Interaction of ligands for the peroxisome proliferator‐activated receptor γ with the endocannabinoid system

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Abstract
Background and purpose: There is good evidence that agents interacting with the endocannabinoid system in the body can also interact with the peroxisome proliferator‐activated receptorγ. The present study was designed to test whether the reverse is true, namely whether peroxisome proliferator‐activated receptorγligands have direct effects upon the activity of the endocannabinoid metabolizing enzyme fatty acid amide hydrolase.Experimental approach: 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.Key results: Peroxisome proliferator‐activated receptorγactivators inhibited the metabolism of the endocannabinoid anandamide in rat brain homogenates with an order of potency MCC‐555 > indomethacin ≈ ciglitazone ≈ 15‐deoxy‐Δ12,14‐prostaglandin J2≈ 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 Kivalue at pH 6.0 was 17μM. In intact C6 glioma cells assayed at pH 6.2, significant inhibition of anandamide hydrolysis was seen at 3μM ciglitazone, whereas 100μM was required to produce significant inhibition at pH 7.4. Ciglitazone also interacted with monoacylglycerol lipase as well as with cannabinoid CB1and CB2receptors.Conclusions and implications: 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 receptorγ.British Journal of Pharmacology(2007)151, 1343–1351; doi:10.1038/sj.bjp.0707352

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