The corollaries of the obesity epidemic that plagues developed societies are malnutrition and resulting biochemical imbalances. Low levels of essential n-3 polyunsaturated fatty acids (n-3 PUFAs) have been linked to neuropsychiatric diseases, but the underlying synaptic alterations are mostly unknown. We found that lifelong n-3 PUFAs dietary insufficiency specifically ablates long-term synaptic depression mediated by endocannabinoids in the prelimbic prefrontal cortex and accumbens. In n-3-deficient mice, presynaptic cannabinoid CB(1) receptors (CB(1)Rs) normally responding to endocannabinoids were uncoupled from their effector G(i/o) proteins. Finally, the dietary-induced reduction of CB(1)R functions in mood-controlling structures was associated with impaired emotional behavior. These findings identify a plausible synaptic substrate for the behavioral alterations caused by the n-3 PUFAs deficiency that is often observed in western diets.

2-Mercaptobenzothiazole (MBT) is employed for the first time as a matrix for the analysis of lipids from tissue extracts using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. We demonstrate that the performance of MBT is superior to that of the matrixes commonly employed for lipids, due to its low vapor pressure, its low acidity, and the formation of small crystals, although because of the strong background at low m/z, it precludes detection of species below approximately 500 Da. This inconvenience can be partly overcome with the formation of Cs adducts. Using a polymer-based dual calibration, a mass accuracy of approximately 10 ppm in lipid extracts and of approximately 80 ppm in tissues is achieved. We present spectra from liver and brain lipid extracts where a large amount of lipid species is identified, in both positive and negative ion modes, with high reproducibility. In addition, the above-mentioned special properties of MBT allow its employment for imaging mass spectrometry. In the present work, images of brain and liver tissues showing different lipid species are presented, demonstrating the advantages of the employment of MBT.

The endocannabinoids 2-araquidonoylglycerol (2-AG) and anandamide (AEA) are bioactive lipids crucially involved in the regulation of brain function in basal and pathological conditions. Blockade of endocannabinoid metabolism has emerged as a promising therapeutic strategy for inflammatory diseases of the central nervous system, including myelin disorders such as multiple sclerosis. Nevertheless, the biological actions of endocannabinoid degradation inhibitors in oligodendrocytes and white matter tracts are still ill defined. Here we show that the selective monoacylglycerol lipase (MAGL) inhibitor JZL184 suppressed cell death by mild activation of AMPA receptors in oligodendrocytes in vitro, an effect that was mimicked by MAGL substrate 2-AG and by the second major endocannabinoid AEA, in a concentration-dependent manner, whereas inhibition of the AEA metabolizing enzyme fatty acid amide hydrolase with URB597 was devoid of effect. Pharmacological experiments suggested that oligodendrocyte protection from excitotoxicity resulting from MAGL blockade involved the activation of cannabinoid CB1 receptors and the reduction of AMPA-induced cytosolic calcium overload, mitochondrial membrane depolarization, and production of reactive oxygen species. Administration of JZL184 under a therapeutic regimen decreased clinical severity, prevented demyelination, and reduced inflammation in chronic experimental autoimmune encephalomyelitis. Furthermore, MAGL inactivation robustly preserved myelin integrity and suppressed microglial activation in the cuprizone-induced model of T-cell-independent demyelination. These findings suggest that MAGL blockade may be a useful strategy for the treatment of immune-dependent and -independent damage to the white matter.

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