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Melatonin Prevents Death of Neuroblastoma Cells Exposed to the Alzheimer Amyloid Peptide
Open accessAbstract
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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“Studies have also reported that antioxidants protect against Aβ induced neuronal toxicity [16,17].”
From Indian Medicinal Herbs and Formulations for Alzheimer’s Disease, from Traditional Knowledge to Scientific Assessment (2020) · cites this paper as [17]
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BACE1 Inhibitor, Neuroprotective, and Neuritogenic Activities of Melatonin Derivatives
Panyatip, P., Tadtong, S., Sousa, E., & Puthongking, P. (2020) · Scientia Pharmaceutica · doi:10.3390/scipharm88040058 · Cited by 15
“The addition of MLT to the cultures significantly reduced these features [13].”
BackgroundFowler, C. J., Ando, Y., & Tiger, G. (1998) · Neurochemistry International · doi:10.1016/s0197-0186(98)00013-8 · Cited by 15
Teh, M., & Sugden, D. (1999) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0702404 · Cited by 15
Davanipour, Z., Tseng, C.-C., Lee, P.-J., Markides, K. S., & Sobel, E. L. (2013) · Journal of Advances in Medicine and Medical Research · doi:10.9734/bjmmr/2014/7317 · Cited by 14
“Research has indicated that (1) melatonin in vitro inhibits the neurotoxicity of Aβ [38–41] and (2) longterm exposure to moderate or high levels of occupational or residential MF exposure can cause down regulation of melatonin production [42–49].”
BackgroundMelatonin exerts protective effect on N2a cells under hypoxia conditions through Zip1/ERK pathway
Liu, X., Zi, Y., Liu, Y.-E., Zhang, Y.-B., Xiang, L., & Hou, M. (2015) · Neuroscience Letters · doi:10.1016/j.neulet.2015.04.013 · Cited by 14
Neuroprotective and neurorestorative strategies for neuronal injury
Beal, M. F., Palomo, T., Kostrzewa, R. M., & Archer, T. (2000) · Neurotoxicity Research · doi:10.1007/bf03033786 · Cited by 14
“Though pharmacological concentrations of the compound protect against free radical damage, physiological levels of melatonin were beneficial against oxidative stress (Acu~a-Castroveijo et al., 1997; Melchiorri et al., 1995; Pappolla et al., 1997; Pozo et al., 1994).”
Lower serum uric acid levels in cerebral amyloid angiopathy: a pilot study
Hu, Q. Z., Liu, A., Huang, M., Cheng, L., Kang, H., Xu, F., Liu, X., Lian, L., Liang, Q., Jiang, H., et al. (2014) · Neurological Sciences · doi:10.1007/s10072-014-1634-7 · Cited by 14
The Role of Free Radicals in the Nervous System
Friedman, J. H. (2010) · Humana Press eBooks · doi:10.1007/978-1-60327-514-9_1 · Cited by 14
“It was speculated [ 85 ] that melatonin, because of its free radical scavenging activity, neutralized the radicals that were generated extracellularly by AbP as well as those produced intracellularly by the markedly increased calcium, thereby reducing the neurotoxicity of the AbP and leading to increased cellular surv…”
BackgroundDistinct mechanisms account for β-amyloid toxicity in PC12 and differentiated PC12 neuronal cells
Sung, Y.-J., Cheng, C.-L., Chen, C.-S., Huang, H.-B., Huang, F.-L., Wu, P.-C., Shiao, M., & Tsay, H.-J. (2003) · Journal of Biomedical Science · doi:10.1007/bf02256429 · Cited by 14
“In accordance with the hypothesis ofROS-mediated A[3 neurotoxicity [28, 29] is the fact that antioxidants and free radical scavengers have been shown to protect neuronal cells against AI3 toxicity [4, 24 , 25, 33, 39, 44].”
BackgroundRan, D., Xie, B., Gan, Z., Sun, X., Gu, H., & Yang, J. (2018) · Biomedical Reports · doi:10.3892/br.2018.1125 · Cited by 13
“The impacts of MT on intracellular Ca 2+ concentration and calcium channel activities (12) have been reported as the potential mechanisms underlying the therapeutic effects of MT on degenerative disease; however, its specific mechanisms of action remain unclear.”
