Molecular Mechanisms Involved in the Antioxidant Effect of Melatonin

Todoroki, Sachiko; Yamaguchi, Mai; Cho, S.; Sumikawa, Koji

doi:10.1097/00000542-199809050-00016

Cited by 6 publications

(8 citation statements)

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“…4A, melatonin was the only antioxidant tested that protected cells against Ab-induced toxicity by preventing ROS production and Ac-DEVD-pNA cleavage. Although melatonin mechanism of action is at present unclear, it is known to bind heavy metals [34] and to increase intracellular GSH levels through an up-regulation of GSHsynthesizing enzymes [35] . It has been reported that antioxidants that act on preventing caspase activation could be the next therapeutical approach to AD [36,37] .…”

Section: Discussionmentioning

confidence: 99%

“…Amyloid b-peptide (Ab), the major component of senile plaques, has been suggested to play an important role in AD pathogenesis [1,2] . The sequence corresponding to amino-acids [25][26][27][28][29][30][31][32][33][34][35] of Ab (Ab 25 -35) forms fibrils and has been shown to contribute to neurodegeneration in a variety of in vitro studies [3,4] . Nevertheless, the mechanisms by which Ab elicits its toxic effect on neurons remain to be established.…”

Section: Introductionmentioning

confidence: 99%

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Glutathione Cycle Impairment Mediates Aβ-induced Cell Toxicity

Cardoso

Oliveira

2003

Free Radical Research

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Alzheimer's disease is widely held to be associated with oxidative stress due, in part, to the action of amyloid beta-peptide (A beta). We observed that A beta 25-35 induced an increase in reactive oxygen species (ROS) in NT2 rho+ cells, leading to protein and lipid oxidation. This oxidative status was partially prevented by the antioxidants, vitamin E, reduced glutathione, and by melatonin. However, NT2 rho0 cells (that lack mitochondrial DNA) in the absence of A beta showed an increase in ROS production, lipid and protein oxidation, as compared with parental rho+ cells. Upon A beta 25-35 treatment, in rho+ cells, a decrease in glutathione reductase activity and in GSH levels was observed, whereas glutathione peroxidase activity was shown to be increased. In NT2 rho0 cells, in the absence of A beta, GSH levels were maintained, whereas glutathione reductase and peroxidase activities were increased. The exposure of A beta to rho0 cells did not induce any change in these parameters. We observed that melatonin prevented caspase activation and DNA fragmentation in rho+ cells treated with A beta. Considering the evidence presented, we argue that the glutathione cycle impairment is a key event in A beta-induced cell toxicity.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Glutathione Cycle Impairment Mediates Aβ-induced Cell Toxicity

Cardoso

Oliveira

2003

Free Radical Research

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“…Similarly, pretreating the cells with melatonin or premixing mercury and melatonin before administration protected cells from the mercury-induced oxidative stress. Melatonin's mechanism of action is at present unclear; however, melatonin is known to bind heavy metals (Limson et al, 1998) and to increase intracellular GSH levels through an up-regulation of GSH-synthesizing enzymes (Todoroki et al, 1998). It is thus possible to speculate on two mechanisms for melatonin's antioxidant action, namely, (a) melatonin as a chelating agent binding mercury, thus eliminating its cytotoxic properties, or (b) melatonin causing production of increased levels of intracellular antioxidants such as GSH (Todoroki et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

Mercury Induces Cell Cytotoxicity and Oxidative Stress and Increases β‐Amyloid Secretion and Tau Phosphorylation in SHSY5Y Neuroblastoma Cells

