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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Background
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Background
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“The receptors combine with ApoE and ingest Aβ, thus reducing the extracellular level of Aβ and reducing nerve injury (Pappolla et al., 1997).”
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“[41, 63] and only recently partially described [30].”
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Background
Apoptosis, Neurotrophic Factors and Neurodegeneration
Dragunow, M., MacGibbon, G. A., Lawlor, P. A., Butterworth, N. J., Connor, B. J., Henderson, C. E., Walton, M. R., Woodgate, A.-M., Hughes, P. E., & Faull, R. L. M. (1997) · Reviews in the Neurosciences · doi:10.1515/revneuro.1997.8.3-4.223 · Cited by 58
Induction of GDNF mRNA expression by melatonin in rat C6 glioma cells
Armstrong, K. J., & Niles, L. P. (2002) · Neuroreport · doi:10.1097/00001756-200203250-00023 · Cited by 57
In vivo protection by the xanthate tricyclodecan-9-yl-xanthogenate against amyloid β-peptide (1–42)-induced oxidative stress
Marzia Perluigi, A., Gururaj Joshi, A., Rukhsana Sultana, A., Calabrese, V., Marco, C. D., Coccia, R., & Butterfield, D. A. (2006) · Neuroscience · doi:10.1016/j.neuroscience.2005.12.004 · Cited by 57
Antioxidant strategies in protection against neurodegenerative disorders
Tan, D.-X., Manchester, L. C., Sainz, R. M., Mayo, J. C., Alvares, F. L., & Reiter, R. J. (2003) · Expert Opinion on Therapeutic Patents · doi:10.1517/13543776.13.10.1513 · Cited by 57
Melatonin blocks rat hippocampal neuronal apoptosis induced by amyloid beta‐peptide 25–35
Shen, Y., Xu, S., Wei, W., Wang, X., Wang, H., & Sun, X. (2002) · Journal of Pineal Research · doi:10.1034/j.1600-079x.2002.1o839.x · Cited by 58
“The ability of melatonin to protect against Ab-induced apoptosis may also relate to the antioxidant actions of melatonin as suggested by Pappolla et al. (1997).”
Background
Protective roles of melatonin against the amyloid-dependent development of Alzheimer’s disease: A critical review
Vincent, B. (2018) · Pharmacological Research · doi:10.1016/j.phrs.2018.06.011 · Cited by 56
“A chronological review of the studies carried out in this field brings us twenty years back when Pappolla and colleagues showed for the first time that melatonin (5 to 50μM for 12–24 hours) was able to prevent Aβ 25-35 and Aβ40-induced cell death, oxidative stress and intracellular calcium increases in rat PC12 pheoch…”
Background
Role of melatonin supplementation in neurodegenerative disorders
Polimeni, G. (2014) · Frontiers in bioscience · doi:10.2741/4217 · Cited by 57
Mechanism of neuroprotection of melatonin against beta-amyloid neurotoxicity
Йонов, М., Burchell, V., Klajnert‐Maculewicz, B., Bryszewska, M. J., & Abramov, A. Y. (2011) · Neuroscience · doi:10.1016/j.neuroscience.2011.02.045 · Cited by 55
Melatonin is protective in necrotic but not in caspasedependent, free radical‐independent apoptotic neuronal cell death in primary neuronal cultures
Harms, C., Lautenschlager, M. M., Bergk, A., Freyer, D., Weih, M., Dirnagl, U., Weber, J. R., & Hörtnagl, H. (2000) · The FASEB Journal · doi:10.1096/fj.99-0899com · Cited by 55
“Furthermore, melatonin protects against glutamate-induced cell death in the clonal hippocampal cell line HT22 (11), prevents delayed neuronal death induced by enhanced excitatory transmission in hippocampal pyramidal neurons in culture (12), and rescues neuroblastoma cells exposed to toxic fragments of Alzheimer’s b-a…”
Relationship between melatonin levels in plasma and gastrointestinal tissues and the incidence and severity of gastric ulcers in pigs
Bubenik, G. A., Ayles, H. L., Friendship, R. M., Brown, G. M., & Ball, R. O. (1998) · Journal of Pineal Research · doi:10.1111/j.1600-079x.1998.tb00367.x · Cited by 55
Melatonin uptake in prostate cancer cells: intracellular transport versus simple passive diffusion
Hevia, D., Sainz, R. M., Blanco, D., Quirós-González, I., Tan, D. X., Rodrı́guez, C., & Mayo, J. C. (2008) · Journal of Pineal Research · doi:10.1111/j.1600-079x.2008.00581.x · Cited by 54
“Thus, melatonin protects bamyloid-induced neuroblastoma cell death [11] by reducing oxidative damage at the mitochondrial level [16].”
