Early melatonin supplementation alleviates oxidative stress in a transgenic mouse model of Alzheimer's disease

Zhao, Feng; Qin, Chuan; Chang, Ying; Zhang, Juntian

doi:10.1016/j.freeradbiomed.2005.08.014

Cited by 139 publications

(115 citation statements)

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“…The use of antioxidant agents to prevent neurodegeneration has been widely described [32,33,[37][38][39][40][41][42]. As in our investigation, combinations of antioxidants have been shown to be more effective than single agents in at least some cases [43].…”

Section: Identifying Treatments To Reduce Neurodegenerative Diseasementioning

confidence: 52%

“…Mitochodrial dysfunction and ROS production have been implicated in numerous neurodegenerative syndromes and diseases [28-34, see 35,36]. The use of antioxidant agents holds significant therapeutic promise for many neurodegenerative processes [32,33,[37][38][39][40][41][42], and there is some suggestion that Correspondence to: C. G. Le Prell, Kresge Hearing Research Institute, University of Michigan, 1301 East Ann Street, Ann Arbor, MI 48109-0506, USA. Tel: +1-734-763-5104; fax +1-734-764-0014.…”

Section: Introductionmentioning

confidence: 99%

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Free radical scavengers vitamins A, C, and E plus magnesium reduce noise trauma

Prell

Hughes

Miller

2007

Free Radical Biology and Medicine

198

188

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Free radical formation in the cochlea plays a key role in the development of noise-induced hearing loss (NIHL). The amount, distribution, and time course of free radical formation have been defined, including a clinically significant formation of both reactive oxygen species and reactive nitrogen species 7-10 days following noise exposure. Reduction in cochlear blood flow as a result of free radical formation has also been described. Here we report that the antioxidant agents, vitamins A, C, and E, act in synergy with magnesium to effectively prevent noise-induced trauma. Neither the antioxidant agents nor magnesium reliably reduced NIHL or sensory cell death with the doses we used when these agents were delivered alone. In combination, however, they were highly effective in reducing both hearing loss and cell death even with treatment initiated just one hour prior to noise exposure. This study supports roles for both free radical formation and noise-induced vasoconstriction in the onset and progression of NIHL. Identification of this safe and effective antioxidant intervention that attenuates NIHL provides a compelling rationale for human trials in which free radical scavengers are used to eliminate this single major cause of acquired hearing loss. Keywords cochlea; free radical; noise; hearing; antioxidant; vasodilation Mechanical destruction of cells in the organ of Corti was once assumed to be the primary cause of noise-induced hearing loss (NIHL) [1][2][3][4][5][6][7][8], with perhaps some effect of reduced blood flow to the inner ear [9][10][11][12][13][14][15][16][17][18]. We now know that another key factor is intense metabolic activity that results in production of excess free radicals [19][20][21][22][23] and lipid peroxidation products [24]. Noise-induced production of reactive oxygen species (ROS) in the cochlea has now been well characterized, and several recent reviews are available [25][26][27]. Mitochodrial dysfunction and ROS production have been implicated in numerous neurodegenerative syndromes and diseases [28-34, see 35,36]. The use of antioxidant agents holds significant therapeutic promise for many neurodegenerative processes [32,33,[37][38][39][40][41][42], and there is some suggestion that Correspondence to: C. G. Le Prell, Kresge Hearing Research Institute, University of Michigan, 1301 East Ann Street, Ann Arbor, MI 48109-0506, USA. Tel: +1-734-763-5104; fax +1-734-764-0014. E-mail address: colleeng@umich.edu. Disclosure. Dr. Miller is a founding member and Chairman of the Board of Directors at OtoMedicine, Inc., a company that has an option to license the intellectual property described in this report. Dr. Le Prell is a paid consultant to OtoMedicine, Inc. Drs. Miller and Le Prell have disclosed these relationships to the Medical School Conflict of Interest Board at the University of Michigan; conflict management plans including semi-annual review by the Board are in place.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publicatio...

