Sevoflurane may affect tau spread in the brain to promote Alzheimer’s disease pathology

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According to the press release of Massachusetts General Hospital sevoflurane may induce changes in the brain leading to Alzheimer disease.

During the development and progression of Alzheimer’s disease, a protein called tau accumulates and spreads in the brain. Understanding the mechanisms behind tau spread—and its consequences—may point to new prevention and treatment strategies for Alzheimer’s disease and other forms of dementia. New insights now come from research that was led by investigators at Massachusetts General Hospital (MGH) and involves an anesthetic known to affect cognitive function. The findings are published in Communications Biology.

The scientists note that inflammation plays an important role in Alzheimer’s disease, and microglia—immune cells that reside in the brain—are thought to be involved in this process by producing an inflammatory molecule called interleukin-6. To see if tau stimulates microglia to drive the development of Alzheimer’s disease pathology, the MGH investigators and their colleagues conducted experiments with an inhaled anesthetic called sevoflurane. Their previous work showed that sevoflurane can cause a change (specifically, phosphorylation, or the addition of phosphate) to tau that leads to cognitive impairment in mice. Other researchers have also found that sevoflurane and certain other anesthetics may affect cognitive function.

The group conducted experiments in mice and cells and discovered that sevoflurane causes tau to leave neurons and enter microglia, where it stimulates the cells’ production of interleukin-6, which in turn leads to inflammation and cognitive impairment. The trafficking of tau from neurons to microglia involves tau phosphorylation and membrane-bound carriers called extracellular vesicles that are released from cells.

The followers of the Cyclodextrin News blog may ask the question how CD complexation may influence the effect of sevoflurane on brain. Making a literature search in Scopus, 78 hits were obtained (18.05.2021) for the keywords: cyclodextrin + sevoflurane.

According to Shityakov et al. (2015) it is possible to prepare a sevoflurane-SBEβCD inclusion complex with high solubility and chemical stability which makes possible the development of i.v. formulation reducing the burden on lung by inhaled anesthetic. Cell viability tests did not detect any signs of toxicity of the complex on primary cerebral endothelial cells (pEND). The inclusion complex exhibited a significantly higher BBB permeation profile as compared with the reference substance (propranolol). Taking into account this high permeability together with the high lipophilicity of sevoflurane, a passive transcellular uptake route can be speculated. The high permeability also permits dose reduction.

Dong, Y., Liang, F., Huang, L. et al. The anesthetic sevoflurane induces tau trafficking from neurons to microglia. Commun Biol 4, 560 (2021).

Shityakov S., Puskás I., Pápai K., et al. Sevoflurane-Sulfobutylether-β-Cyclodextrin Complex: Preparation, Characterization, Cellular Toxicity, Molecular Modeling and Blood-Brain Barrier Transport Studies.
Molecules 20, 10264-10279 (2015). doi:10.3390/molecules200610264

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