Cited by 359Circadian rhythm and melatoninAlzheimer's disease research and treatmentsParkinson's Disease Mechanisms and Treatments

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Melatonin Prevents Death of Neuroblastoma Cells Exposed to the Alzheimer Amyloid Peptide

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Pappolla, Miguel A., Sos, Melisa, Omar, Rawhi A., Bick, Roger J., Hickson-Bick, Diane L. M., Reiter, Russel J., Efthimiopoulos, Spiros, Robakis, Nickolaos K.·1997·The Journal of Neuroscience

DOI 10.1523/jneurosci.17-05-01683.1997PMC PMC6573387

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Abstract

Studies from several laboratories have generated evidence suggesting that oxidative stress is involved in the pathogenesis of Alzheimer's disease (AD). The finding that the amyloid beta protein (Abeta) has neurotoxic properties and that such effects are, in part, mediated by free radicals has provided insights into mechanisms of cell death in AD and an avenue to explore new therapeutic approaches. In this study we demonstrate that melatonin, a pineal hormone with recently established antioxidant properties, is remarkably effective in preventing death of cultured neuroblastoma cells as well as oxidative damage and intracellular Ca2+ increases induced by a cytotoxic fragment of Abeta. The effects of melatonin were extremely reproducible and corroborated by multiple quantitative methods, including cell viability studies by confocal laser microscopy, electron microscopy, and measurements of intracellular calcium levels. The importance of this finding is that, in contrast to conventional antioxidants, melatonin has a proposed physiological role in the aging process. Secretion levels of this hormone are decreased in aging and more severely reduced in AD. The reported phenomenon may be of therapeutic relevance in AD.

