Effects of sevoflurane anesthesia on cognitive function and cholinergic signaling

In recent years, concerns have been raised regarding the potential negative impact of anesthetic drugs in postoperative cognitive dysfunction. This thesis is an attempt to contribute to the understanding of the underlying mechanisms. Previous animal studies have suggested that volatile anesthetics can cause long-lasting cognitive alterations in various settings. Based on the strong association between cholinergic function and cognitive performance, we have focused our studies on the long-term effects of volatile anesthetics on cholinergic neurotransmission.

By using a combination of laboratory animal experiments and molecular biology techniques in cultured cells, we have described effects of sevoflurane anesthesia on cognitive function and cholinergic signaling. Our studies on spontaneous exploratory behavior, anxiety, object memory and analyses of behavioral organization in mice show that for some aspects of cognitive performance sevoflurane can cause long-lasting effects, while other aspects are unaltered by anesthesia. We have shown that age and preexisting cholinergic dysfunction are factors that influence the results. A normal cholinergic system, as represented by young wild type mice, seems to protect from behavioral alterations after anesthesia.

Our results suggest that sevoflurane causes a sustained attenuation in acetylcholine-induced phosphorylation of important intracellular kinases. We have linked our findings to signaling via muscarinic acetylcholine receptors, and we have also demonstrated that the effect of sevoflurane is not likely exerted by reducing the receptor population on the cell surface, nor by altering the total amount of receptor protein available for ligand binding.

The overall conclusion from the results of this thesis is that under certain experimental conditions, sevoflurane induces long-lasting alterations both in animal behavior and in cellular signaling.

List of scientific papers

I. Wiklund A, Granon S, Cloëz-Tayarani I, Faure P, le Sourd AM, Sundman E, Changeux JP, Eriksson LI. Sevoflurane anesthesia alters exploratory and anxiety-like behavior in mice lacking the beta2 nicotinic acetylcholine receptor subunit. Anesthesiology. 2008 Nov;109(5):790-8.
https://doi.org/10.1097/ALN.0b013e31818a379a

II. Wiklund A, Granon S, Faure P, Sundman E, Changeux JP, Eriksson LI. Object memory in young and aged mice after sevoflurane anaesthesia. Neuroreport. 2009 Oct 28;20(16):1419-23.
https://doi.org/10.1097/WNR.0b013e328330cd2b

III. Wiklund A, Gustavsson D, Ebberyd A, Sundman E, Schulte G, Jonsson Fagerlund M, Eriksson L.I. Prolonged attenuation of acetylcholine-induced phosphorylation of ERK 1/2 in PC12 cells following sevoflurane exposure. [Submitted]

IV. Wiklund A, Gustavsson D, Ebberyd A, Mkrtchian S, Jonsson Fagerlund M, Eriksson L.I, Schulte G. Muscarinic acetylcholine receptor gene expression profile in PC12 cells following sevoflurane exposure. [Manuscript]