Melatonin prevents diabetes‐associated cognitive dysfunction from microglia‐mediated neuroinflammation by activating autophagy via TLR4/Akt/mTOR pathway

Cui, Yixin; Wang, Yilin; Ren, Jianmin; Lin, Peng; Song, Jia; He, Qin; Hu, Huiqing; Wang, Kexin; Sun, Yu

doi:10.1096/fj.202002247rr

Cited by 47 publications

(42 citation statements)

References 49 publications

(102 reference statements)

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“…In a highly-nutrient state, mTOR is activated [ 35 ], which would fit with the fructose diet nutrient overload. Melatonin’s role in the mTOR pathway was not clarified and both activation and inhibition of the mTOR pathway were described in different contexts [ 36 , 37 ]. Melatonin treatment increased the mTOR activity in the regular chow-fed hamsters ( Figure 3 C, p < 0.01), which might be fostering the mTOR role in storing nutrients [ 38 ].…”

Section: Resultsmentioning

confidence: 99%

“…However, in the fructose-fed hamsters displaying an inflammatory environment caused by impaired lipid handling, melatonin treatment inhibited mTOR activity ( Figure 3 C, p < 0.001). This latter result would suggest that melatonin stimulates protective mechanisms when present in a toxic scenario [ 37 ]. We also found an increased expression in the autophagy inductor Beclin 1 produced by a fructose diet ( Figure 3 C, p < 0.001) and a further increase after melatonin treatment in both diets ( Figure 3 C, p < 0.001).…”

Section: Resultsmentioning

confidence: 99%

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Melatonin Ameliorates Autophagy Impairment in a Metabolic Syndrome Model

et al. 2021

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Metabolic syndrome is a global health problem in adults and its prevalence among children and adolescents is rising. It is strongly linked to a lifestyle with high-caloric food, which causes obesity and lipid metabolism anomalies. Molecular damage due to excessive oxidative stress plays a major role during the development of metabolic syndrome complications. Among the different hormones, melatonin presents strong antioxidant properties, and it is used to treat metabolic diseases. However, there is not a consensus about its use as a metabolic syndrome treatment. The aim of this study was to identify melatonin effects in a metabolic syndrome model. Golden hamsters were fed with 60% fructose-enriched food to induce metabolic syndrome and were compared to hamsters fed with regular chow diet. Both groups were also treated with melatonin. Fructose-fed hamsters showed altered blood lipid levels (increased cholesterol and LDL) and phenotypes restored with the melatonin treatment. The Harderian gland (HG), which is an ideal model to study autophagy modulation through oxidative stress, was the organ that was most affected by a fructose diet. Redox balance was altered in fructose-fed HG, inducing autophagic activation. However, since LC3-II was not increased, the impairment must be in the last steps of autophagy. Lipophagy HG markers were also disturbed, contributing to the dyslipidemia. Melatonin treatment improved possible oxidative homeostasis through autophagic induction. All these results point to melatonin as a possible treatment of the metabolic syndrome.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Melatonin Ameliorates Autophagy Impairment in a Metabolic Syndrome Model

et al. 2021

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“…Similar protection was obtained with the antioxidant N -acetylcysteine, which may indicate a role of ROS scavenging [ 34 ]. The prevention of microglial inflammasome activation may be largely explained by the downregulation of TLR4 (toll-like receptor 4) [ 35 , 36 , 37 , 38 ] and its adapter protein MyD88 (myeloid differentiation factor 88) [ 36 ], effects that have been observed in very different models and under various conditions. However, reduced TLR4-dependent signaling may also occur upon the prevention of HMGB1 (high mobility group box 1) release, an alarmin that activates TLR4, as reported for LPS-treated BV2 microglial cells [ 39 ].…”