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“Also melatonin is effective in reducing amyloid b-induced lipid peroxidation in vitro [30, 31] as well as in vivo (unpublished data).”
Background
Protective effect of melatonin on β-amyloid-induced apoptosis in rat astroglioma c6 cells and its mechanism
Zheng, F., & Zhang, J. (2004) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2004.08.023 · Cited by 127
Impaired hippocampal long-term potentiation in melatonin MT2 receptor-deficient mice
Larson, J., Jessen, R. E., Uz, T., Arslan, A. D., Kürtüncü, M., Imbesi, M., & Manev, H. (2005) · Neuroscience Letters · doi:10.1016/j.neulet.2005.09.040 · Cited by 123
Indoles as essential mediators in the gut-brain axis. Their role in Alzheimer's disease
Pappolla, M. A., Perry, G. L., Fang, X., Zagorski, M. G., Sambamurti, K., & Pöeggeler, B. (2021) · Neurobiology of Disease · doi:10.1016/j.nbd.2021.105403 · Cited by 124
Extension of life span and stress resistance of Drosophila melanogaster by long-term supplementation with melatonin
Bonilla, E., Medina-Leendertz, S., & Díaz, S. V. (2002) · Experimental Gerontology · doi:10.1016/s0531-5565(01)00229-7 · Cited by 120
A Systematic, Updated Review on the Antidepressant Agomelatine Focusing on its Melatonergic Modulation
Fornaro, M., Prestía, D., Colicchio, S., & Perugi, G. (2010) · Current Neuropharmacology · doi:10.2174/157015910792246227 · Cited by 120
“Melatonin also inhibits the aggregation of the amyloid beta protein into neurotoxic micro-aggregates which seem to underlie the neurotoxicity of this protein, causing neuronal death and formation of neurofibrillary tangles, which are the other neuropathological landmark of Alzheimer's disease [90].”
Background
Two neuronal cell lines expressing the myelin basic protein gene display differences in their in vitro survival and in their response to glia
Bongarzone, E. R., Foster, L. M., Byravan, S., Casaccia‐Bonnefil, P., Schonmann, V., & Campagnoni, A. T. (1998) · Journal of Neuroscience Research · doi:10.1002/(sici)1097-4547(19981101)54:3 · Cited by 21
Alterations in the circadian rhythm of salivary melatonin begin during middle‐age
Zhou, J., Liu, R., van Heerikhuize, J. J., Hofman, M. A., & Swaab, D. F. (2002) · Journal of Pineal Research · doi:10.1034/j.1600-079x.2003.01897.x · Cited by 112
The Melatonin Conformer Space: Benchmark and Assessment of Wave Function and DFT Methods for a Paradigmatic Biological and Pharmacological Molecule
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Inhibition of Alzheimer's disease β‐amyloid aggregation, neurotoxicity, and in vivo deposition by nitrophenols: implications for Alzheimer's therapy
Felice, F. G. D., Houzel, J., Garcia-Abreu, J., Louzada, P. R., Afonso, R. C. D. H., Meirelles, M. N. L., Lent, R., Neto, V. M., & Ferreira, S. T. (2001) · The FASEB Journal · doi:10.1096/fj.00-0676fje · Cited by 113
“For example, the pineal hormone, melatonin, has been reported to interact with Aβ, inhibiting fibrillogenesis and neurotoxicity (19, 20).”
Background
Melatonin as a Pharmacological Agent against Neuronal Loss in Experimental Models of Huntington's Disease, Alzheimer's Disease and Parkinsonism
Reiter, R. J., Cabrera, J., Sainz, R. M., Mayo, J. C., Manchester, L. C., & Tan, D. X. (1999) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1999.tb08028.x · Cited by 112
Dietary supplementation with melatonin reduces levels of amyloid beta‐peptides in the murine cerebral cortex
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“Thirdly, melatonin prevents death of neuroblastoma cells exposed to the peptide [35], and melatonin promotes nerve growth factor (NGF)-mediated neuronal differentiation in cell cultures [36].”
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Alpha-Secretase ADAM10 Regulation: Insights into Alzheimer’s Disease Treatment
Peron, R., Vatanabe, I. P., Manzine, P. R., Camins, A., & Cominetti, M. R. (2018) · Pharmaceuticals · doi:10.3390/ph11010012 · Cited by 117
On the central role of mitochondria dysfunction and oxidative stress in Alzheimer’s disease
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Indian Medicinal Herbs and Formulations for Alzheimer’s Disease, from Traditional Knowledge to Scientific Assessment
Mehla, J., Gupta, P., Pahuja, M., Diwan, D., & Diksha, D. (2020) · Brain Sciences · doi:10.3390/brainsci10120964 · Cited by 108
“Studies have also rep rted that antioxidants protect against Aβ induced neuronal toxicity [16,17].”
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Efficient Host–Guest Energy Transfer in Polycationic Cyclophane–Perylene Diimide Complexes in Water
Ryan, S. T. J., del Barrio, J., Ghosh, I., Biedermann, F., Lazar, A. I., Lan, Y., Coulston, R. J., Nau, W. M., & Scherman, O. A. (2014) · Journal of the American Chemical Society · doi:10.1021/ja5032437 · Cited by 109
Protective effect of melatonin in a model of traumatic brain injury in mice
Mésenge, C., Margaill, I., VERRECCHIA, C., Allix, M., Boulu, R. G., & Plotkine, M. (1998) · Journal of Pineal Research · doi:10.1111/j.1600-079x.1998.tb00384.x · Cited by 109
Reciprocal interactions between sleep, circadian rhythms and Alzheimer's disease: Focus on the role of hypocretin and melatonin
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Effect of chronic treatment of melatonin on learning, memory and oxidative deficiencies induced by intracerebroventricular streptozotocin in rats
Sharma, M., & Gupta, Y. K. (2001) · Pharmacology Biochemistry and Behavior · doi:10.1016/s0091-3057(01)00611-6 · Cited by 107
Ergothioneine rescues PC12 cells from β-amyloid-induced apoptotic death
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Melatonin protects human retinal pigment epithelial (RPE) cells against oxidative stress
Liang, F.-Q., Green, L., Wang, C., Alssadi, R., & Godley, B. F. (2004) · Experimental Eye Research · doi:10.1016/j.exer.2004.02.003 · Cited by 106