Whitehead, A. J., Mares, J. A., & Danis, R. P. (2017) · Cited by 13
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Reiter, R. J., & Tan, D. (2004) · The Endocrinologist · doi:10.1097/01.ten.0000134935.40718.8d · Cited by 12
Chi, C., Lin, Y., Wang, Y.-H., Chen, C., Wang, C., & Shiao, Y. (2008) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2008.02.058 · Cited by 12
Cellular and molecular mechanisms mediating melatonin action: A review
Olcese, J. (1998) · The Aging Male · doi:10.3109/13685539809148610 · Cited by 12
Singrang, N., Nopparat, C., Panmanee, J., & Govitrapong, P. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25105225 · Cited by 11
Bayati, S., Yazdanparast, R., Majd, S. S., & Oh, S. (2010) · Journal of Applied Toxicology · doi:10.1002/jat.1594 · Cited by 11
Syntheses of spiroindole melatonin analogues via 2-(indolin-3-ylidene)acetonitrile cycloadditions
Lozinskaya, N. A., Volkova, M. S., Seliverstov, M. Y., Temnov, V. V., Sosonyuk, S. E., Proskurnina, M. V., & Zefirov, N. S. (2014) · Mendeleev Communications · doi:10.1016/j.mencom.2014.09.003 · Cited by 10
Combinatorial Treatment Effects in a Cell Culture Model of Alzheimer’s Disease
Beesley, S., Olcese, J., Saunders, C. E., & Bienkiewicz, E. A. (2016) · Journal of Alzheimer s Disease · doi:10.3233/jad-160459 · Cited by 10
In Vitro Effects of Melatonin on Tumor Cells
Cos, S., & Sánchez‐Barceló, E. J. (2001) · Springer eBooks · doi:10.1007/978-3-642-59512-7_10 · Cited by 10
Detection of interactions of the β‐amyloid peptide with small molecules employing transferred NOEs
Benaki, D. C., Σταθοπούλου, Κ., Leondiadis, L., Ferderigos, N., Pelecanou, M., & Mikros, E. (2009) · Journal of Peptide Science · doi:10.1002/psc.1138 · Cited by 9
Sisodia, R., Kumari, S., Verma, R., & Bhatia, A. L. (2006) · Journal of Radiological Protection · doi:10.1088/0952-4746/26/2/007 · Cited by 9
Melatonin and cortisol rhythm in patients with extensive nasal polyposis
Fidan, V., Hakan, H., Kalkandelen, S., & Cingi, C. (2012) · American Journal of Otolaryngology · doi:10.1016/j.amjoto.2012.09.001 · Cited by 9
“In addition, it has a role in the antioxidative defense system and the antiinflammatory cascade [7–9].”
BackgroundApproaches to therapy for depressions in neurology: prospects for the use of agomelatine
Romanov, D. V., Volel, B. A., & Petelin, D. S. (2018) · Neurology neuropsychiatry Psychosomatics · doi:10.14412/2074-2711-2018-4-101-110 · Cited by 9
“Мелатонин и агонисты мелатониновых рецепторов оказывают протективное действие в отношении деменции, главным образом альцгеймеровского типа, за счет нарушения агрегации амилоида [38] и снижения гиперфосфорилирования тау-белков [39].”
Immunization treatment approaches in Alzheimer’s and prion diseases
Wısnıewskı, T., & Sigurdsson, E. M. (2002) · Current Neurology and Neuroscience Reports · doi:10.1007/s11910-002-0065-7 · Cited by 9
“Several other compounds have also been shown to disassemble Aβ fibrils using in vitro assays, such as melatonin [25,26], nicotine [27], apolipoprotein J [28], anthracy-”
BackgroundDhivya, P., Selvamani, P., Latha, S., Mani, V., & Azahan, N. S. M. (2020) · Pharmacognosy Journal · doi:10.5530/pj.2020.12.171 · Cited by 8
“24 Aβ(25-35) is an undecapeptide that is typically involved in neurotoxic properties, and it leads to neurodegeneration.”
BackgroundDesign and synthesis of melatonin receptors agonists and antagonists
Tarzia, G., Diamantini, G., Mor, M., & Spadoni, G. (2000) · Il Farmaco · doi:10.1016/s0014-827x(00)00017-3 · Cited by 8
Circadian Dysregulation and Melatonin Rhythm Suppression in the Context of Aging
Reiter, R. J., Rosales‐Corral, S., Tan, D. X., Alatorre-Jiménez, M. A., & Lopez, C. A. (2017) · Healthy ageing and longevity · doi:10.1007/978-3-319-64543-8_1 · Cited by 6
Özşimşek, A., & Övey, İ. S. (2022) · Nöro Psikiyatri Arşivi · doi:10.29399/npa.28183 · Cited by 7
Lower levels of cerebrospinal fluid amyloid ß (Aß) in non-demented Indian controls
Subramanian, S., Sandhyarani, B., Shree, A., Murthy, K. K., Kalyani, K., Kumar, S., Pradeep, P., Noone, M. J., & Taly, A. B. (2006) · Neuroscience Letters · doi:10.1016/j.neulet.2006.08.018 · Cited by 7
Metadata
- 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)
- 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
- 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
- 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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