title: GLC756 decreases TNF-alpha 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-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.
authors.affiliation: Department of Toxicology/Pathology, Novartis Pharma AG, MUT-2881.1.33, CH-4002 Basel, Switzerland. ulrich.laengle@novartis.com
authors.forename: Ulrich W
authors.initials: UW
authors.lastname: Laengle
authors.forename: Anne U
authors.initials: AU
authors.lastname: Trendelenburg
authors.forename: Rudolf
authors.initials: R
authors.lastname: Markstein
authors.forename: Vicente
authors.initials: V
authors.lastname: Nogues
authors.forename: Anne
authors.initials: A
authors.lastname: Provencher-Bollinger
authors.forename: Danielle
authors.initials: D
authors.lastname: Roman
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D058672:Adrenergic beta-2 Receptor Antagonists; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D004195:Disease Models, Animal; D008070:Lipopolysaccharides; D020926:Medetomidine / Q000494:pharmacology; D011412:Propanolamines / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew; D011941:Receptors, Adrenergic / Q000378:metabolism*; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors; D017448:Receptors, Dopamine D2 / Q000819:agonists; D058829:Serotonin 5-HT1 Receptor Antagonists; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis*; D014605:Uveitis / Q000378:metabolism*
chemical_list: D000316:Adrenergic alpha-Agonists; D058672:Adrenergic beta-2 Receptor Antagonists; D000319:Adrenergic beta-Antagonists; D008070:Lipopolysaccharides; D011412:Propanolamines; D011804:Quinolines; D011941:Receptors, Adrenergic; D018341:Receptors, Adrenergic, alpha-2; D018343:Receptors, Adrenergic, beta-2; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; C102871:SDZ GLC 756; D058829:Serotonin 5-HT1 Receptor Antagonists; D017366:Serotonin Receptor Agonists; D014409:Tumor Necrosis Factor-alpha; C026777:ICI 118551; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D020926:Medetomidine