Abstract
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.
Highlights
About 10–50% of patients receiving surgery under anesthesia demonstrate cognitive impairments occurring between 1 month and 1 year after surgery following treatment, termed postoperative cognitive dysfunction (POCD) (James, 2020)
We investigated whether long-term isoflurane inhalation induces cognitive deficits in adult mice and aggravates cognitive dysfunction in type 2 diabetes mellitus (T2DM) mice
Decrease insulin resistance and increased insulin sensitivity are the main mechanisms underlying the therapeutic effects of metformin (Giannarelli et al, 2003), so we examined changes in the insulin signaling pathway components insulin receptor substrates 1 and 2 (IRS1 and Insulin receptor substrates 2 (IRS2)), Akt, and GSK-3β among adult wild type (WT) mice and T2DM mice intraperitoneally pretreated with metformin 50 mg/kg or vehicle 1 h before long-term isoflurane or control inhalation
Summary
About 10–50% of patients receiving surgery under anesthesia demonstrate cognitive impairments occurring between 1 month and 1 year after surgery following treatment, termed postoperative cognitive dysfunction (POCD) (James, 2020). T2DM disrupts brain structure and function, especially in cognition-related regions, and increases the risks of both POCD and age-related cognitive decline compared to age-matched non-diabetics (Feinkohl et al, 2017; Sanjari Moghaddam et al, 2019). Our pilot study found that T2DM predicts POCD at 1 week after orthopedic surgery in elderly patients (over 60 years of age) and patients with T2DM had a 2.6-fold higher risk of POCD compared with patients without diabetes at 1 week after surgery (Supplementary Table 1). These observations suggest that the molecular signaling mechanisms disrupted in T2DM may contribute to POCD
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