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

Abstract

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