Melatonin protects nigral dopaminergic neurons from 1-methyl-4-phenylpyridinium (MPP+) neurotoxicity in rats

Jin, Byung Kwan; Shin, Dong Yeon; Jeong, Mi Young; Gwag, Mi R; Baik, Haing Woon; Yoon, Kyung Sik; Cho, Yong H; Joo, Wan Seok; Kim, Yong Sik; Baik, Hee Jung

doi:10.1016/s0304-3940(98)00170-0

Cited by 90 publications

(57 citation statements)

References 23 publications

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“…One, the protective effect of both compounds against DA autoxidation [32], since DA accumulates extraneuronally mainly due to a massive DA efflux induced by the MPP + [50] plus the deprenyl-dependent DA uptake inhibition [26]. In addition, deprenyl-induced TH enzyme may be favored by the increase of TH activity due to melatonin [7,31]. A third factor involved in melatonin-deprenyl synergy come from their effect to enhance gene expression of glial cell line-derived neurotrophic factor [54], which in turn protects nigrostriatal pathway against MPTP [45].…”

Section: Discussionmentioning

confidence: 99%

“…Since LPO, a reliable index of oxidative damage induced by MPTP in striatal neurons, was counteracted by melatonin, the antioxidant role of the indoleamine seems be involved in its neuroprotective action. In fact, melatonin attenuates MPP + -induced neurodegeneration and glutathionc impairment in the nigrostriatal dopaminergic pathway [14], protects against MPTP-induced oxidative stress and apoptosis [4,29,31,44] by a mechanism partially involving hydroxyl radical scavenging [35], counteracts MPTP-induced inhibition of complex I [1], reverts 6-OHDA-induced Parkinsonism [17], and increases mitochondrial GSH content [37]. Besides these mechanisms, it has been recently reported that melatonin reverts 6-OHDA-induced striatal neurochemical alterations in association with striatal D 1 /D 2 DA receptor modification [6].…”

Section: Discussionmentioning

confidence: 99%

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Synergistic effects of melatonin and deprenyl against MPTP-induced mitochondrial damage and DA depletion

Khaldy

Escames

León

et al. 2003

Neurobiology of Aging

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Previous studies showed a synergistic effect of melatonin and deprenyl against dopamine (DA) autoxidation in vitro. Since oxidative stress is implicated in Parkinson's disease (PD), we explored the effects of melatonin plus deprenyl administration in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD in C57/Bl6 mice. Melatonin, but not deprenyl prevents the inhibition of mitochondrial complex I and the oxidative damage in nigrostriatal neurons induced by MPTP. With the dose used deprenyl recovers 50% DA levels and tyrosine hydroxylase activity depressed by the neurotoxin, normalizing locomotor activity of mice. Melatonin, which was unable to counteract MPTP-induced DA depletion and inhibition of tyrosine hydroxylase activity, potentiates the effect of deprenyl on catecholamine turnover and mice ambulatory activity. These results suggest a dissociation of complex I inhibition from DA depletion in this model of Parkinson's disease. The data also support that a combination of melatonin, which improves mitochondrial electron transport chain and reduces oxidative damage, and deprenyl, which promotes the specific function of the rescued neurons, i.e. DA turnover, may be a promising strategy for the treatment of PD.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Synergistic effects of melatonin and deprenyl against MPTP-induced mitochondrial damage and DA depletion

Khaldy

Escames

León

et al. 2003

Neurobiology of Aging

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“…Experimental evidence suggests that melatonin is able to scavenge free radicals, maintain the integrity of mitochondrial respiratory chain, inhibit dopamine auto-oxidation, and regulate other intracellular antioxidant defense systems [23][24][25][26]. However, only some [25,[26][27][28][29][30], but not all animal experiments [32][33][34] found that melatonin at pharmacologic dosages attenuates the neurotoxicities of 1-methyl-4-phenyl) 1,2,3,6-tetrahydropyridine or 6-hydroxy-dopamine, agents that are used to generate animal models of acute neuronal dopaminergic cell deaths. Interestingly, one study [34] also directly examined the potential effect of light exposure in a rat model of PD, showing that light significantly reduced the severity of PD symptoms both under 6-OHDA and MPTP treatment, whereas intracerebroventricular implants of slow release melatonin increased the severity of the symptoms.…”

Section: Etiology Of Parkinson's Disease and Role Of Melatoninmentioning

confidence: 99%

Circulating Melatonin Levels: Possible Link Between Parkinson’s Disease and Cancer Risk?

