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

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 receptor γ . The present study was designed to test whether the reverse is true, namely whether peroxisome proliferator‐activated receptor γ ligands 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 receptor γ activators inhibited the metabolism of the endocannabinoid anandamide in rat brain homogenates with an order of potency MCC‐555 > indomethacin ≈ ciglitazone ≈ 15‐deoxy‐Δ 12,14 ‐prostaglandin J 2 ≈ 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 μ M. In intact C6 glioma cells assayed at pH 6.2, significant inhibition of anandamide hydrolysis was seen at 3 μ M ciglitazone, whereas 100 μ M 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. 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 receptor γ . British Journal of Pharmacology (2007) 151 , 1343–1351; doi: 10.1038/sj.bjp.0707352