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Section: Identifying Treatments To Reduce Neurodegenerative Diseasementioning

confidence: 52%

Section: Introductionmentioning

confidence: 99%

Free radical scavengers vitamins A, C, and E plus magnesium reduce noise trauma

Prell

Hughes

Miller

2007

Free Radical Biology and Medicine

198

188

View full text Add to dashboard Cite

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“…There is also a set of compounds, including melatonin, that promote expression of mitochondrial antioxidant enzymes such as SOD or glutathione [121][122][123][124]. Mitoquinone mesylate (MitoQ) has been proposed for treatment of AD and other neurodegenerative diseases because its antioxidant activity localizes to the mitochondrial inner membrane to prevent oxidative damage [131].…”

Section: Oxidative Damage As a Therapeutic Targetmentioning

confidence: 99%

“…A balance between mitophagy and mitochondrial biogenesis provides an efficient energy transducing system required for neuronal survival [144], whereas mitochondrial dysfunction contributes to neuronal death and AD pathology (Fig. 2) [98,123,145]. Elevated oxidative stress and induction of apoptotic proteases can inactivate mitophagy and impair pathways required for clearance of aberrant mitochondria [83,85,101,146,147].…”

Section: Apoptosis and Mitophagy As Therapeutic Targetsmentioning

confidence: 99%

Targeting the Prodromal Stage of Alzheimer's Disease: Bioenergetic and Mitochondrial Opportunities

2015

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Alzheimer's disease (AD) has a complex and progressive neurodegenerative phenotype, with hypometabolism and impaired mitochondrial bioenergetics among the earliest pathogenic events. Bioenergetic deficits are well documented in preclinical models of mammalian aging and AD, emerge early in the prodromal phase of AD, and in those at risk for AD. This review discusses the importance of early therapeutic intervention during the prodromal stage that precedes irreversible degeneration in AD. Mechanisms of action for current mitochondrial and bioenergetic therapeutics for AD broadly fall into the following categories: 1) glucose metabolism and substrate supply; 2) mitochondrial enhancers to potentiate energy production; 3) antioxidants to scavenge reactive oxygen species and reduce oxidative damage; 4) candidates that target apoptotic and mitophagy pathways to either remove damaged mitochondria or prevent neuronal death. Thus far, mitochondrial therapeutic strategies have shown promise at the preclinical stage but have had little-to-no success in clinical trials. Lessons learned from preclinical and clinical therapeutic studies are discussed. Understanding the bioenergetic adaptations that occur during aging and AD led us to focus on a systems biology approach that targets the bioenergetic system rather than a single component of this system. Bioenergetic system-level therapeutics personalized to bioenergetic phenotype would target bioenergetic deficits across the prodromal and clinical stages to prevent and delay progression of AD.

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“…These include downregulation of Bax, caspases, and inhibition of mitochondrial DNA fragmentation, apoptosis, cytochrome c release, and closure of the permeability transition pore. Depression of these adverse events is accompanied by induction of Bcl-2 and improved function of the respiratory chain and ATP synthesis [120][121][122]. Maintenance of mitochondrial glutathione levels has been also attributed to melatonin [94,123].…”

Section: Melatonin and Mitochondriamentioning

confidence: 99%

Melatonin, Oxidative Stress, and the Aging Brain

Bondy

Sharman

2010

Aging and Age-Related Disorders

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The changes associated with brain aging are discussed with emphasis on altered oxidative and inflammatory events and on mitochondrial dysfunction. Many of these changes are exacerbated in a variety of age-related neurologic diseases. This commonality has led to the idea that similar therapeutic approaches may be used in the treatment of several apparently unrelated neurodegenerative disorders. When aspects of these diseases are modeled in experimental animals and cell lines, the application of melatonin has been reported to be advantageous. The means by which melatonin can be protective probably is mediated by way of activation of melatonin receptors, of which several subtypes can be identified. This can initiate a sequence of intracellular signaling events and by activation of transcription factors lead to altered gene expression. The culmination of this cascade can lead to increased levels of antioxidant enzymes and depressed levels of inflammation. Melatonin may be useful both in the retardation of nonpathologic brain aging and in the amelioration of chronic brain disease associated with aging. The inexpensive nature and ready availability of melatonin together with its very low toxicity reinforce the need to place the beneficial properties of this agent on a firmer basis.

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Early melatonin supplementation alleviates oxidative stress in a transgenic mouse model of Alzheimer's disease

Cited by 139 publications

References 57 publications

Free radical scavengers vitamins A, C, and E plus magnesium reduce noise trauma

Free radical scavengers vitamins A, C, and E plus magnesium reduce noise trauma

Targeting the Prodromal Stage of Alzheimer's Disease: Bioenergetic and Mitochondrial Opportunities

Melatonin, Oxidative Stress, and the Aging Brain

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