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Tau hyperphosphorylation induced by the anesthetic agent ketamine/xylazine involved the calmodulin‐dependent protein kinase II
Author(s) -
Hector Audrey,
McAnulty Christina,
PichéLemieux MaudeÉloïse,
AlvesPires Claire,
BuéeScherrer Valérie,
Buée Luc,
Brouillette Jonathan
Publication year - 2020
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/fj.201902135r
Subject(s) - hyperphosphorylation , ketamine , xylazine , anesthetic , kinase , pharmacology , phosphorylation , protein kinase a , chemistry , calmodulin , tau protein , gsk 3 , microbiology and biotechnology , medicine , biology , biochemistry , anesthesia , alzheimer's disease , enzyme , disease
Tau hyperphosphorylation is a major neuropathological hallmark of many neurodegenerative disorders such as Alzheimer’s disease. Several anesthetics have been shown previously to induced marked tau hyperphosphorylation. Although the ketamine/xylazine mixture is one of the most commonly used anesthetic agents in animal research and veterinary practice, the effect of this anesthetic agent on tau phosphorylation still remains to be determined. Here, we found that ketamine‐/xylazine‐induced a rapid and robust hyperphosphorylation of tau in a dose‐dependent manner under normothermic and hypothermic conditions in mice. When used together, ketamine and xylazine exerted a synergistic action on tau phosphorylation most strongly not only on epitopes S396 and S262, but also on other residues (T181, and S202/T205). We observed that activation of the calmodulin‐dependent protein kinase II (CaMKII) is the major upstream molecular event leading to tau hyperphosphorylation following ketamine/xylazine anesthesia in mice. Moreover, we observed that intracerebroventricular injection of the selective CaMKII inhibitor KN93 attenuated tau hyperphosphorylation. Since ketamine/xylazine also had a marked impact on other key molecular signaling pathways involving the MAP/microtubule affinity‐regulating kinase (MARK), extracellular signal‐regulated kinase (ERK), and glycogen synthase kinase‐3 (GSK3), our study calls for high caution and careful monitoring when using this anesthetic agent in laboratory animal settings across all fields of biological sciences in order to avoid artifactual results.