Interaction of ligands for the peroxisome proliferator-activated receptor c 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 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. 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 gamma activators inhibited the metabolism of the endocannabinoid anandamide in rat brain homogenates with an order of potency MCC-555 > indomethacin approximate to ciglitazone approximate to 15-deoxy-Delta(12,14)-prostaglandin J(2) approximate to 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 mu M. In intact C6 glioma cells assayed at pH 6.2, significant inhibition of anandamide hydrolysis was seen at 3 mu M ciglitazone, whereas 100 mu M was required to produce significant inhibition at pH 7.4. Ciglitazone also interacted with monoacylglycerol lipase as well as with cannabinoid CB1 and CB2 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 gamma.