Melatonin and Rapamycin Attenuate Isoflurane-Induced Cognitive Impairment Through Inhibition of Neuroinflammation by Suppressing the mTOR Signaling in the Hippocampus of Aged Mice

Yuan, Hui; Wu, Guorong; Zhai, Xiaojie; Lu, Bo; Meng, Bo; Chen, Junping

doi:10.3389/fnagi.2019.00314

Cited by 27 publications

(21 citation statements)

References 47 publications

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“…Lipopolysaccharide as cytokine inducer evoke peripheral and central immune activation in animal leading to neuroinflammation, accompanied by depressive-like behaviors (Sekio and Seki, 2015;Micheli et al, 2018;Zhao X. et al, 2019). In agreement with the previous findings (Raghavendra et al, 2000;Yu et al, 2017;Yuan et al, 2019), our results demonstrated depressive-like behaviors upon LPS-treatment, which was reversed by melatonin treatment. Besides, LPS dysregulates PI3K/Akt/GSk3b signalings, which plays a crucial role in survival, proliferation, and invasion by generating the second messengers (Guijarro-Munoz et al, 2014).…”

Section: Discussionsupporting

confidence: 92%

Melatonin Act as an Antidepressant via Attenuation of Neuroinflammation by Targeting Sirt1/Nrf2/HO-1 Signaling

Ali

Hao

Ullah

et al. 2020

Front. Mol. Neurosci.

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Physical or psychological stress can cause an immunologic imbalance that disturbs the central nervous system followed by neuroinflammation. The association between inflammation and depression has been widely studied in recent years, though the molecular mechanism is still largely unknown. Thus, targeting the signaling pathways that link stress to neuroinflammation might be a useful strategy against depression. The current study investigated the protective effect of melatonin against lipopolysaccharide (LPS)-induced neuroinflammation and depression. Our results showed that LPS treatment significantly induced depressive-like behavior in mice. Moreover, LPStreatment enhanced oxidative stress, pro-inflammatory cytokines including TNFα, IL-6, and IL-1β, NF-κB phosphorylation, and glial cell activation markers including GFAP and Iba-1 in the brain of mice. Melatonin treatment significantly abolished the effect of LPS, as indicated by improved depressive-like behaviors, reduced cytokines level, reduced oxidative stress, and normalized LPS-altered Sirt1, Nrf2, and HO-1 expression. However, the melatonin protective effects were reduced after luzindole administration. Collectively, it is concluded that melatonin receptor-dependently protects against LPSinduced depressive-like behaviors via counteracting LPS-induced neuroinflammation.

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Section: Discussionsupporting

confidence: 92%

Melatonin Act as an Antidepressant via Attenuation of Neuroinflammation by Targeting Sirt1/Nrf2/HO-1 Signaling

Ali

Hao

Ullah

et al. 2020

Front. Mol. Neurosci.

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“…Previous studies have suggested that the process of autophagy is negatively regulated by the activation of mTOR (Kim et al, 2011;Alers et al, 2012;Abada and Elazar, 2014). Numerous studies have shown that the role of mTOR signaling in protein homeostasis appears to be particularly important in learning and memory function (Bavley et al, 2018;Gao et al, 2018;Yuan et al, 2019). In the present study, we found that the levels of p-mTOR increased and Beclin-1 and LC3-II decreased in the hippocampus of mice undergone anesthesia/surgery.…”

Section: Discussionsupporting

confidence: 65%

Role of mTOR-Regulated Autophagy in Synaptic Plasticity Related Proteins Downregulation and the Reference Memory Deficits Induced by Anesthesia/Surgery in Aged Mice

Gao

Zhang

Zhou

et al. 2021

Front. Aging Neurosci.

