PMID- 34512303
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20210914
IS  - 1663-4365 (Print)
IS  - 1663-4365 (Electronic)
IS  - 1663-4365 (Linking)
VI  - 13
DP  - 2021
TI  - Amelioration of Hippocampal Insulin Resistance Reduces Tau Hyperphosphorylation 
      and Cognitive Decline Induced by Isoflurane in Mice.
PG  - 686506
LID - 10.3389/fnagi.2021.686506 [doi]
LID - 686506
AB  - General anesthetics can induce cognitive impairments and increase the risk of 
      Alzheimer's disease (AD). However, the underlying mechanisms are still unknown. 
      Our previous studies shown that long-term isoflurane exposure induced peripheral 
      and central insulin resistance (IR) in adult mice and aggravated IR in type 2 
      diabetes mellitus (T2DM) mice. Clinical and preclinical studies revealed an 
      association between impaired insulin signaling and tau pathology in AD and other 
      tauopathies. We investigated if alleviation of hippocampal IR by the antidiabetic 
      agent metformin could reduce tau hyperphosphorylation and cognitive decline 
      induced by isoflurane in mice. The effects of prolonged (6 h) isoflurane 
      anesthesia on hippocampal IR, hippocampal tau hyperphosphorylation, and 
      hippocampus-dependent cognitive function were evaluated in wild type (WT) adult 
      mice and the high-fat diet plus streptozotocin (HFD/STZ) mouse model of T2DM. 
      Here we shown that isoflurane and HFD/STZ dramatically and synergistically 
      induced hippocampal IR and fear memory impairment. Metformin pretreatment 
      strongly ameliorated hippocampal IR and cognitive dysfunction caused by 
      isoflurane in WT mice, but was less effective in T2DM mice. Isoflurane also 
      induced hippocampal tau hyperphosphorylation and metformin reversed this effect. 
      In addition, isoflurane significantly increased blood glucose levels in both 
      adult and T2DM mice, and metformin reversed this effect as well. Administration 
      of 25% glucose to metformin-pretreated mice induced hyperglycemia, but 
      surprisingly did not reverse the benefits of metformin on hippocampal insulin 
      signaling and fear memory following isoflurane anesthesia. Our findings show 
      hippocampal IR and tau hyperphosphorylation contribute to acute 
      isoflurane-induced cognitive dysfunction. Brief metformin treatment can mitigate 
      these effects through a mechanism independent of glycemic control. Future studies 
      are needed to investigate whether long-term metformin treatment can also prevent 
      T2DM-induced hippocampal IR and cognitive decline.
CI  - Copyright (c) 2021 Peng, Fang, Xu, Liu, Qian, Gong, Zhao, Ma, Xia and Gu.
FAU - Peng, Liangyu
AU  - Peng L
AD  - Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical 
      Department of Nanjing University, Nanjing, China.
FAU - Fang, Xin
AU  - Fang X
AD  - Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical 
      Department of Nanjing University, Nanjing, China.
FAU - Xu, Fangxia
AU  - Xu F
AD  - Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical 
      Department of Nanjing University, Nanjing, China.
FAU - Liu, Shuai
AU  - Liu S
AD  - Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical 
      Department of Nanjing University, Nanjing, China.
FAU - Qian, Yue
AU  - Qian Y
AD  - Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical 
      Department of Nanjing University, Nanjing, China.
FAU - Gong, Xiangdan
AU  - Gong X
AD  - Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical 
      Department of Nanjing University, Nanjing, China.
FAU - Zhao, Xin
AU  - Zhao X
AD  - Medical School of Nanjing University, Nanjing, China.
AD  - Department of Anesthesiology, Nanjing Stomatological Hospital, Medical School of 
      Nanjing University, Nanjing, China.
FAU - Ma, Zhengliang
AU  - Ma Z
AD  - Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical 
      Department of Nanjing University, Nanjing, China.
FAU - Xia, Tianjiao
AU  - Xia T
AD  - Medical School of Nanjing University, Nanjing, China.
AD  - Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, China.
FAU - Gu, Xiaoping
AU  - Gu X
AD  - Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical 
      Department of Nanjing University, Nanjing, China.
LA  - eng
PT  - Journal Article
DEP - 20210825
PL  - Switzerland
TA  - Front Aging Neurosci
JT  - Frontiers in aging neuroscience
JID - 101525824
PMC - PMC8425557
OTO - NOTNLM
OT  - blood glucose
OT  - cognitive impairment
OT  - hippocampus
OT  - insulin resistance
OT  - isoflurane
OT  - metformin
COIS- The authors declare that the research was conducted in the absence of any 
      commercial or financial relationships that could be construed as a potential 
      conflict of interest.
EDAT- 2021/09/14 06:00
MHDA- 2021/09/14 06:01
PMCR- 2021/01/01
CRDT- 2021/09/13 06:42
PHST- 2021/03/27 00:00 [received]
PHST- 2021/05/12 00:00 [accepted]
PHST- 2021/09/13 06:42 [entrez]
PHST- 2021/09/14 06:00 [pubmed]
PHST- 2021/09/14 06:01 [medline]
PHST- 2021/01/01 00:00 [pmc-release]
AID - 10.3389/fnagi.2021.686506 [doi]
PST - epublish
SO  - Front Aging Neurosci. 2021 Aug 25;13:686506. doi: 10.3389/fnagi.2021.686506. 
      eCollection 2021.