Manipulating endocannabinoids degradation does not lead to good myelin repair

ProfG tweeted "I wonder what the MouseDoctor will have to say about this study? #ResearchSpeak Deregulation of the endocannabinoid system and therapeutic potential of ABHD6 blockade in the cuprizone model of demyelination. "
The answer is....I have not got much to say on this one. 

There are two main endocannabinoids that bind to the cannabinoid receptors. One is anandamide and the other is 2-arachidonoyl glycerol, or 2-AG. There are degraded by enzymes. 

Fatty acid amide hydrolase (FAAH) degrades anadamide. However, a FAAH inhibitor had an off-target effect and killed some people in a trial. Therefore, I doubt there are people rushing to do trials with these types of drug. Other side effects could be a fatty liver and low sperm count.

2-AG is more complex in how it gets degraded. Mono aceyl glycerol lipase (MAGLipase) degrades about 85% of  2-AG, FAAH about 1% and the rest is degraded by ABHD6 and ABHD12

In this paper they report that there is limited damage after administration of an ABHD6 inhibitor in a myelin repair paradigmn.

So this should increase 2-AG in areas where ABHD6 may be involved in break down and they suggest there is some protection.

This does not surprise me as the endocannabinoids are cytoprotective (protects cells) and they are involved in lipid metabolism, so you will find them in oligodendrocytes and other cells. 

In this study they do not find much influence on the oligodendrocytes but as can be seen by BrainSeq oligodendrocytes may express more of the other enzymes. 

Blocking a lipid degradation enzyme was not good enough as a promoter of myelin formation, so it is back to the drawing board.

Is this surprising?

Deregulation of the endocannabinoid system and therapeutic potential of ABHD6 blockade in the cuprizone model of demyelination.Manterola A, Bernal-Chico A, Cipriani R, Canedo-Antelo M, Moreno-García Á, Martín-Fontecha M, Pérez-Cerdá F, Victoria Sánchez-Gómez M, Ortega-Gutiérrez S, Mark Brown J, Hsu KL, Cravatt B, Matute C, Mato S.Biochem Pharmacol. 2018 . pii: S0006-2952(18)30311-3. 

Multiple sclerosis (MS) is a chronic demyelinating disease of unknown etiology in which tissue pathology suggests both immune-dependent attacks to oligodendroglia and primary oligodendrocyte demise. The endocannabinoid system has been crucially involved in the control of autoimmune demyelination and cannabinoid-based therapies exhibit therapeutic potential, but also limitations, in MS patients. In this context, growing evidence suggests that targeting the hydrolysis of the main endocannabinoid 2-arachidonoylglycerol (2-AG) may offer a more favorable benefit-to-risk balance in MS than existing cannabinoid medicines. Here we evaluated the modulation of endocannabinoid signaling and the therapeutic potential of targeting the 2-AG hydrolytic enzyme alpha/beta-hydrolase domain-containing 6 (ABHD6) in the cuprizone model of non-immune dependent demyelination. The concentrations of N-arachidonoylethanolamine (anandamide, AEA) and its congener N-palmitoylethanolamine (PEA) were reduced following 6 weeks of cuprizone feeding. Deregulation of AEA and PEA levels was not due to differences in the expression of the hydrolytic and biosynthetic enzymes fatty acid amide hydrolase and N-acylphosphatidylethanolamine-phospholipase D, respectively. Conversely, we measured elevated transcript levels of 2-AG hydrolytic enzymes monoacylglycerol lipase, ABHD6 and ABHD12 without changes in bulk 2-AG concentration. Upregulated CB1 and CB2 receptors expression, ascribed in part to microglia, was also detected in the brain of cuprizone-treated mice. Administration of an ABHD6 inhibitor partially attenuated myelin damage, astrogliosis and microglia/macrophage reactivity associated to cuprizone feeding. However, ABHD6 blockade was ineffective at engaging protective or differentiation promoting effects in oligodendrocyte cultures. These results show specific alterations of the endocannabinoid system and modest beneficial effects resulting from ABHD6 inactivation in a relevant model of primary demyelination.

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