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Postoperative cognitive dysfunction increases mortality and morbidity in perioperative patients and has become a major concern for patients and caregivers. Previous studies demonstrated that synaptic plasticity is closely related to cognitive function, anesthesia and surgery inhibit synaptic function. In central nervous system, autophagy is vital to synaptic plasticity, homeostasis of synapticproteins, synapse elimination, spine pruning, proper axon guidance, and when dysregulated, is associated with behavioral and memory functions disorders. The mammalian target of rapamycin (mTOR) negatively regulates the process of autophagy. This study aimed to explore whether rapamycin can ameliorate anesthesia/surgery-induced cognitive deficits by inhibiting mTOR, activating autophagy and rising synaptic plasticity-related proteins in the hippocampus. Aged C57BL/6J mice were used to establish POCD models with exploratory laparotomy under isoflurane anesthesia. The Morris Water Maze (MWM) was used to measure reference memory after anesthesia and surgery. The levels of mTOR phosphorylation (p-mTOR), Beclin-1 and LC3-II were examined on postoperative days 1, 3 and 7 by western blotting. The levels of synaptophysin (SYN) and postsynaptic density protein 95 (PSD-95) in the hippocampus were also examined by western blotting. Here we showed that anesthesia/surgery impaired reference memory and induced the activation of mTOR, decreased the expression of autophagy-related proteins such as Beclin-1 and LC3-II. A corresponding decline in the expression of neuronal/synaptic, plasticity-related proteins such as SYN and PSD-95 was also observed. Pretreating mice with rapamycin inhibited the activation of mTOR and restored autophagy function, also increased the expression of SYN and PSD-95. Furthermore, anesthesia/surgery-induced learning and memory deficits were also reversed by rapamycin pretreatment. In conclusion, anesthesia/surgery induced mTOR hyperactivation and autophagy impairments, and then reduced the levels of SYN and PSD-95 in the hippocampus. An mTOR inhibitor, rapamycin, ameliorated anesthesia/surgery-related cognitive impairments by inhibiting the mTOR activity, inducing activation of autophagy, enhancing SYN and PSD-95 expression.

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“…An experimental study showed that melatonin administration effectively prevented mild inflammation in high-fat diet-induced metabolic syndrome (MS) rats [ 35 ]. Through inhibition of neuroinflammation, melatonin can attenuate cognitive impairment induced by various pathological conditions [ 36 , 37 ]. Besides, the anti-inflammatory action of melatonin might be associated with its antiobesity effect.…”

Section: Discussionmentioning

confidence: 99%

Association of Serum Melatonin Level with Mild Cognitive Impairment in Type 2 Diabetic Patients: A Cross-Sectional Study

Zhang

Zhu

et al. 2021

International Journal of Endocrinology

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Objectives. Melatonin is an essential neuroendocrine hormone that participates in the regulation of sleep rhythm and cognitive function. This study aimed to determine serum melatonin levels with mild cognitive impairment (MCI) in patients with type 2 diabetes (T2DM). Methods. A total of 247 T2DM patients were recruited in this retrospective study and divided into 75 subjects with MCI and 172 with normal cognition. Cognitive function was evaluated by the Montreal Cognitive Assessment (MoCA). Their blood sample was examined for the level of melatonin and other biochemical parameters. Results. Melatonin concentration was decreased in MCI patients to non-MCI patients ( P < 0.001). Melatonin level was negatively correlated with age (r = −0.202; P = 0.001), diabetes duration (r = −0.282; P < 0.001), serum HbA1c (r = −0.195; P = 0.002), hs-CRP (r = −0.324; P < 0.001), and TSH (r = −0.184; P = 0.004) levels and positively correlated with MoCA score, serum HDL-C (r = 0.145; P < 0.001), FT3 (r = 0.241; P < 0.001), and FT4 (r = 0.169; P = 0.008) levels. The multivariable analysis indicated that fewer years of formal education, longer diabetes duration, higher serum HbA1c, higher serum hs-CRP, and lower serum melatonin are the predisposing factors for MCI. Conclusion. Lower melatonin level was associated with cognitive impairment in patients with T2DM. Melatonin might serve as a potential protective molecule against cognitive dysfunction in T2DM.

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Melatonin and Rapamycin Attenuate Isoflurane-Induced Cognitive Impairment Through Inhibition of Neuroinflammation by Suppressing the mTOR Signaling in the Hippocampus of Aged Mice

Cited by 27 publications

References 47 publications

Melatonin Act as an Antidepressant via Attenuation of Neuroinflammation by Targeting Sirt1/Nrf2/HO-1 Signaling

Melatonin Act as an Antidepressant via Attenuation of Neuroinflammation by Targeting Sirt1/Nrf2/HO-1 Signaling

Role of mTOR-Regulated Autophagy in Synaptic Plasticity Related Proteins Downregulation and the Reference Memory Deficits Induced by Anesthesia/Surgery in Aged Mice

Association of Serum Melatonin Level with Mild Cognitive Impairment in Type 2 Diabetic Patients: A Cross-Sectional Study

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