Broad impact of deleting endogenous cannabinoid hydrolyzing enzymes and the CB1 cannabinoid receptor on the endogenous cannabinoid-related lipidome in eight regions of the mouse brain

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• 作者：Emma Leishman^a ; Ben Cornett^b ; Karl Spork^b ; Alex Straiker^b ; Ken Mackie^a ; ^b ; Heather B. Bradshaw^a ; ^{hbbradsh@indiana.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：2-AG ; 2-arachidonoyl glycerol ; 2-LG ; 2-linoleoyl glycerol ; 2-OG ; 2-oleoyl glycerol ; AA ; arachidonic acid ; ABHD6 ; α/β hydrolase domain-6 ; ABHD12 ; α/β hydrolase domain-12 ; AEA ; N-arachidonoyl ethanolamine ; A-GABA ; N-arachidonoyl GABA ; A-Phe ; N-arachidonoyl phenylalanine ; A-Ser ; N-arachidonoyl serine ; A-Taur ; N-arachidonoyl taurine ; A-Tyr ; N-arachidonoyl tyrosine ; CER ; cerebellum ; COX ; cyclooxygenase ; CTX ; cortex ; CXCL2 ; chemokine (C-X-C motif) ligand 2 ; DEA ; N-docosahexaenoyl ethanolamine ; DSE/I
• 刊名：Pharmacological Research
• 出版年：2016
• 出版时间：August 2016
• 年：2016
• 卷：110
• 期：Complete
• 页码：159-172
• 全文大小：1431 K

文摘

The enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) hydrolyze endogenous cannabinoids (eCBs), N-arachidonoyl ethanolamine (AEA) and 2-arachidonoyl glycerol (2-AG), respectively. These enzymes also metabolize eCB analogs such as lipoamines and 2-acyl glycerols, most of which are not ligands at CB₁. To test the hypothesis that deleting eCB hydrolyzing enzymes and CB₁ shifts lipid metabolism more broadly and impacts more families of eCB structural analogs, targeted lipidomics analyses were performed on FAAH KO, MAGL KO, and CB₁ KO mice and compared to WT controls in 8 brain regions.

Experimental approach

Methanolic extracts of discrete brain regions (brainstem, cerebellum, cortex, hippocampus, hypothalamus, midbrain, striatum and thalamus) were partially purified on C-18 solid-phase extraction columns. Over 70 lipids per sample were then analyzed with HPLC/MS/MS.

Key results

AEA and 2-AG were unaffected throughout the brain in CB₁ KO mice; however, there was an increase in the arachidonic acid (AA) metabolite, PGE₂ in the majority of brain areas. By contrast, PGE₂ and AA levels were significantly reduced throughout the brain in the MAGL KO corresponding to significant increases in 2-AG. No changes in AA or PGE₂ were seen throughout in the FAAH KO brain, despite significant increases in AEA, suggesting AA liberated by FAAH does not contribute to steady state levels of AA or PGE₂. Changes in the lipidome were not confined to the AA derivatives and showed regional variation in each of the eCB KO models.

Conclusions and implications

AEA and 2-AG hydrolyzing enzymes and the CB₁ receptor link the eCB system to broader lipid signaling networks in contrasting ways, potentially altering neurotransmission and behavior independently of cannabinoid receptor signaling.