NF-κB activation mediates LPS-or zymosan-induced hypotension and inflammation reversed by BAY61-3606, a selective Syk inhibitor, in rat models of septic and non-septic shock.

Abstract

We have previously demonstrated that the activation of the spleen tyrosine kinase (Syk)/inhibitory-κB (IκB)-α/nuclear factor-κB (NF-κB) p65 signalling pathway contributes to hypotension and inflammatory response in a rat models of zymosan (ZYM)-induced non-septic shock. The purpose of this study was to further examine the possible mechanism underlying the effect of inhibition of Syk by BAY61-3606 via NF-κB activity at the level of nuclear translocation regarding the production of vasodilator and proinflammatory mediators in lipopolysaccharide (LPS) (septic)- and ZYM (non-septic)-induced shock. Administration of LPS (10 mg/kg, ip) or ZYM (500 mg/kg, ip) to male Wistar rats decreased mean arterial pressure and increased heart rate that was associated with an increase in the activities of cyclooxygenase and nitric oxide synthase, tumour necrosis factor-α, and interleukin-8 levels, and NF-κB activation and nuclear translocation in sera and/or cardiovascular and renal tissues. BAY61-3606 (3 mg/kg, ip), the selective Syk inhibitor, given 1 hour after LPS- or ZYM injection reversed all the above-mentioned effects. These results suggest that Syk contributes to the LPS- or ZYM-induced hypotension and inflammation associated with transactivation of NF-κB in septic and non-septic shock.

• Authors: Seyhan Sahan-Firat, Meryem Temiz-Resitoglu, Demet Sinem Guden, Sefika Pinar Senol, Ayse Nihal Sari, Meltem Cil, Demet Unsal, Belma Korkmaz, Bahar Tunctan, Kafait U Malik, Cuneyt Kemal Buharalioglu
• Journal: Clinical and experimental pharmacology & physiology (Clin Exp Pharmacol Physiol) Vol. 46 Issue 2 Pg. 173-182 (02 2019) ISSN: 1440-1681 [Electronic] Australia
• PMID: 30347478 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 John Wiley & Sons Australia, Ltd.

Chemical References

• 2-(7-(3,4-dimethoxyphenyl)imidazo(1,2-c)pyrimidin-5-ylamino)nicotinamide
• Interleukin-8
• Lipopolysaccharides
• NF-kappa B
• Protein Kinase Inhibitors
• Pyrimidines
• Tumor Necrosis Factor-alpha
• NF-KappaB Inhibitor alpha
• Niacinamide
• Zymosan
• Nitric Oxide Synthase Type II
• Cyclooxygenase 2
• Ptgs2 protein, rat
• Syk Kinase

Topics

• Animals
• Cyclooxygenase 2 (metabolism)
• Disease Models, Animal
• Gene Expression Regulation (drug effects)
• Gene Expression Regulation, Enzymologic (drug effects)
• Hypotension (drug therapy, metabolism, pathology)
• Inflammation (drug therapy, metabolism, pathology)
• Interleukin-8 (metabolism)
• Lipopolysaccharides (pharmacology)
• Male
• NF-KappaB Inhibitor alpha (metabolism)
• NF-kappa B (metabolism)
• Niacinamide (analogs & derivatives, pharmacology, therapeutic use)
• Nitric Oxide Synthase Type II (metabolism)
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• Pyrimidines (pharmacology, therapeutic use)
• Rats
• Rats, Wistar
• Shock, Septic (drug therapy)
• Syk Kinase (antagonists & inhibitors)
• Tumor Necrosis Factor-alpha (metabolism)
• Zymosan (pharmacology)