Olivieri

Brack

Müller‐Spahn

et al. 2000

Journal of Neurochemistry

173

118

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Abstract:Concentrations of heavy metals, including mercury, have been shown to be altered in the brain and body fluids of Alzheimer's disease (AD) patients. To explore potential pathophysiological mechanisms we used an in vitro model system (SHSY5Y neuroblastoma cells) and investigated the effects of inorganic mercury (HgCl 2 ) on oxidative stress, cell cytotoxicity, ␤-amyloid production, and tau phosphorylation. We demonstrated that exposure of cells to 50 g/L (180 nM) HgCl 2 for 30 min induces a 30% reduction in cellular glutathione (GSH) levels (n ϭ 13, p Ͻ 0.001). Preincubation of cells for 30 min with 1 M melatonin or premixing melatonin and HgCl 2 appeared to protect cells from the mercury-induced GSH loss. Similarly, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MT T ) cytotoxicity assays revealed that 50 g/L HgCl 2 for 24 h produced a 50% inhibition of MT T reduction (n ϭ 9, p Ͻ 0.001). Again, melatonin preincubation protected cells from the deleterious effects of mercury, resulting in MT T reduction equaling control levels. The release of ␤-amyloid peptide (A␤) 1-40 and 1-42 into cell culture supernatants after exposure to HgCl 2 was shown to be different: A␤ 1-40 showed maximal (15.3 ng/ml) release after 4 h, whereas A␤ 1-42 showed maximal (9.3 ng/ml) release after 6 h of exposure to mercury compared with untreated controls (n ϭ 9, p Ͻ 0.001). Preincubation of cells with melatonin resulted in an attenuation of A␤ 1-40 and A␤ 1-42 release. Tau phosphorylation was significantly increased in the presence of mercury (n ϭ 9, p Ͻ 0.001), whereas melatonin preincubation reduced the phosphorylation to control values. These results indicate that mercury may play a role in pathophysiological mechanisms of AD. Key Words: Mercury-Oxidative stress-␤-Amyloid-TauMelatonin-SHSY5Y neuroblastoma cells.

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“…Incubation of cells with melatonin was used to block the deleterious actions of Ab and H 2 O 2 . Apparently exerting its neuroprotective effects through activation of the GSH system, melatonin increases synthesis of GSH-synthesizing enzymes such as c-glutamylcysteine synthetase (Todoroki et al, 1998;Urata et al, 1999); increases the activity of antioxidant enzymes superoxide dismutase, catalase, and GSH reductase (Liu and Ng, 2000); inhibits Abinduced lipid peroxidation (Daniels et al, 1998); and acts as a general antioxidant (Reiter, 1995;Sewerynek et al, 1995;Pappolla et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

Oxidative Stress Modulates Tyrosine Kinase Receptor A and p75 Receptor (Low-Affinity Nerve Growth Factor Receptor) Expression in SHSY5Y Neuroblastoma Cells

Olivieri¹,

Otten²,

Meier³

et al. 2002

Neurology &Amp; Clinical Neurophysiology

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The interaction of neurotrophins and their tyrosine kinase receptors (trks) is essential for differentiation and survival of brain cells. In Alzheimer's disease (AD), the number of neurotrophins and receptors is markedly decreased. The cause of this reduction is unclear, but the role of beta-amyloid (Abeta) seems central in understanding the mechanisms controlling neurotrophin and trk expression. In the study reported here, we exposed SHSY5Y neuroblastoma cells to Abeta or hydrogen peroxide (H(2)O(2)) and measured the expression of trk-A and p75 at the protein and molecular levels. Both Abeta and H(2)O(2) induced oxidative stress (measured by a decrease in cellular glutathione), which decreased trk-A levels and increased p75 levels, decreased messenger RNA (mRNA) levels of both receptors, and increased nerve growth factor (NGF) secretion. Pretreatment of cells with the antioxidant melatonin returned levels of protein expression, mRNA, and NGF secretion to normal. These results are significant, as they can help in the planning and implementation of AD treatment strategies involving neurotrophins.

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Molecular Mechanisms Involved in the Antioxidant Effect of Melatonin

Cited by 6 publications

References 0 publications

Glutathione Cycle Impairment Mediates Aβ-induced Cell Toxicity

Glutathione Cycle Impairment Mediates Aβ-induced Cell Toxicity

Mercury Induces Cell Cytotoxicity and Oxidative Stress and Increases β‐Amyloid Secretion and Tau Phosphorylation in SHSY5Y Neuroblastoma Cells

Oxidative Stress Modulates Tyrosine Kinase Receptor A and p75 Receptor (Low-Affinity Nerve Growth Factor Receptor) Expression in SHSY5Y Neuroblastoma Cells

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