Melatonin attenuates nicotine-induced autophagy and neurological changes by decreasing the production of reactive oxygen species

Feng, Yue; Xu, Feng-Qing; Wang, Songmei; Wu, Shaoxiong; Zhang, Xuehui; Gao, Yanxiang; Li, Yaling; Zhong, Du-bo; Yin, Jie; Feng, Yuemei

doi:10.1080/00207454.2019.1692833

Cited by 6 publications

(4 citation statements)

References 27 publications

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“…Melatonin signi cantly increased the level of autophagy in prion protein-induced apoptosis [21]. However, other studies report that melatonin attenuated autophagy [40,41]. In the present study, we showed that melatonin inhibited autophagy in neuronal cells.…”

Section: Discussioncontrasting

confidence: 43%

Melatonin-mediated Calcineurin Inactivation Attenuates Prion Protein-induced Nf-Kb- Driven Pro-Inflammation Response

Hong

Moon

Seol

et al. 2021

Preprint

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Background: Prion diseases are a group of prevalent and rapidly progressive neurodegenerative disorders that lead to chronic inflammation and neuronal cell death. Calcineurin and autophagy mediate prion-induced neurodegeneration, suggesting that inhibition of calcineurin and autophagy could be a target for therapy. Melatonin has been reported to exert neuroprotective effects against calcium-dependent neuronal cell death.Methods: Real-time quantitative PCR was used to detect mRNA levels of proinflammatory cytokines. Western blot was used to analysis p-nfkb, p-bcl10, calcineurin, prpc and autophagy flux pathway. Immunocytochemistry was used to analysis p-nfkb and calcineurin. Ca2+ levels were measured by fluo-4 using confocal microscope. Calcineurin activity was used to detect with calcineurin cellular activity assay kit. Transmission electron microscopy (TEM) was used to detect autophagy flux.Results: In the present study, we investigated whether melatonin attenuates prion peptide-mediated neuroinflammation and reduces calcineurin. We found that melatonin treatment inhibits prion protein-induced apoptosis. Melatonin inhibited calcium up-regulation and protected the cells against prion peptide‑induced neuron cell death by calcineurin inactivation. Furthermore, melatonin increased p62 protein levels and decrease LC3-II protein levels indicating autophagic flux inhibition and melatonin inhibited prion protein-induced neurotoxicity through autophagy flux inhibition.Conclusions: Taken together, our results illuminate that melatonin attenuated prion protein-induced neurinflammation through calcineurin inactivation and autophagic flux reduction, and also suggest that melatonin may provide effective strategy for therapy against neurodegenerative diseases, including prion diseases.

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Section: Discussioncontrasting

confidence: 43%

Melatonin-mediated Calcineurin Inactivation Attenuates Prion Protein-induced Nf-Kb- Driven Pro-Inflammation Response

Hong

Moon

Seol

et al. 2021

Preprint

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“…Alterations in the lysosomal autophagy system increase α‐synuclein accumulation, and excessive and/or abnormal α‐synuclein then further impedes the lysosomal autophagy system in a vicious cycle 38 . Of note, nicotine has been shown to induce autophagy in several tissues outside of the brain, although the effects of this range from beneficial to harmful depending on the tissue 39‐46 . Here we found that nicotine treatment rescued impaired autophagic flux in α‐synuclein flies and that this rescue was dependent on the intact expression of SV2C (Figs.…”

Section: Discussionmentioning

confidence: 55%

“…38 Of note, nicotine has been shown to induce autophagy in several tissues outside of the brain, although the effects of this range from beneficial to harmful depending on the tissue. [39][40][41][42][43][44][45][46] Here we found that nicotine treatment rescued impaired autophagic flux in α-synuclein flies and that this rescue was dependent on the intact expression of SV2C (Figs. 4 and 5).…”

Section: Discussionmentioning

confidence: 59%

Nicotine‐Mediated Rescue of α‐Synuclein Toxicity Requires Synaptic Vesicle Glycoprotein 2 in Drosophila

