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Selective alpha7 nicotinic receptor activation improves survival in murine sepsis
Author(s) -
Pavlov Valentin A,
Ochani Mahendar,
Yang Lihong,
GallowitschPuerta Margot,
Ochani Kanta,
Lin Xinchun,
Czura Christopher J.,
LaRosa Greg,
Miller Edmund J.,
Tracey Kevin J.,
AlAbed Yousef
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.a1383
Sepsis is a lethal disorder, characterized by overwhelming systemic inflammation, mediated by TNF and other pro‐inflammatory cytokines. The vagus nerve attenuates systemic inflammation by inhibiting TNF through alpha7 nicotinic acetylcholine receptor (alpha7nAchR)‐mediated cholinergic signaling (Nature 421:384). Here we tested the hypothesis that alpha7nAchR activation by the selective agonist GTS‐21 could inhibit pro‐inflammatory cytokine release and improve survival in sepsis. In vitro GTS‐21 (1–100 mcM) dose‐dependently inhibited TNF and high mobility group box1 (HMGB1) release from endotoxin‐activated RAW 264.7 cells and suppressed NF‐kappaB activation. GTS‐21 (0.4–4 mg/kg, i.p.) dose‐dependently reduced serum TNF in endotoxemic mice. Drug (4 mg/kg, i.p.) treatment of endotoxemic mice for 3 consecutive days, resulted in 90% survival, as compared to 20% survival in controls (p<0.0001). GTS‐21 (4 mg/kg) significantly inhibited serum HMGB1 levels in mice with cecal ligation and puncture‐induced severe sepsis. GTS‐21 (4 mg/kg) treatment for 3 days, initiated 24h after the onset of sepsis, improved survival to 86% as compared to 43% in controls (P<0.0006). These findings demonstrate the therapeutic potential of selective alpha7nAchR activation in the treatment of sepsis. This study was funded by the IMR, NIH/NIGMS and Critical Therapeutics Inc.