The role of melatonin in targeting cell signaling pathways in neurodegeneration

Shukla, Mayuri; Chinchalongporn, Vorapin; Govitrapong, Piyarat; Reíter, Russel J.

doi:10.1111/nyas.14005

Cited by 45 publications

(39 citation statements)

References 210 publications

(233 reference statements)

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“…44,45 Melatonin plays a critical role in controlling inflammation, oxidative stress, autophagy, mitochondrial homeostasis, apoptosis, calcium excitotoxicity, and pivotal signaling pathways in neurodegeneration. 25 However, the effect of melatonin on DM-induced neuronal death is still unclear. The results herein showed that melatonin alleviated neuronal death in both diabetic mice and HG-treated neuronal cells.…”

Section: Discussionmentioning

confidence: 99%

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Melatonin exerts neuroprotective effects by inhibiting neuronal pyroptosis and autophagy in STZ‐induced diabetic mice

Che

Yang

et al. 2020

FASEB j.

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Diabetes mellitus (DM) patients are at a higher risk of developing brain injury characterized by neuronal death. Melatonin, a hormone produced by the pineal gland, exerts neuroprotective effects against brain damage. However, the effect of melatonin on diabetes‐induced brain injury has not been elucidated. This study was to evaluate the role of melatonin against neuronal death in DM and to elucidate the underlying mechanisms. Herein, we found that melatonin administration significantly alleviated the neuronal death in both streptozotocin (STZ)‐induced diabetic mice and high glucose (HG)‐treated neuronal cells. Melatonin inhibited neuronal pyroptosis and excessive autophagy, as evidenced by decreased levels of NLRP3, cleaved caspase‐1, GSDMD‐N, IL‐1β, LC3, Beclin1, and ATG12 both in vivo and in vitro. MicroRNA‐214‐3p (miR‐214‐3p) was decreased in DM mice and HG‐treated cells, and such a downregulation was corrected by melatonin, which was accompanied by repression of caspase‐1 and ATG12. Furthermore, downregulation of miR‐214‐3p abrogated the anti‐pyroptotic and anti‐autophagic actions of melatonin in vitro. Our results indicate that melatonin exhibits a neuroprotective effect by inhibiting neuronal pyroptosis and excessive autophagy through modulating the miR‐214‐3p/caspase‐1 and miR‐214‐3p/ATG12 axes, respectively, and it might be a potential agent for the treatment of brain damage in the setting of DM.

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Section: Discussionmentioning

confidence: 99%

“…24 In studies on neurovegetative disorders, melatonin was found to protect against AD, stroke, traumatic brain injury, and hypertension by repressing inflammation, apoptosis, oxidative stress, and autophagy. 25 However, whether melatonin also regulates brain injury associated with DM remains unknown.…”

Section: Introductionmentioning

confidence: 99%

Melatonin exerts neuroprotective effects by inhibiting neuronal pyroptosis and autophagy in STZ‐induced diabetic mice

Che

Yang

et al. 2020

FASEB j.

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“…They are typically characterized by abnormal proteostasis, where the cell is unable to maintain regulation of protein folding, translation, and degradation pathways. These defects in proteostasis lead to processes of cell death such as apoptosis and disrupted signaling mechanisms within the cell from oxidative stress, glutamate-mediated cytotoxicity, neuroinflammation, mitochondrial dysfunction, and increased endoplasmic reticulum (ER) stress [2][3][4][5][6][7]. However, the early factors involved in neuronal cell death are still not understood.…”

Section: Introductionmentioning

confidence: 99%

Metabolite therapy guided by liquid biopsy proteomics delays retinal neurodegeneration

