Receptors Modulate Neuronal Morphology and AnkyrinG Density at the Axon Initial Segment

Tapia

Dominguez

Zhang

et al. 2017

Front. Cell. Neurosci.

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Neuronal polarization underlies the ability of neurons to integrate and transmit information. This process begins early in development with axon outgrowth, followed by dendritic growth and subsequent maturation. In between these two steps, the axon initial segment (AIS), a subcellular domain crucial for generating action potentials (APs) and maintaining the morphological and functional polarization, starts to develop. However, the cellular/molecular mechanisms and receptors involved in AIS initial development and maturation are mostly unknown. In this study, we have focused on the role of the type-1 cannabinoid receptor (CB1R), a highly abundant G-protein coupled receptor (GPCR) in the nervous system largely involved in different phases of neuronal development and differentiation. Although CB1R activity modulation has been related to changes in axons or dendrites, its possible role as a modulator of AIS development has not been yet explored. Here we analyzed the potential role of CB1R on neuronal morphology and AIS development using pharmacological and RNA interference approaches in cultured hippocampal neurons. CB1R inhibition, at a very early developmental stage, has no effect on axonal growth, yet CB1R activation can promote it. By contrast, subsequent dendritic growth is impaired by CB1R inhibition, which also reduces ankyrinG density at the AIS. Moreover, our data show a significant correlation between early dendritic growth and ankyrinG density. However, CB1R inhibition in later developmental stages after dendrites are formed only reduces ankyrinG accumulation at the AIS. In conclusion, our data suggest that neuronal CB1R basal activity plays a role in initial development of dendrites and indirectly in AIS proteins accumulation. Based on the lack of CB1R expression at the AIS, we hypothesize that CB1R mediated modulation of dendritic arbor size during early development indirectly determines the accumulation of ankyrinG and AIS development. Further studies will be necessary to determine which CB1R-dependent mechanisms can coordinate these two domains, and what may be the impact of these early developmental changes once neurons mature and are embedded in a functional brain network.

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“…Also, oligodendrocyte (the cell responsible for the production of myelin) excitotoxicity and white matter damage have been reported to be ameliorated by the administration of a MAG lipase inhibitor via enhancing endogenous levels of 2-AG, in contrast to the inhibition of FAAH, which had no effect in this animal model of MS (Bernal-Chico et al 2015). In another study, EAE was also ameliorated via the selective inhibition of MAG lipase (Hernández- Torres et al 2014).…”

Section: Experimental Evidencementioning

confidence: 92%

Endocannabinoids

2015

Handbook of Experimental Pharmacology

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A Reversible and Selective Inhibitor of Monoacylglycerol Lipase Ameliorates Multiple Sclerosis

Cited by 98 publications

References 35 publications

Monoglyceride lipase: Structure and inhibitors

Monoglyceride lipase: Structure and inhibitors

Cannabinoid Receptors Modulate Neuronal Morphology and AnkyrinG Density at the Axon Initial Segment

Endocannabinoids

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