GLC756 decreases TNF-alpha via an alpha2 and beta2 adrenoceptor related mechanism.

GLC756, a polyvalent anti-glaucoma drug showed in an endotoxin-induced-uveitis model (EIU) in rats a significant tumor necrosis factor-alpha (TNF-alpha) decrease in serum, indicating an additional anti-inflammatory potential of this compound. The receptors on which GLC756 binds (D1, D2, D4, alpha-1, alpha-2, 5-HT1A, 5-HT2C, 5-HT1D, 5-HT2 A, beta-1, and beta-2) were suggested to play a role. In order to identify a receptor type mediating the TNF-alpha lowering response, GLC756 was combined with various counteracting compounds (CP). For EIU, 8-week-old Lewis rats were intravenously injected at 160 microg lipopolysaccharide (LPS) from Salmonella typhimurium. Before EIU-induction animals received either one of the CP's or GLC756 alone, or GLC756 in combination with one of the CP's. TNF-alpha was determined in serum 2h post EIU-induction. Treatment with CP's alone indicated that agonistic effects on beta-2 adrenoceptors and antagonistic effects on alpha-2, 5-HT1A and 5-HT1D receptors resulted in statistically significant decreased TNF-alpha levels in comparison to the LPS-control group. In combination with GLC756, the counteracting CP's domitor (alpha-2 adrenoceptor agonist) and ICI 118551 (beta-2 adrenoceptor antagonist) inhibited completely the TNF-alpha decreasing effect of GLC756. Counteracting the 5-HT1A receptor with the 5-HT1A agonist 8-OH-DPAT could not prevent the TNF-alpha decreasing effect of GLC756. In conclusion, the antagonistic effect on alpha-2 adrenoceptors and the agonistic effect on beta-2 adrenoceptors were identified as mechanism for the TNF-alpha decreasing effect of GLC756.