Wert

Vélez

Vijayalakshmi

et al. 2019

Preprint

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One Sentence Summary: The study shows protein and metabolite pathways affected during neurodegeneration and that replenishing metabolites provides a neuroprotective effect on the retina. Abstract: 244Main Text: 9,039References: 83 AbstractNeurodegenerative diseases are debilitating, incurable disorders caused by progressive neuronal cell death.Retinitis pigmentosa (RP) is a blinding neurodegenerative disease that results in retinal photoreceptor cell death and progresses to the loss of the entire neural retinal network. We previously found that proteomic analysis of the adjacent vitreous serves as way to indirectly biopsy the neural retina and identify changes in the retinal proteome. We therefore analyzed protein expression in liquid vitreous biopsies from autosomal recessive retinitis pigmentosa (arRP) patients with PDE6A mutations and arRP mice with Pde6ɑ mutations. Proteomic analysis of retina and vitreous samples identified molecular pathways affected at the onset of photoreceptor cell death. Based on affected molecular pathways, arRP mice were treated with a ketogenic diet or metabolites involved in fatty-acid synthesis, oxidative phosphorylation, and the tricarboxylic acid (TCA) cycle. Dietary supplementation of a single metabolite, ɑ-ketoglutarate, increased docosahexaeonic acid (DHA) levels, provided neuroprotection, and enhanced visual function in arRP mice. A ketogenic diet delayed photoreceptor cell loss, while vitamin B supplementation had a limited effect. Finally, desorption electrospray ionization mass spectrometry imaging (DESI-MSI) revealed restoration of key metabolites that correlated with our proteomic findings: pyrimidine and purine metabolism (uridine, dihydrouridine, and thymidine), glutamine and glutamate (glutamine/glutamate conversion), and succinic and aconitic acid (TCA cycle). This study demonstrates that replenishing TCA cycle metabolites via oral supplementation prolongs vision and provides a neuroprotective effect on the photoreceptor cells and inner retinal network.

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“…For a comprehensive review on melatonin activity to reverse disrupted signaling mechanisms in neurodegeneration, including proteostasis dysfunction, disruption of autophagic integrity, and anomalies in the insulin, Notch, and Wnt/β-catenin signaling pathways see ref. (116). Table 3 summarizes the effect of melatonin treatment in transgenic models of AD.…”

Section: Evidence For the Therapeutic Value Of Melatonin In Animal Momentioning

confidence: 99%

Are melatonin doses employed clinically adequate for melatonin-induced cytoprotection?

Cardinali

2019

Melatonin Res.

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This review article discusses the special role that melatonin, a molecule with chronobiotic/cytoprotective properties, may have in prevention and treatment of the metabolic syndrome (MS), ischemic and non-ischemic cardiovascular diseases and Alzheimer´s disease (AD). Prevention of these diseases is a major goal for governmental and non-governmental organizations, and melatonin, an unusual phylogenetically conserved molecule present in all aerobic organisms, merits consideration in this respect. In humans, circulating melatonin levels are consistently reduced in MS, ischemic and non-ischemic cardiovascular diseases and AD, the potential therapeutic value of melatonin being suggested by a limited number of clinical trials generally employing melatonin in the 2-5 mg/day range. In animal model studies of MS, ischemic and non-ischemic cardiovascular diseases and AD melatonin was very effective to curtail symptomatology. However, calculations derived from animal studies indicate projected cytoprotective melatonin doses for humans in the 40-100 mg/day range, doses that are rarely employed clinically. Hence, controlled studies employing melatonin doses in this range are urgently needed. Since the pharmaceutical industry is refractive to support them because of the lack of protective patents for a natural compound, only the involvement of governmental and non-profit organizations can achieve that goal. Within this prospect, the off-label use of melatonin is discussed.

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The role of melatonin in targeting cell signaling pathways in neurodegeneration

Cited by 45 publications

References 210 publications

Melatonin exerts neuroprotective effects by inhibiting neuronal pyroptosis and autophagy in STZ‐induced diabetic mice

Melatonin exerts neuroprotective effects by inhibiting neuronal pyroptosis and autophagy in STZ‐induced diabetic mice

Metabolite therapy guided by liquid biopsy proteomics delays retinal neurodegeneration

Are melatonin doses employed clinically adequate for melatonin-induced cytoprotection?

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