Section: Melatonin Suppresses Proinflammatory and Favors Anti-inflammatory Signalingmentioning

confidence: 99%

“…However, reduced TLR4-dependent signaling may also occur upon the prevention of HMGB1 (high mobility group box 1) release, an alarmin that activates TLR4, as reported for LPS-treated BV2 microglial cells [ 39 ]. Downstream signaling that is inhibited by melatonin can concern different pathway branches, in particular, the phosphorylation of Akt, mTOR [ 37 , 40 ], and the stress kinases JNK and p38 [ 37 , 40 ]; the prevention of NADPH oxidase activation/assembly [ 38 , 40 , 41 ]; and the prevention of caspase-3 cleavage [ 35 , 36 , 42 ]. As a common feature that is observed throughout practically all pertinent studies, the suppression of NF-κB activation, which was often accompanied by Nrf2 upregulation, reflects the anti-inflammatory and antioxidant actions of melatonin in microglia [ 26 , 32 , 36 , 38 , 39 , 43 , 44 , 45 , 46 , 47 , 48 ].…”

Section: Melatonin Suppresses Proinflammatory and Favors Anti-inflammatory Signalingmentioning

confidence: 99%

Melatonin and Microglia

Hardeland

2021

IJMS

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Melatonin interacts in multiple ways with microglia, both directly and, via routes of crosstalk with astrocytes and neurons, indirectly. These effects of melatonin are of relevance in terms of antioxidative protection, not only concerning free-radical detoxification, but also in prevention of processes that cause, promote, or propagate oxidative stress and neurodegeneration, such as overexcitation, toxicological insults, viral and bacterial infections, and sterile inflammation of different grades. The immunological interplay in the CNS, with microglia playing a central role, is of high complexity and includes signaling toward endothelial cells and other leukocytes by cytokines, chemokines, nitric oxide, and eikosanoids. Melatonin interferes with these processes in multiple signaling routes and steps. In addition to canonical signal transduction by MT1 and MT2 melatonin receptors, secondary and tertiary signaling is of relevance and has to be considered, e.g., via the upregulation of sirtuins and the modulation of pro- and anti-inflammatory microRNAs. Many details concerning the modulation of macrophage functionality by melatonin are obviously also applicable to microglial cells. Of particular interest is the polarization toward M2 subtypes instead of M1, i.e., in favor of being anti-inflammatory at the expense of proinflammatory activities, which is well-documented in macrophages but also applies to microglia.

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“…A double-blind study of melatonin in AD demonstrated decreased nocturnal activity, increased nocturnal sleep, and cognition improvement [ 162 ]. Moreover, one recent study showed that melatonin could prevent cognitive dysfunction in T2DM mice [ 163 ], while another recent study indicated that a lower melatonin level was related to cognitive impairment in T2DM patients [ 164 ]. Therefore, melatonin might be used as a potential protective molecule against both T2DM and AD.…”

Section: Treatment For T2dm and Ad Targeting Circadian Rhythmsmentioning

confidence: 99%

A Growing Link between Circadian Rhythms, Type 2 Diabetes Mellitus and Alzheimer’s Disease

Peng

Fan

Xie

et al. 2022

IJMS

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Type 2 diabetes mellitus (T2DM) patients are at a higher risk of developing Alzheimer’s disease (AD). Mounting evidence suggests the emerging important role of circadian rhythms in many diseases. Circadian rhythm disruption is considered to contribute to both T2DM and AD. Here, we review the relationship among circadian rhythm disruption, T2DM and AD, and suggest that the occurrence and progression of T2DM and AD may in part be associated with circadian disruption. Then, we summarize the promising therapeutic strategies targeting circadian dysfunction for T2DM and AD, including pharmacological treatment such as melatonin, orexin, and circadian molecules, as well as non-pharmacological treatments like light therapy, feeding behavior, and exercise.

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Melatonin prevents diabetes‐associated cognitive dysfunction from microglia‐mediated neuroinflammation by activating autophagy via TLR4/Akt/mTOR pathway

Abstract: This is an open access article under the terms of the Creat ive Commo ns Attri butio n-NonCo mmercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Cited by 47 publications

References 49 publications

Melatonin Ameliorates Autophagy Impairment in a Metabolic Syndrome Model

Melatonin Ameliorates Autophagy Impairment in a Metabolic Syndrome Model

Melatonin and Microglia

A Growing Link between Circadian Rhythms, Type 2 Diabetes Mellitus and Alzheimer’s Disease

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