2022

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Background Parkinson's disease (PD) is characterized by α‐synuclein aggregation and loss of dopamine neurons. Risk of PD arises due to a combination of genetic and environmental factors, which may interact, termed gene–environment (G×E) interactions. An inverse association between smoking and the risk of PD is well established, and a previous genome‐wide G×E interaction study identified genetic variation in the synaptic‐vesicle glycoprotein 2C (SV2C) locus as an important mediator of the degree to which smoking is inversely associated with PD. Objective We sought to determine the mechanism of the smoking–SV2C interaction in a Drosophila model of PD. Methods Flies expressing human α‐synuclein in all neurons develop the hallmarks of PD, including motor dysfunction, loss of dopaminergic (DA) neurons, and formation of α‐synuclein inclusions. We assessed the effects of increasing doses of nicotine on these parameters of neurodegeneration, in the presence or absence of knockdown of two Drosophila orthologues of SV2, hereafter referred to as SV2L1 and SV2L2. Results The α‐synuclein–expressing flies treated with nicotine had improved locomotion, DA neuron counts, and α‐synuclein aggregation. However, in α‐synuclein–expressing flies in which SV2L1 and SV2L2 were knocked down, nicotine failed to rescue neurodegeneration. Conclusions This work confirms a G×E interaction between nicotine and SV2, defines a role for this interaction in α‐synuclein proteostasis, and suggests that future clinical trials on nicotine should consider genetic variation in SV2C. Furthermore, this provides proof of concept that our model can be used for the mechanistic study of G×E, paving the way for the investigation of additional G×E interactions or the identification of novel G×E. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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“…Alterations in the lysosomal autophagy system increase α-synuclein accumulation, and excessive and/or abnormal α-synuclein then further impedes the lysosomal autophagy system in a vicious cycle 35 . Of note, nicotine has been shown to induce autophagy in several tissues outside of the brain, though the effects of this range from beneficial to harmful depending on the tissue [36][37][38][39][40][41][42][43] . Here we found that nicotine treatment rescued impaired autophagic flux in α-synuclein flies, and that this rescue was dependent on intact expression of SV2C (Figure 6-7).…”

Section: Discussionmentioning

confidence: 99%

Nicotine-mediated rescue of α-synuclein toxicity requires synaptic vesicle glycoprotein 2

Olsen

Clemens

Feany

2022

Preprint

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Background: Parkinson's disease (PD) is characterized by alpha-synuclein aggregation and loss of dopamine (DA) neurons in the substantia nigra. Risk of PD arises due to a combination of genetic and environmental factors, which may interact, termed gene-environment (GxE) interactions. An inverse association between smoking and risk of PD is well-established, and a previous genome-wide GxE interaction study identified genetic variation in the synaptic-vesicle glycoprotein 2C (SV2C) locus as an important mediator of the degree to which smoking is inversely associated with PD. Objective: We sought to determine the mechanism of the smoking-SV2C interaction in a Drosophila model of PD. Methods: Flies expressing human alpha-synuclein in all neurons develop the hallmarks of PD, including motor dysfunction, loss of DA neurons, and formation of alpha-synuclein inclusions. We assessed the effects of increasing doses of nicotine on these parameters of neurodegeneration, in the presence or absence of SV2 knockdown. Results: alpha-synuclein-expressing flies treated with nicotine had improvement in locomotion, DA neuron counts, and in alpha-synuclein aggregation. However, in alpha-synuclein-expressing flies in which Drosophila orthologs of SV2 were knocked down, nicotine failed to rescue neurodegeneration. Conclusions: This work confirms a GxE interaction between nicotine and SV2, defines a role for this interaction in alpha-synuclein proteostasis, and suggests that future clinical trials on nicotine should consider genetic variation in SV2C. Further, this provides proof of concept that our model can be used for mechanistic study of GxE, paving the way for investigation of additional GxE interactions or identification of novel GxE.

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Melatonin attenuates nicotine-induced autophagy and neurological changes by decreasing the production of reactive oxygen species

Cited by 6 publications

References 27 publications

Melatonin-mediated Calcineurin Inactivation Attenuates Prion Protein-induced Nf-Kb- Driven Pro-Inflammation Response

Melatonin-mediated Calcineurin Inactivation Attenuates Prion Protein-induced Nf-Kb- Driven Pro-Inflammation Response

Nicotine‐Mediated Rescue of α‐Synuclein Toxicity Requires Synaptic Vesicle Glycoprotein 2 in Drosophila

Nicotine-mediated rescue of α-synuclein toxicity requires synaptic vesicle glycoprotein 2

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