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Postnatal ethanol exposure alters levels of 2‐arachidonylglycerol‐metabolizing enzymes and pharmacological inhibition of monoacylglycerol lipase does not cause neurodegeneration in neonatal mice
Author(s) -
Subbanna Shivakumar,
Psychoyos Delphine,
Xie Shan,
Basavarajappa Balapal S.
Publication year - 2015
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.13120
Subject(s) - monoacylglycerol lipase , diacylglycerol lipase , endocannabinoid system , neurodegeneration , ethanol , medicine , endocrinology , diacylglycerol kinase , chemistry , pharmacology , neuroscience , enzyme , biochemistry , biology , receptor , protein kinase c , disease
The consumption of ethanol by pregnant women may cause neurological abnormalities, affecting learning and memory processes in children, and are collectively described as fetal alcohol spectrum disorders. However, the molecular mechanisms underlying these changes are still poorly understood. In our previous studies, we found that ethanol treatment of postnatal day 7 (P7) mice significantly enhances the anandamide levels but not the 2‐arachidonylglycerol (2‐ AG ) levels and induces widespread neurodegeneration, but the reason for the lack of significant effects of ethanol on the 2‐ AG level is unknown. In this study, we examined developmental changes in diacylglycerol lipase‐α, β ( DAGL ‐α and β) and monoacylglycerol lipase ( MAGL ). We found that the levels of these proteins were significantly higher in adult brains compared to those detected early in brain development. Next, we examined the influence of P7 ethanol treatment on these enzymes, finding that it differentially altered the DAGL ‐α protein and mRNA levels but consistently enhanced those of the DAGL ‐β. Interestingly, the ethanol treatment enhanced MAGL protein and mRNA levels. Inhibition of MAGL with KML 29 failed to induce neurodegeneration in P7 mice. Collectively, these findings suggest that ethanol significantly activates DAGL ‐β and MAGL in the neonatal brain, resulting in no net change in 2‐ AG levels. The consumption of ethanol by pregnant women may cause neurological abnormalities, affecting learning and memory processes in children, and are collectively described as fetal alcohol spectrum disorders (FASDs). In our study, ethanol treatment of postnatal day 7 (P7) mice significantly enhanced the levels of the developmentally relevant endocannabinoids anandamide (AEA) but not 2‐arachidonylglycerol (2‐AG), and induced widespread neurodegeneration, yet the reason for the lack of effects of ethanol on the 2‐AG level is unknown. Here, the ethanol treatment of P7 mice causes the specific up‐regulation of AEA‐CB1R signaling over the 2‐AG‐CB1R pathway by the specific reorganization of the enzymes that synthesize (DAGL‐α/β) and degrade (MAGL) 2‐AG. This study demonstrates the neuro‐regulatory role of 2‐AG metabolizing enzymes in ethanol‐induced neurodegeneration in neonatal mice.