Selective α7-nicotinic acetylcholine receptor agonist GTS-21 improves survival in murine endotoxemia and severe sepsis
In: Critical care medicine, Jg. 35 (2007), Heft 4, S. 1139-1144
Online
academicJournal
- print, 28 ref
Zugriff:
Objective: Tumor necrosis factor and high mobility group box 1 are critical cytokine mediators of inflammation. The efferent vagus nerve inhibits cytokine release through α7-nicotinic acetylcholine receptor-mediated cholinergic signaling. Here we studied whether GTS-21, a selective a7-nicotinic acetylcholine receptor agonist, inhibits proinflammatory cytokines in vitro and in vivo and improves survival in murine endotoxemia and severe sepsis. Design: Randomized and controlled in vitro and in vivo study. Settings: Research laboratory and animal facility rooms. Subjects: RAW 264.7 cells and BALB/c mice treated with endotoxin or subjected to cecal ligation and puncture (CLP). Interventions: RAW 264.7 cells were exposed to endotoxin (4 ng/mL or 10 ng/mL) in the presence or absence of GTS-21 (1-100 μM), and tumor necrosis factor and high mobility group box 1 release and nuclear factor-κB activation were analyzed. Mice were treated with GTS-21 (0.4 mg/kg or 4 mg/kg, intraperitoneally) or saline 30 mins before endotoxin (6 mg/kg, intraperitoneally), and serum tumor necrosis factor was analyzed 1.5 hrs after the onset of endotoxemia. In survival experiments, mice were treated with GTS-21 (0.4 or 4.0 mg/kg, intraperitoneally) or saline 30 mins before and 6 hrs after endotoxin and then twice daily for 3 days. Severe sepsis was induced by CLP. Mice were treated with GTS-21 (4 mg/kg) or saline immediately and 6 hrs and 24 hrs after CLP, and serum high mobility group box 1 was analyzed 30 hrs after CLP. In survival experiments, GTS-21 (0.4 or 4 mg/kg) treatment was initiated 24 hrs after CLP and continued twice daily for 3 days. Measurements and Main Results: GTS-21 dose-dependently inhibited tumor necrosis factor and high mobility group box 1 release and nuclear factor-κB activation in vitro. GTS-21 (4 mg/ kg) significantly inhibited serum tumor necrosis factor during endotoxemia and improved survival (p <.0001). GTS-21 (4 mg/ kg) significantly inhibited serum high mobility group box 1 levels in CLP mice and improved survival (p <.0006). Conclusion: These findings are of interest for the development of a7-nicotinic acetylcholine receptor agonists as a new class of antiinflammatory therapeutics.
Titel: |
Selective α7-nicotinic acetylcholine receptor agonist GTS-21 improves survival in murine endotoxemia and severe sepsis
|
---|---|
Autor/in / Beteiligte Person: | PAVLOV, Valentin A ; OCHANI, Mahendar ; LAROSA, Gregory J ; MILLER, Edmund J ; TRACEY, Kevin J ; AL-ABED, Yousef ; YANG, Li-Hong ; GALLOWITSCH-PUERTA, Margot ; OCHANI, Kanta ; XINCHUN, LIN ; LEVI, Jelena ; PARRISH, William R ; ROSAS-BALLINA, Mauricio ; CZURA, Christopher J |
Link: | |
Zeitschrift: | Critical care medicine, Jg. 35 (2007), Heft 4, S. 1139-1144 |
Veröffentlichung: | Hagerstown, MD: Lippincott, 2007 |
Medientyp: | academicJournal |
Umfang: | print, 28 ref |
ISSN: | 0090-3493 (print) |
Schlagwort: |
|
Sonstiges: |
|