Prolonged attenuation of acetylcholine-induced phosphorylation of extracellular signal-regulated kinase 1/2 following sevoflurane exposure

作者：Wiklund A^*; Gustavsson D; Ebberyd A; Sundman E; Schulte G; Fagerlund M Jonsson; Eriksson L I

来源：Acta Anaesthesiologica Scandinavica, 2012, 56(5): 608-615.

DOI：10.1111/j.1399-6576.2011.02632.x

Background: Volatile anaesthetics are known to affect cholinergic receptors. Perturbation of cholinergic signalling can cause cognitive deficits. In this study, we wanted to evaluate acetylcholine-induced intracellular signalling following sevoflurane exposure.
Methods: Pheochromocytoma12 PC12 cells were exposed to 4.6% sevoflurane for 2 h. Subsequently, Western blotting was used to measure acetylcholine-induced phosphorylation of extracellular signal-regulated kinase 1/2 (ERK) 1/2 and basal Protein kinase B (AKT) phosphorylation.
Results: After exposure, acetylcholine-induced ERK 1/2 phosphorylation was reduced to 58 +/- 8% [95% confidence interval (CI): 38-77%, P = 0.003] compared with non-exposed controls. At 30 min after the end of sevoflurane administration [at 0.7% sevoflurane (0.102 mM)], ERK 1/2 phosphorylation remained reduced to 57 +/- 7% (95% CI: 39-74%, P = 0.001) and was at 120 min [0.02% (0.003 mM] still reduced to 63 +/- 10% (95% CI: 37-88%, P = 0.01), compared with control. At 360 min after exposure, acetylcholine-induced ERK 1/2 phosphorylation had recovered to 98 +/- 16% (95% CI: 45-152%, P = 0.98) compared with control. In contrast, immediately after sevoflurane expo-sure, basal AKT phosphorylation was increased by 228 +/- 37% (95% CI: 133-324%, P = 0.02) but had returned to control levels at 30 min after exposure, 172 +/- 67% (95% CI: 0-356%, P = 0.34).
Conclusion: Sevoflurane exposure has differential effects on different intracellular signalling pathways. On one hand, we observed a prolonged attenuation of acetylcholine-induced ERK 1/2 phosphorylation that persisted even when sevoflurane concentrations close to detection level. On the other hand, basal AKT phosphorylation was increased twofold during sevoflurane exposure, with a rapid return to baseline levels after exposure. We speculate that the effects on acetylcholine-induced intracellular signalling observed in our in vitro model could be of relevance also for cholinergic signalling in vivo following sevoflurane exposure.

• 出版日期2012-5