Interaction of ligands for the peroxisome proliferator-activated receptor gamma with the endocannabinoid system.
OBJECTIVE
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.


METHODS
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.


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 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.


CONCLUSIONS
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.
Lenman
A
A
Department of Pharmacology and Clinical Neuroscience, Umeå University, SE-901 87 Umeå, Sweden.
Fowler
C J
CJ
D000581:Amidohydrolases / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001921:Brain / Q000201:enzymology; D001932:Brain Neoplasms / Q000201:enzymology / Q000473:pathology; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D063388:Endocannabinoids; D005910:Glioma / Q000201:enzymology / Q000473:pathology; D006863:Hydrogen-Ion Concentration; D015471:Leukemia, Basophilic, Acute / Q000201:enzymology / Q000473:pathology; D008024:Ligands; D008297:Male; D008994:Monoacylglycerol Lipases / Q000187:drug effects / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000187:drug effects / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000187:drug effects / Q000378:metabolism; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000494:pharmacology; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D000893:Anti-Inflammatory Agents; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D008024:Ligands; D008994:Monoacylglycerol Lipases; D047495:PPAR gamma; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D045162:Thiazolidinediones; D000099252:Fatty Acid Amide Hydrolases; C039671:ciglitazone