Schernhammer

Chen

Ritz

2006

Cancer Causes Control

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Lower rates of cancer mortality/incidence in patients with Parkinson's disease (PD) have given rise to speculations about risk or preventative factors common to both diseases, including life-style factors (such as smoking) and genetic susceptibility. Melatonin, a hormone known for its sleep regulatory effects, may play an important role in carcinogenesis as suggested by substantial laboratory and less direct epidemiologic evidence. Particularly, a reduction in melatonin, such as experienced by persons who are exposed to light at night, appears to increase cancer risk. Variations in melatonin levels have been linked to PD in several different ways. Some studies show higher morning melatonin levels in PD patients than in healthy controls. One could speculate that the sleep disorders that affect almost two thirds of those suffering from PD and can precede PD motor symptoms by several years may be associated with variations in melatonin levels. Moreover, in animal models, interventions that increase the bioavailability of melatonin appears to increase the severity of parkinsonian symptoms, whereas reduction in melatonin by pinealectomy or exposure to bright light can enhance recovery from parkinsonisms symptoms. Finally, preliminary epidemiological evidence suggests that longer years of working night shifts is associated with a reduced risk of PD among participants of the Nurses' Health Study (NHS), whereas longer hours of sleep appear to increase their risk. In sum, while lower melatonin concentrations may predict a higher cancer risk, there is also some evidence that they may be associated with a lower risk of PD. We therefore hypothesize that elevated circulating melatonin levels in PD patients may contribute to their lower cancer rates.

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“…[32][33][34] As a naturally occurring compound, melatonin has potential effects on inhibiting autophagy through a redox-mediated scavenge of free radicals and lipid peroxidation, 35 as well as its well-known antioxidant properties. 36 Emerging evidence suggests that melatonin can be used as a neuroprotective agent in the rodent models of PD 32,37,38 by ameliorating the dysfunction of mitochondria, [39][40][41][42] blocking CASP3 (caspase 3, apoptosis-related cysteine peptidase) activation and cellular apoptosis, 43 and protecting TH (tyrosine hydroxylase)-positive nerve terminals. 44 However, the molecular underpinning of protective effect of melatonin on the loss of DAergic neurons in PD mouse model is still unknown.…”

Section: Introductionmentioning

confidence: 99%

Melatonin attenuates MPTP-induced neurotoxicity via preventing CDK5-mediated autophagy and SNCA/α-synuclein aggregation

et al. 2015

Autophagy

102

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Keywords: autophagy, CDK5, melatonin, MPTP, SNCA, TH Abbreviations: ATG7, autophagy-related 7; BAFA1, bafilomycin A 1 ; CDK5, cyclin-dependent kinase 5; CDK5R1/p35/p25, cyclindependent kinase 5, regulatory subunit 1 (p35); DA, dopamine; DAPI, 4 0 ,6-diamidino-2-phenylindole; i.p, intraperitoneally; s.c, subcutaneously; ICV, intracerebroventricular; MAP1LC3B/LC3B, microtubule-associated protein 1 light chain 3 b; MAP2, microtube-associated protein 2; MPTP, 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine; PD, Parkinson disease; PEBP1, phosphatidylethanolamine binding protein 1; PI, propidium iodide; SNc, substantia nigra pars compacta; SNCA/a-synuclein, synuclein, a (non A4 component of amyloid precursor); TH, tyrosine hydroxylase.Autophagy is involved in the pathogenesis of neurodegenerative diseases including Parkinson disease (PD). However, little is known about the regulation of autophagy in neurodegenerative process. In this study, we characterized aberrant activation of autophagy induced by neurotoxin 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) and demonstrated that melatonin has a protective effect on neurotoxicity. We found an excessive activation of autophagy in monkey brain tissues and C6 cells, induced by MPTP, which is mediated by CDK5 (cyclin-dependent kinase 5). MPTP treatment significantly reduced total dendritic length and dendritic complexity of cultured primary cortical neurons and melatonin could reverse this effect. Decreased TH (tyrosine hydroxylase)-positive cells and dendrites of dopaminergic neurons in the substantia nigra pars compacta (SNc) were observed in MPTP-treated monkeys and mice. Along with decreased TH protein level, we observed an upregulation of CDK5 and enhanced autophagic activity in the striatum of mice with MPTP injection. These changes could be salvaged by melatonin treatment or knockdown of CDK5. Importantly, melatonin or knockdown of CDK5 reduced MPTP-induced SNCA/ a-synuclein aggregation in mice, which is widely thought to trigger the pathogenesis of PD. Finally, melatonin or knockdown of CDK5 counteracted the PD phenotype in mice induced by MPTP. Our findings uncover a potent role of CDK5-mediated autophagy in the pathogenesis of PD, and suggest that control of autophagic pathways may provide an important clue for exploring potential target for novel therapeutics of PD.

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Melatonin protects nigral dopaminergic neurons from 1-methyl-4-phenylpyridinium (MPP+) neurotoxicity in rats

Cited by 90 publications

References 23 publications

Synergistic effects of melatonin and deprenyl against MPTP-induced mitochondrial damage and DA depletion

Synergistic effects of melatonin and deprenyl against MPTP-induced mitochondrial damage and DA depletion

Circulating Melatonin Levels: Possible Link Between Parkinson’s Disease and Cancer Risk?

Melatonin attenuates MPTP-induced neurotoxicity via preventing CDK5-mediated autophagy and SNCA/α-synuclein aggregation

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