N‐acetyl‐serotonin (normelatonin) and melatonin protect neurons against oxidative challenges and suppress the activity of the transcription factor NF‐κB
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Acteoside inhibits apoptosis in D-Galactosamine and lipopolysaccharide-induced liver injury
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Strategy to reduce free radical species in Alzheimer’s disease: an update of selected antioxidants
Domenico, F. D., Barone, E., Marzia Perluigi, A., & Butterfield, D. A. (2014) · Expert Review of Neurotherapeutics · doi:10.1586/14737175.2015.955853 · Cited by 103
“Melatonin also averted Ab-induced increased intracellular Ca and lipid peroxidation [207], thus suggesting melatonin as a potential therapeutic approach in AD.”
Background
Current advances in the treatment of Alzheimer's disease: focused on considerations targeting Aβ and tau
Yang, H., Sun, Z., & Chen, S. (2012) · Translational Neurodegeneration · doi:10.1186/2047-9158-1-21 · Cited by 105
“was the demonstration that this neurohormone prevents neuronal death caused by exposure to the amyloid beta protein [54].”
Background
Melatonin regulates glucocorticoid receptor: an answer to its antiapoptotic action in thymus
Sainz, R. M., Mayo, J. C., Reiter, R. J., Antolı́n, I., Esteban, M. M., & Rodrı́guez, C. (1999) · The FASEB Journal · doi:10.1096/fasebj.13.12.1547 · Cited by 101
“The most recently described properties of melatonin are 1) its antioxidant capability, acting both as a free radical scavenger (11, 12) and a stimulator of activity (13, 14) and mRNA levels for several antioxidant enzymes (8, 15, 16) and 2) its antiapoptotic effects in thymocytes (17, 18) and neuronal cells (16, 19, 2…”
Background
Melatonin reduces oxidative stress and increases gene expression in the cerebral cortex and cerebellum of aluminum‐exposed rats
Esparza, J. L., Gómez, M., Nogués, M. R., Paternain, J. L., Mallol, J., & Domingo, J. L. (2005) · Journal of Pineal Research · doi:10.1111/j.1600-079x.2005.00225.x · Cited by 103
“Melatonin protects neurons against oxidative stress induced by H2O2 and glutamate [15, 17, 42, 43].”
Background
A novel melatonin agonist Neu-P11 facilitates memory performance and improves cognitive impairment in a rat model of Alzheimer' disease
He, P., Ouyang, X.-P., Zhou, S., Yin, W., Tang, C., Laudon, M., & Tian, S. (2013) · Hormones and Behavior · doi:10.1016/j.yhbeh.2013.04.009 · Cited by 100
“, 2001) and exerts neuroprotective and antioxidant properties against Aβ-induced oxidative injury in vitro and in vivo (Matsubara et al., 2003; Pappolla et al., 1997).”
Melatonin prevents increases in neural nitric oxide and cyclic GMP production after transient brain ischemia and reperfusion in the Mongolian gerbil ( Meriones Unguiculatus )
Guerrero, J. M., Reiter, R. J., Ortíz, G. G., Pablos, M. I., Sewerynek, E., & Chuang, J. (1997) · Journal of Pineal Research · doi:10.1111/j.1600-079x.1997.tb00331.x · Cited by 98
Intranasal therapeutic strategies for management of Alzheimer’s disease
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“Melatonin, an indole amide neurohormone, secreted by pineal gland has been found to protect neurons against Ab toxicity and inhibit the progressive formation of b-sheets and amyloid fibrils [184,185].”
Background
Oxidative Stress and Aging as Risk Factors for Alzheimer’s Disease and Parkinson’s Disease: The Role of the Antioxidant Melatonin
Tchekalarova, J. D., & Tzoneva, R. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24033022 · Cited by 105
Melatonin maintains adult hippocampal neurogenesis and cognitive functions after irradiation
Manda, K., & Reiter, R. J. (2009) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2009.10.019 · Cited by 95
Apoptosis modulators in the therapy of neurodegenerative diseases
Deigner, H., Haberkorn, U., & Kinscherf, R. (2000) · Expert Opinion on Investigational Drugs · doi:10.1517/13543784.9.4.747 · Cited by 94
“Melatonin, a pineal hormone with established anti-amyloidogenic and anti-oxidant properties, prevents death and oxidative damage of neuroblastoma cells exposed to Alzheimer Aβ peptide [60,61].”
Background
Melatonin reduces oxidative neurotoxicity due to quinolinic acid:
Cabrera, J., Reiter, R. J., Tan, D. X., Qi, W., Sainz, R. M., Mayo, J. C., García, J. J., Kim, S. J., & El‐Sokkary, G. H. (2000) · Neuropharmacology · doi:10.1016/s0028-3908(99)00128-8 · Cited by 94
Melatonin attenuates amyloid beta25–35-induced apoptosis in mouse microglial BV2 cells
Jang, M.-H., Jung, S.-B., Lee, M., Kim, C., Oh, Y.-T., Kang, I., Kim, J., & Kim, E. (2005) · Neuroscience Letters · doi:10.1016/j.neulet.2005.01.003 · Cited by 93
Products of Cu(II)-catalyzed oxidation in the presence of hydrogen peroxide of the 1–10, 1–16 fragments of human and mouse β-amyloid peptide
Kowalik-Jankowska, T., Ruta, M., Wiśniewska, K., Łankiewicz, L., & Dyba, M. (2004) · Journal of Inorganic Biochemistry · doi:10.1016/j.jinorgbio.2004.03.001 · Cited by 92
Treatment of Alzheimer’s Disease: Beyond Symptomatic Therapies
Buccellato, F. R., D’Anca, M., Tartaglia, G. M., Del Fabbro, M., Scarpini, E., & Galimberti, D. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241813900 · Cited by 94
“In addition, melatonin inhibits the β -ﬁbrillogenesis with neuroprotective and antioxidant activities in vitro and in vivo AD models [153,154].”
Background
The neuroprotective activities of melatonin against the Alzheimer β‐protein are not mediated by melatonin membrane receptors
Pappolla, M. A., Simovich, M. J., Bryant‐Thomas, T., Chyan, Y., Pöeggeler, B., Dubocovich, M. L., Bick, R. J., Perry, G. L., Cruz-Sánchez, F., & Smith, M. A. (2002) · Journal of Pineal Research · doi:10.1034/j.1600-079x.2002.1o838.x · Cited by 91
“A large body of data suggests that Ab has neurotoxic properties and that such effects are mediated by oxygen free radicals (Bozner et al., 1997; Pappolla et al., 1997, 1999; Chyan et al., 1999).”
BackgroundMethodInfluential

