Document Detail


Selective inhibition of alpha/beta-hydrolase domain 6 attenuates neurodegeneration, alleviates blood brain barrier breakdown, and improves functional recovery in a mouse model of traumatic brain injury.
MedLine Citation:
PMID:  23151067     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
2-arachidonylglycerol (2-AG) is the most abundant endocannabinoid in the central nervous system and is elevated after brain injury. Because of its rapid hydrolysis, however, the compensatory and neuroprotective effect of 2-AG is short-lived. Although inhibition of monoacylglycerol lipase, a principal enzyme for 2-AG degradation, causes a robust increase of brain levels of 2-AG, it also leads to cannabinoid receptor desensitization and behavioral tolerance. Alpha/beta hydrolase domain 6 (ABHD6) is a novel 2-AG hydrolytic enzyme that accounts for a small portion of 2-AG hydrolysis, but its inhibition is believed to elevate the levels of 2-AG within the therapeutic window without causing side effect. Using a mouse model of traumatic brain injury (TBI), we found that post-insult chronic treatment with a selective ABHD6 inhibitor WWL70 improved motor coordination and working memory performance. WWL70 treatment reduced lesion volume in the cortex and neurodegeneration in the dendate gyrus. It also suppressed the expression of inducible nitric oxide synthase and cyclooxygenase-2 and enhanced the expression of arginase-1 in the ipsilateral cortex at 3 and 7 days post-TBI, suggesting microglia/macrophages shifted from M1 to M2 phenotypes after treatment. The blood-brain barrier dysfunction at 3 and 7 days post-TBI was dramatically reduced. Furthermore, the beneficial effects of WWL70 involved up-regulation and activation of cannabinoid type 1 and type 2 receptors and were attributable to the phosphorylation of the extracellular signal regulated kinase and the serine/threonine protein kinase AKT. This study indicates that the fine-tuning of 2-AG signaling by modulating ABHD6 activity can exert anti-inflammatory and neuroprotective effects in TBI.
Authors:
Flaubert Tchantchou; Yumin Zhang
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2013-04-05
Journal Detail:
Title:  Journal of neurotrauma     Volume:  30     ISSN:  1557-9042     ISO Abbreviation:  J. Neurotrauma     Publication Date:  2013 Apr 
Date Detail:
Created Date:  2013-04-29     Completed Date:  2013-11-26     Revised Date:  2014-04-01    
Medline Journal Info:
Nlm Unique ID:  8811626     Medline TA:  J Neurotrauma     Country:  United States    
Other Details:
Languages:  eng     Pagination:  565-79     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Arachidonic Acids / metabolism*
Biphenyl Compounds / pharmacology*
Blood-Brain Barrier* / pathology
Blotting, Western
Brain Injuries / enzymology*,  pathology
Carbamates / pharmacology*
Disease Models, Animal
Endocannabinoids / metabolism*
Enzyme Inhibitors / pharmacology*
Glycerides / metabolism*
Immunohistochemistry
Male
Mice
Mice, Inbred C57BL
Monoacylglycerol Lipases / antagonists & inhibitors*
Nerve Degeneration / metabolism,  pathology,  prevention & control*
Recovery of Function / drug effects*
Chemical
Reg. No./Substance:
0/Arachidonic Acids; 0/Biphenyl Compounds; 0/Carbamates; 0/Endocannabinoids; 0/Enzyme Inhibitors; 0/Glycerides; 0/N-methyl-N-((3-(4-pyridinyl)phenyl)methyl)-4'-(aminocarbonyl)(1,1'-biphenyl)-4-yl ester, carbamic acid; 53847-30-6/2-arachidonylglycerol; EC 3.1.1.23/ABHD6 protein, mouse; EC 3.1.1.23/Monoacylglycerol Lipases
Comments/Corrections

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