Background
N‐Acetylserotonin, Melatonin and Their Derivatives Improve Cognition and Protect against β‐Amyloid‐Induced Neurotoxicity
Бачурин, С. О., Oxenkrug, G. F., Lermontova, N., Afanasiev, A. V., Beznosko, B. K., Van’kin, G. I., Shevtzova, E. F., Mukhina, T. V., & Serkova, T. P. (1999) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1999.tb07990.x · Cited by 54
Brain washing and neural health: role of age, sleep, and the cerebrospinal fluid melatonin rhythm
Reiter, R. J., Sharma, R., Cucielo, M. S., Tan, D. X., Rosales‐Corral, S., Gancitano, G., & Chuffa, L. G. D. A. (2023) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-023-04736-5 · Cited by 55
“Cell and transgenic rodent models of AD have provided clues of the possible mechanisms by which melatonin limits AD pathophysiology [87, 88].”
Background
Neuroprotection against Aβ and glutamate toxicity by melatonin: Are GABA receptors involved?
Paula-Lima, A. C., Louzada, P. R., Mello, F. G. D., & Ferreira, S. T. (2003) · Neurotoxicity Research · doi:10.1007/bf03033152 · Cited by 53
“Neuroprotective effects of melatonin against Aβ-induced toxicity have also been reported, and the mechanism of protection has been linked to the antioxidant and anti-amyloidogenic properties of this hormone ( Pappolla et al., 1997; 1998 ).”
Background
Melatonin and colon carcinogenesis
Anisimov, V. N., Popovich, I. G., Shtylik, A. V., Zabezhinski, M. A., Ben-Huh, H., Gurevich, P., Berman, V., Tendler, Y., & Zusman, I. (2000) · Experimental and Toxicologic Pathology · doi:10.1016/s0940-2993(00)80022-6 · Cited by 53
Melatonin and Its Agonist Ramelteon in Alzheimer′s Disease: Possible Therapeutic Value
Srinivasan, V., Kaur, C., Pandi-Perumal, S. R., Brown, G. M., & Cardinali, D. P. (2010) · International Journal of Alzheimer s Disease · doi:10.4061/2011/741974 · Cited by 53
Vitamin E But Not 17β-Estradiol Protects against Vascular Toxicity Induced by β-Amyloid Wild Type and the Dutch Amyloid Variant
Muñoz, F. J., Opazo, C., Gil‐Gómez, G., Tapia, G., Fernández, V., Valverde, M. A., & Inestrosa, N. C. (2002) · Journal of Neuroscience · doi:10.1523/jneurosci.22-08-03081.2002 · Cited by 52
“In accordance with the oxidative pathophysiological hypothesis, vitamin E (vit E) and other antioxidants have demonstrated protective properties on neuronal cells against the A-mediated neurotoxicity (Behl et al., 1992; Pappolla et al., 1997 ).”
BackgroundInfluential
Aging and oxygen toxicity: Relation to changes in melatonin
Reiter, R. J. (1997) · AGE · doi:10.1007/s11357-997-0020-2 · Cited by 52
Long-term exposure to magnetic fields and the risks of Alzheimer's disease and breast cancer: Further biological research
Davanipour, Z., & Sobel, E. L. (2009) · Pathophysiology · doi:10.1016/j.pathophys.2009.01.005 · Cited by 50
Protective role of melatonin in domoic acid‐induced neuronal damage in the hippocampus of adult rats
Ananth, C. V., Gopalakrishnakone, P., & Kaur, C. (2003) · Hippocampus · doi:10.1002/hipo.10090 · Cited by 50
Is Antioxidant Therapy a Viable Alternative for Mild Cognitive Impairment? Examination of the Evidence
Ancelin, M., Christen, Y., & Ritchie, K. A. (2007) · Dementia and Geriatric Cognitive Disorders · doi:10.1159/000102567 · Cited by 50
Neuroprotection by Melatonin on Astrocytoma Cell Death
Radogna, F., Nuccitelli, S., Mengoni, F., & Ghibelli, L. (2009) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2009.04900.x · Cited by 39
Melatonin protects SH‐SY5Y neuroblastoma cells from calyculin A‐induced neurofilament impairment and neurotoxicity
Li, S. P., Deng, Y., Wang, X. C., Wang, Y. P., & Wang, J. (2004) · Journal of Pineal Research · doi:10.1111/j.1600-079x.2004.00116.x · Cited by 48
Opposite effects of pinealectomy and melatonin administration on brain damage following cerebral focal ischemia in rat
Joo, J., Uz, T., & Manev, H. (1998) · Restorative Neurology and Neuroscience · doi:10.3233/rnn-1998-00065 · Cited by 46
“[10,11,15–18,23,30,32,35,50,51], amyloid peptide [6,38,39], 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) [3], L-cysteine [55], cyanide [56], or d-aminolevulinic acid [41].”
Protective melatonin effect on oxidative stress induced by okadaic acid into rat brain
Túnez, I., Muñoz, M. D. C., Feijóo, M., Muñoz-Castañeda, J. R., Bujalance, I., Valdelvira, M. E., & López, P. M. (2003) · Journal of Pineal Research · doi:10.1034/j.1600-079x.2003.00039.x · Cited by 45
“Furthermore, the degree of Ab-induced lipid peroxidation in the cells was reduced in presence of melatonin [22].”
