urb937 and Inflammation

Radiation-induced lung injury (RILI) is a potentially life-threatening complication of radiotherapy. In the current study, we examined the potential protective effects of URB937, an inhibitor of fatty acid amide hydrolase using a mouse model of RILI. Briefly, male C57BL/6 mice received 16Gy irradiation to the thoracic region and then intraperitoneal injection of either URB937 (1 mg/kg) or vehicle every 2 days for 30 days. The extent of the lung injury was evaluated histologically at the end of the drug treatment as well as 3 months after the cessation of the treatment. The data showed URB937 attenuated radiation-induced lung injury and increased endocannabinoid concentration in lung tissue. Treatment with URB937 decreased leukocyte migration and inflammatory cytokines in bronchoalveolar lavage fluid and plasma at day 30. Histopathological examination revealed URB937 could restore lung structure and restrain inflammatory cell and fibroblast accumulation caused by irradiation in lung tissue. URB937 also decreased radiation-induced pro-inflammatory (e.g., interleukin-1β, interleukin-6, tumor necrosis factor-α) and pro-fibrotic cytokines (e.g., transforming growth factor-β1) level in lung tissue, as well as lipid peroxidation in the lungs. Mouse survival examined in a separate group of experimental subjects indicated that URB937 could prolong animal survival. Experiments using a mouse bearing Lewis lung carcinoma cells showed that URB937 does not affect irradiation-induced inhibition of tumor growth. These results suggest that inhibiting fatty acid amide hydrolase could ameliorate RILI without compromising the efficacy of irradiation on tumor control.

Topics: Amidohydrolases; Animals; Cannabinoids; Inflammation; Lung Injury; Male; Mice; Mice, Inbred C57BL; Radiation-Protective Agents; Radiotherapy; Survival; Thorax; Tumor Burden

URB937 is a peripherally restricted inhibitor of the anandamide-deactivating enzyme fatty-acid amide hydrolase (FAAH). Despite its limited access to the CNS, URB937 produces marked antinociceptive effects in rodents. URB937 is actively extruded from the CNS by the ATP-binding cassette (ABC) membrane transporter, Abcg2. Tissue Abcg2 levels are markedly different between males and females, and this transporter is known to limit the access of xenobiotics to the fetoplacental unit in gestating female rodents. In the present study, we investigated the tissue distribution and antinociceptive properties of URB937 in female mice and rats.. We studied the systemic disposition of URB937 in female mice and the antinociceptive effects of this compound in models of visceral (acetic acid-induced writhing) and inflammatory nociception (carrageenan-induced hyperalgesia) in female mice and rats. Furthermore, we evaluated the interaction of URB937 with the blood-placenta barrier in gestating mice and rats.. Abcg2 restricted the access of URB937 to the CNS of female mice and rats. Nevertheless, URB937 produced a high degree of antinociception in female mice and rats in models of visceral and inflammatory pain. Moreover, the compound displayed a restricted access to placental and fetal tissues in pregnant mice and rats.. Peripheral FAAH blockade with URB937 reduces nociception in female mice and rats, as previously shown for males of the same species. In female mice and rats, Abcg2 limits the access of URB937, not only to the CNS, but also to the fetoplacental unit. LINKED ARTICLES This article is part of a themed section on Cannabinoids. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.167.issue-8.

Topics: Acetic Acid; Amidohydrolases; Analgesics; Animals; Arachidonic Acids; ATP Binding Cassette Transporter, Subfamily G, Member 2; ATP-Binding Cassette Transporters; Cannabinoids; Carrageenan; Endocannabinoids; Enzyme Inhibitors; Female; Gene Expression Regulation; Inflammation; Male; Mice; Mice, Inbred C57BL; Pain; Placenta; Polyunsaturated Alkamides; Pregnancy; Rats; Rats, Sprague-Dawley; Sex Characteristics; Tissue Distribution