Elsevier

Medical Hypotheses

Volume 82, Issue 1, January 2014, Pages 94-96
Medical Hypotheses

Tau hyperphosphorylation: A downstream effector of isoflurane-induced neuroinflammation in aged rodents

https://doi.org/10.1016/j.mehy.2013.11.015Get rights and content

Abstract

Postoperative cognitive dysfunction (POCD) is a severe neurological sequela after anesthesia and surgery. Multiple risk factors, such as advanced age and anesthesia duration, relevant to POCD have been made out, although the pathophysiological mechanisms of this complication need to be further elucidated. To date, there is a substantial body of evidence implicating that neuroinflammatory cytokines and the subsequent neuroinflammatory response contribute to the cognitive impairment in aged rodents exposed to isoflurane, a commonly used general anesthetic. Interestingly, this cognitive disorder is mitigated by anti-inflammatory agents even 14 days after isoflurane exposure. In addition, isoflurane-induced upregulation of neuroinflammatory cytokines is only limited within 48 h. So a first possibility to consider is a downstream effector of isoflurane-induced neuroinflammatory cytokines which contributes to the long-lasting cognitive dysfunction. In Alzheimer’s disease (AD) models, proinflammatory cytokines can induce tau hyperphosphorylation which is associated with synaptic abnormality and further cognitive impairment. It is unknown whether isoflurane-induced neuroinflammatory cytokines can trigger tau hyperphosphorylation. Taken together, we hypothesize that tau hyperphosphorylation is a downstream target of isoflurane-induced neuroinflammatory response and thus bridges the isoflurane-induced relatively transient neuroinflammatory process to the long-term cognitive impairment.

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.

References (42)

  • M. Morris et al.

    The many faces of tau

    Neuron

    (2011)
  • S.A. Small et al.

    Linking Abeta and tau in late-onset Alzheimer’s disease: a dual pathway hypothesis

    Neuron

    (2008)
  • R.E. Mrak et al.

    Glia and their cytokines in progression of neurodegeneration

    Neurobiol Aging

    (2005)
  • C.X. Wang et al.

    Involvement of inflammatory cytokines in central nervous system injury

    Prog Neurobiol

    (2002)
  • P. Williams-Russo et al.

    Cognitive effects after epidural vs general anesthesia in older adults. A randomized trial

    JAMA

    (1995)
  • L.S. Rasmussen

    Defining postoperative cognitive dysfunction

    Eur J Anaesthesiol

    (1998)
  • J. Steinmetz et al.

    Long-term consequences of postoperative cognitive dysfunction

    Anesthesiology

    (2009)
  • T.G. Monk et al.

    Predictors of cognitive dysfunction after major noncardiac surgery

    Anesthesiology

    (2008)
  • K.A. Hartholt et al.

    Societal consequences of falls in the older population: injuries, healthcare costs, and long-term reduced quality of life

    J Trauma

    (2011)
  • Z. Feng et al.

    China’s rapidly aging population creates policy challenges in shaping a viable long-term care system

    Health Aff (Millwood)

    (2012)
  • F. Clergue et al.

    French survey of anesthesia in 1996

    Anesthesiology

    (1999)
  • Cited by (15)

    • Dexmedetomidine suppresses the isoflurane-induced neurological damage by upregulating Heme Oxygenase-1 via activation of the mitogen-activated protein kinase kinase 1/extracellular regulated protein kinases 1/nuclear factor erythroid 2-related factor 2 axis in aged rats

      2022, Chemico-Biological Interactions
      Citation Excerpt :

      It has also been reported that endoplasmic reticulum stress and subsequent nerve cell apoptosis in the brain are factors leading to ISO-induced neurological damage [5,6]. Several anti-inflammatory agents are reported to alleviate the neuroinflammation and cognitive deficiency that can persist up to 14 days after ISO exposure [7]. Additionally, pretreatment with the dephosphoryaze inhibitor salubrinal also mitigated against isoflurane-induced neuroinflammation and CI [8].

    • The Role of Histone Acetylation in the Sevoflurane-induced Inhibition of Neurogenesis in the Hippocampi of Young Mice

      2020, Neuroscience
      Citation Excerpt :

      However, the molecular mechanisms by which sevoflurane inhibits neurogenesis are currently unclear. Studies have shown that epigenetic dysfunction is closely related to neurodegenerative diseases of the brain (Jakovcevski and Akbarian, 2012); the pathogenesis of these diseases is similar to that of anaesthesia-induced developmental neurotoxicity (Luo et al., 2014). Epigenetic markers can change during memory formation, ageing, or neurodegenerative diseases, and histone acetylation is a common epigenetic modification involved in learning and memory processes induced by environmental stimuli (Peixoto and Abel, 2013; Liang and Fang, 2016; Wu et al., 2018).

    • Isoflurane anesthesia exacerbates learning and memory impairment in zinc-deficient APP/PS1 transgenic mice

      2016, Neuropharmacology
      Citation Excerpt :

      Zn treatment improves learning and memory function in APP/PS1 mice, and prevents isoflurane-induced potential neurotoxicity. The commonly used general anesthetic isoflurane has been shown to impair cognitive function in aged rodents (Liu et al., 2013; Ni et al., 2015; Li et al., 2014a,b; Xie and Tanzi, 2006) and induce neurotoxicity including neuronal apoptosis (Xie et al., 2007; Xu et al., 2011a,b, 2012; Loop et al., 2005; Wei et al., 2005; Matsuoka et al., 2001; Kvolik et al., 2005), Aβ aggregation (Xie and Xu, 2013; Perucho et al., 2010; Xie et al., 2007; Dong et al., 2013), and tau hyperphosphorylation (Dong et al., 2012; Li et al., 2014a,b; Xu et al., 2012; Luo et al., 2014), which is associated with AD. Studies have shown that Zn deficiency contributed to the onset and progression of AD pathogenesis (Gower-Winter and Levenson, 2012; Lovell, 2009; Tyszka-Czochara et al., 2014) and a growing body of evidence suggests that AD patients are more likely to suffer from Zn deficiency (Baum et al., 2010; Brewer et al., 2010; Vural et al., 2010; Ventriglia et al., 2015).

    View all citing articles on Scopus
    View full text