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Interaction of ligands for the peroxisome proliferator-activated receptor gamma with the endocannabinoid system.
- Source :
- British Journal of Pharmacology; Aug2007, Vol. 151 Issue 8, p1343-1351, 9p, 5 Graphs
- Publication Year :
- 2007
-
Abstract
- <bold>Background and Purpose: </bold>There is good evidence that agents interacting with the endocannabinoid system in the body can also interact with the peroxisome proliferator-activated receptor gamma. The present study was designed to test whether the reverse is true, namely whether peroxisome proliferator-activated receptor gamma ligands have direct effects upon the activity of the endocannabinoid metabolizing enzyme fatty acid amide hydrolase.<bold>Experimental Approach: </bold>Fatty acid amide hydrolase activity was measured in rat brain homogenates, C6 glioma and RBL2H3 basophilic leukaemia cells. Cellular uptake of anandamide was also assessed in these cells.<bold>Key Results: </bold>Peroxisome proliferator-activated receptor gamma activators inhibited the metabolism of the endocannabinoid anandamide in rat brain homogenates with an order of potency MCC-555 > indomethacin approximately ciglitazone approximately 15-deoxy-Delta(12,14)-prostaglandin J(2) approximately pioglitazone > rosiglitazone > troglitazone. The antagonists BADGE, GW9662 and T0070907 were poor inhibitors of anandamide hydrolysis. The inhibition by ciglitazone was competitive and increased as the pH of the assay buffer was decreased; the K(i) value at pH 6.0 was 17 microM. In intact C6 glioma cells assayed at pH 6.2, significant inhibition of anandamide hydrolysis was seen at 3 microM ciglitazone, whereas 100 microM was required to produce significant inhibition at pH 7.4. Ciglitazone also interacted with monoacylglycerol lipase as well as with cannabinoid CB(1) and CB(2) receptors.<bold>Conclusions and Implications: </bold>Ciglitazone may be useful as a template for the design of novel dual action anti-inflammatory agents which are both inhibitors of fatty acid amide hydrolase and agonists at the peroxisome proliferator-activated receptor gamma. [ABSTRACT FROM AUTHOR]
- Subjects :
- LIGANDS (Biochemistry)
PEROXISOMES
FATTY acids
ANALYTICAL biochemistry
PHARMACOLOGY
DRUG metabolism
AMIDASES
ANIMAL experimentation
ANTI-inflammatory agents
BRAIN
BRAIN tumors
CELL lines
CELL receptors
COMPARATIVE studies
DRUGS
DOSE-effect relationship in pharmacology
ESTERASES
GLIOMAS
HYDROGEN-ion concentration
RESEARCH methodology
MEDICAL cooperation
NEUROTRANSMITTERS
PROTEINS
RATS
RESEARCH
DRUG development
EVALUATION research
ACUTE myeloid leukemia
THIAZOLIDINEDIONES
PHARMACODYNAMICS
Subjects
Details
- Language :
- English
- ISSN :
- 00071188
- Volume :
- 151
- Issue :
- 8
- Database :
- Complementary Index
- Journal :
- British Journal of Pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 26448338
- Full Text :
- https://doi.org/10.1038/sj.bjp.0707352