Tau hyperphosphorylation: A downstream effector of isoflurane-induced neuroinflammation in aged rodents
Introduction
Postoperative cognitive dysfunction (POCD) is characterized by a decline in cognitive performance after anesthesia and surgery [1], [2], [3]. The neurological symptom lasts for days to months or even remains permanent in the suffered. This complication can seriously reduce the patients’ life quality and increases the healthcare costs [2], [4]. Although many studies have focused on the etiology of POCD, the exact pathophysiological mechanism of POCD largely needs to be further elucidated. It is generally accepted that POCD is multi-factorial. Monk and colleague demonstrate that advanced age and duration of anesthesia are major factors contributed to POCD [5].
It is reported that more than 200 million patients receive surgery every year in the world [6]. As the global acceleration of population aging, the number of elderly people receiving anesthesia and surgery will dramatically increase [7], [8]. A large number of patients undergo their surgery under general anesthesia [9]. Therefore, there is growing concern on safety of general anesthesia in aged people in recent years. Accumulating data demonstrated that isoflurane, a commonly used volatile anesthetic in clinical practice and preclinical experiments, causes cognitive disorder in aged rodent animals [6], [10], [11], [12]. However, the mechanism involved in isoflurane-induced cognitive dysfunction needs to be further elucidated. The proposed mechanisms of isoflurane-induced cognitive impairment is most likely as a result of neuroinflammation [13], [14], [15], [16]. Isoflurane-induced neuroinflammation is transient which cannot explain why the cognitive dysfunction can exists weeks following isoflurane exposure [10], [15], [16]. Incredibly, several studies suggest that inhibition of the transient inflammation by minocycline improves the long-term cognitive function [13], [16], which implies that there might be some downstream effectors of neuroinflammatory response. Proinflammatory cytokines, such as tumor-necrosis-factor (TNF) α, Interleukin (IL)-1β and IL-6 can induce or exacerbate tau hyperphosphorylation which is known to contribute to chronic cognitive abnormality in AD models [17], [18], [19], [20], [21]. However, it is unclear whether isoflurane-induced upregulation of proinflammatory cytokines can trigger tau hyperphosphorylation and thus result in long-term memorial dysfunction.
Section snippets
The hypothesis
We hypothesize that isoflurane-induced neuroinflammation initiates the tau hyperphosphorylation which impairs the cognitive function in aged rodents. This relationship may shed light on the mechanism of isoflurane-induced cognitive impairment in the elderly and provide theoretical basis to explore preventive measurements.
Isoflurane anesthesia induces neuroinflammation in aged rodents
The exact mechanism of isoflurane-induced cognitive impairment is still unclear, but emerging studies suggest that neuroinflammation induced by isoflurane is closely associated with this deficit [13], [15], [16]. Overproduction of proinflammatory cytokines, such as TNFα, IL-1β and IL-6 in central nervous system or in peripheral tissues mediate neuroinflammation and induce sickness behavior in animal models, as the cytokines derived from peripheral immune cells can penetrate into brain via
Conclusions
In summary, isoflurane anesthesia induces excessive release of proinflammatory cytokines, transient neuroinflammation and long-lasting cognitive disorder in aged rodents. Tau hyperphosphorylation is possibly one downstream target of isoflurane-induced neuroinflammation, which is also the reasonable answer to the doubt that inhibiting transient isoflurane-induced neuroinflammatory response attenuates long-term cognitive dysfunction. As proinflammatory cytokines play bidirectional role in memory
Financial support
This work was supported by a grant from the National Natural Science Foundation of China (No. 81271233, No. 3124003).
Conflict of interest
All authors of this article promise there is no financial support and potential conflicts of interest for the work.
Acknowledgments
The present work was supported by a grant from the National Natural Science Foundation of China (No. 81271233, No. 31240030). Thanks for Mr. Honghui Yu’s generous help in revising the manuscript.
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