Background
Homer2 and Homer3 interact with amyloid precursor protein and inhibit Aβ production
Parisiadou, L., Bethani, I., Michaki, V., Krousti, K., Rapti, G., & Efthimiopoulos, S. (2008) · Neurobiology of Disease · doi:10.1016/j.nbd.2008.02.004 · Cited by 43
Neuroprotective Effect of Melatonin on Cortical Impact Injury in the Rat
Sarrafzadeh, A. S., Thomale, U. W., Kroppenstedt, S. N., & Unterberg, A. W. (2000) · Acta Neurochirurgica · doi:10.1007/s007010070028 · Cited by 44
“Several in vitro and in vivo studies have confirmed the protective actions of melatonin in neuronal tissue [13, 14, 15, 18 ] and reducing neuronal deficits [16].”
Result
Adenosine Triphosphate (ATP) Reduces Amyloid-β Protein Misfolding in vitro
Coskuner‐Weber, O., & Murray, I. V. J. (2014) · Journal of Alzheimer s Disease · doi:10.3233/jad-132300 · Cited by 44
Nose-to-Brain Delivery of Antioxidants as a Potential Tool for the Therapy of Neurological Diseases
Bonferoni, M. C., Rassu, G., Gavini, E., Sorrenti, M., Catenacci, L., & Giunchedi, P. (2020) · Pharmaceutics · doi:10.3390/pharmaceutics12121246 · Cited by 44
“Several works reported that melatonin has neuroprotective and antioxidant properties against oxidative injury mediated by amyloid β-protein in vitro [86].”
Background
Aluminum and Glyphosate Can Synergistically Induce Pineal Gland Pathology: Connection to Gut Dysbiosis and Neurological Disease
Seneff, S., Swanson, N., & Li, C. (2015) · Agricultural Sciences · doi:10.4236/as.2015.61005 · Cited by 43
“Furthermore, researchers have used several different methods to confirm that melatonin protects cultured cells from death following exposure to toxic fragments of amyloid-β [182], another hallmark of Alzheimer’s disease.”
Background
Riluzole But Not Melatonin Ameliorates Acute Motor Neuron Degeneration and Moderately Inhibits SOD1-Mediated Excitotoxicity Induced Disrupted Mitochondrial Ca2+ Signaling in Amyotrophic Lateral Sclerosis
Jaiswal, M. K. (2017) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2016.00295 · Cited by 41
Amyloid β oligomers inhibit growth of human cancer cells
Pavliukevičienė, B., Zentelytė, A., Jankunec, M., Valiulienė, G., Talaikis, M., Navakauskienė, R., Niaura, G., & Valinčius, G. (2019) · PLoS ONE · doi:10.1371/journal.pone.0221563 · Cited by 42
Mitochondrial medicine: neuroprotection and life extension by the new amphiphilic nitrone LPBNAH1 acting as a highly potent antioxidant agent
Pöeggeler, B., Durand, G., Polidori, A., Pappolla, M. A., Vega‐Naredo, I., Coto‐Montes, A. M., Böker, J., Hardeland, R., & Pucci, B. (2005) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2005.03425.x · Cited by 41
Alterations in circadian rhythms of melatonin and cortisol in patients with bronchial asthma.
Fei, G., Liu, R., Zhang, Z., & Zhou, J. (2004) · PubMed · Cited by 41
A glycine zipper motif mediates the formation of toxic β-amyloid oligomers in vitro and in vivo
Fonte, V. G., Dostal, V., Roberts, C. M., Gonzales, P. K., Lacor, P. N., Magrané, J., Dingwell, N., Fan, E. Y., Silverman, M. A., Stein, G. H., et al. (2011) · Molecular Neurodegeneration · doi:10.1186/1750-1326-6-61 · Cited by 37
“Synthetic Ab is toxic in both neuronal cell lines [2,3] and primary neurons [4], and Alzheimer’s-like pathology has been observed in a range of transgenic models that accumulate Ab [5-8].”
Background
Amyloid, Cholinesterase, Melatonin, and Metals and Their Roles in Aging and Neurodegenerative Diseases
Lahiri, D. K., Chen, D., Lahiri, P., BONDY, S., & Greig, N. H. (2005) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1352.008 · Cited by 39
Study of the non‐covalent interaction between amyloid‐β‐peptide and melatonin using electrospray ionization mass spectrometry
Bazoti, F. N., Tsarbopoulos, A., Markides, K. E., & Bergquist, J. (2005) · Journal of Mass Spectrometry · doi:10.1002/jms.738 · Cited by 38
Factors influencing the processing and function of the amyloid β precursor protein—a potential therapeutic target in Alzheimer's disease?
Coughlan, C. M. (2000) · Pharmacology & Therapeutics · doi:10.1016/s0163-7258(00)00036-x · Cited by 39
Melatonin for Sleep Disorders in Patients with Neurodegenerative Diseases
Trotti, L. M., & Karroum, E. G. (2016) · Current Neurology and Neuroscience Reports · doi:10.1007/s11910-016-0664-3 · Cited by 38

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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