Monoacylglycerol lipase inhibitor JZL184 reduces neuroinflammatory response in APdE9 mice and in adult mouse glial cells

Abstract

BackgroundRecently, the role of monoacylglycerol lipase (MAGL) as the principal regulator of simultaneous prostaglandin synthesis and endocannabinoid receptor activation in the CNS was demonstrated. To expand upon previously published research in the field, we observed the effect of the MAGL inhibitor JZL184 during the early-stage proinflammatory response and formation of beta-amyloid (Aβ) in the Alzheimer’s disease mouse model APdE9. We also investigated its effects in proinflammatory agent - induced astrocytes and microglia isolated from adult mice.FindingsTransgenic APdE9 mice (5 months old) were treated with JZL184 (40 mg/kg) or vehicle every day for 1 month. In vivo binding of the neuroinflammation-related, microglia-specific translocator protein (TSPO) targeting radioligand [18 F]GE-180 decreased slightly but statistically non-significantly in multiple brain areas compared to vehicle-treated mice. JZL184 treatment induced a significant decrease in expression levels of inflammation-induced, Iba1-immunoreactive microglia in the hippocampus (P < 0.01) and temporal and parietal (P < 0.05) cortices. JZL184 also induced a marked decrease in total Aβ burden in the temporal (P < 0.001) and parietal (P < 0.01) cortices and, to some extent, in the hippocampus. Adult microglial and astrocyte cultures pre-treated with JZL184 and then exposed to the neuroinflammation-inducing agents lipopolysaccharide (LPS), interferon-gamma (IFN-γ), and Aβ42 had significantly reduced proinflammatory responses compared to cells without JZL184 treatment.ConclusionsJZL184 decreased the proinflammatory reactions of microglia and reduced the total Aβ burden and its precursors in the APdE9 mouse model. It also reduced the proinflammatory responses of microglia and astrocytes isolated from adult mice.

A chemical proteomic atlas of brain serine hydrolases identifies cell type-specific pathways regulating neuroinflammation

“…In contrast, treatment of microglia with the MGLL inhibitor KML29 ( Chang et al, 2012 ) significantly lowered basal and LPS-induced prostaglandins ( Figure 2G ), as well as LPS-induced cytokine production ( Figure 2H ). These data are consistent with recent reports showing that MGLL-inactivated microglia are impaired in LPS-induced prostaglandin production and inflammatory responses ( Pihlaja et al, 2015 , Viader et al, 2015 ).…”

Metabolic Interplay between Astrocytes and Neurons Regulates Endocannabinoid Action

“…Consistent with the absence of changes in bulk brain lipids in MAGL-MKO mice, these animals displayed no alterations in LPS-induced prostaglandin and cytokines production or microglial activation ( Figure S4A-D ). We did find, however, that cultured MAGL –/– microglia were impaired in producing prostaglandins and also displayed substantially reduced in vitro inflammatory responses ( Figure S4E and F ), consistent with recent reports (Pihlaja et al, 2015). It is possible that incomplete removal of MAGL from all brain microglia in the MAGL-MKO mice ( Figure S1E ) prevented observation of a contribution from microglia-derived MAGL to neuroinflammatory responses in vivo .…”

Inhibition of 2-arachydonoylgycerol degradation attenuates orofacial neuropathic pain in trigeminal nerve-injured mice

“…Although our study design did not allow us to determine whether the MAGL-IR neurons observed in VC and C1-C2 areas were presynaptic or postsynaptic, previous electron microscopic studies reported MAGL expression on presynaptic neurons (64,65). MAGL was also found to be expressed in microglia and astrocytes and may be involved in inactivation of released ECs (66,67).…”