Anti-inflammatory effects of peripheral benzodiazepine receptor ligands intwo mouse models of inflammation

In vivo treatment of mice with peripheral benzodiazepine receptor ligands e xerts an inhibitory effect on the inflammatory response in two models of ac ute inflammation. In the first model, pretreatment of the animals (24 h) wi th 1-(2-chlorophenyl)-N-methyl-N( 1-methylpropyl)-3-isoquinoline carboxamid e (PK11195) and 7-chloro-5-(4-Chlorophenyl)-1,3-dihydro-1-methyl-2-H-1,4-be nzodiazepin-2 (Ro5-4864), at different doses (0.00001-10 mg/kg, i.p.) dose dependently inhibited the formation of mouse paw oedema induced by carragee nan with mean ID50, of 0.009 (95% confidence limits = 0.0076-0.013) and 0.0 4 (95% confidence Limits = 0.025-0.0086) mg/kg, respectively. Both ligands (0.1 mg/kg, i.p.) inhibited in the same way the mouse paw oedema induced by carrageenan in animals with and without adrenal glands. PK11195 and Ro5-48 64 (0.1 mg/kg, i.p.) inhibited the mouse paw oedema induced by several infl ammatory mediators. In the second model, the pretreatment (24 h) with perip heral benzodiazepine receptor ligands (0.1 mg/kg, i.p.) exerted an inhibito ry effect on neutrophil influx and produce a marked inhibition of carrageen an-produced interleukin-13 and interleukin-6 in pleural exudation. Our resu lts extend previous findings that peripheral benzodiazepine receptor is inv olved in the inflammatory response, and suggest that this action may be Lin ked to the action of different inflammatory mediators, probably mainly by t he inhibition of the release of pro-inflammatory cytokines. (C) 2000 Elsevi er Science B.V. All rights reserved.