Authors: Pappolla, M. A., Sos, M., Omar, R. A., Bick, R. J., Hickson-Bick, D. L. M., Reiter, R. J., Efthimiopoulos, S., & Robakis, N. K.
Affiliations: University of South Alabama (US)
The University of Texas Health Science Center at Houston (US)
University of Louisville (US)
The University of Texas at San Antonio Health Science Center (US)
Icahn School of Medicine at Mount Sinai (US)
ORCID: Pappolla, Miguel A.
Reiter, Russel J.
Efthimiopoulos, Spiros
Venue: The Journal of Neuroscience
Publisher: Society for Neuroscience
Published: 1997-03-01
Volume: 17
Issue: 5
Pages: 1683-1690
ISSN: 0270-6474 (ISSN-L)
1529-2401
DOI: 10.1523/jneurosci.17-05-01683.1997
PMC: PMC6573387
OpenAlex: W2137034584
Cited by: 359
References: 63
Citations by year: 2026: 2 · 2025: 2 · 2024: 4 · 2023: 4 · 2022: 3 · 2021: 4 · 2020: 9 · 2019: 6 · 2018: 12 · 2017: 5 · 2016: 9 · 2015: 7 · 2014: 16 · 2013: 15 · 2012: 14
FWCI: 8.23
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by-nc-sa
creativecommons.org/licenses/by-nc-sa/4.0/ (vor, 184 d)
Locations: Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health (5r01ag011130-03)
National Institute on Aging (RF1AG008200, R56AG008200, AG-08200, AG-11130, R01AG008200)
Topics: Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
Keywords: melatonin, Alzheimer's disease, amyloid-beta, neuroblastoma cells, oxidative stress, neurotoxicity, cell death, intracellular calcium, aging, pineal hormone
MeSH terms: Alzheimer Disease, Animals, Antioxidants, Calcium, Ditiocarb, Doxorubicin, Melatonin, Neuroblastoma, Neurons, Peptide Fragments, Peptides, Superoxide Dismutase, Reproducibility of Results, Lipid Peroxidation, Amyloid beta-Peptides, PC12 Cells, Apoptosis, Oxidative Stress, Mice, Rats

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Melatonin Prevents Death of Neuroblastoma Cells Exposed to the Alzheimer Amyloid Peptide

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