title: The neuroprotective activities of melatonin against the Alzheimer beta-protein are not mediated by melatonin membrane receptors.
abstract: Exposure of neuronal cells to the Alzheimer's amyloid beta protein (Abeta) results in extensive oxidative damage of bio-molecules that are profoundly harmful to neuronal homeostasis. It has been demonstrated that melatonin protects neurons against Abeta-mediated neurotoxicity, including cell death and a spectrum of oxidative lesions. We undertook the current study to determine whether melatonin membrane receptors are involved in the mechanism of neuroprotection against Abeta neurotoxicity. For this purpose, we characterized the free-radical scavenging potency of several compounds exhibiting various affinities for melatonin membrane receptors (MLT 1a and 1b). Abeta-mediated neurotoxicity was assessed in human neuroblastoma cells and in primary hippocampal neurons. In sharp contrast with melatonin, no neuroprotection against Abeta toxicity was observed when we used melatonin membrane receptor agonists that were devoid of antioxidant activity. In contrast, the cells were fully protected in parallel control experiments when either melatonin, or the structurally unrelated free-radical scavenger phenyl-N-t-butyl nitrone (PBN), were added to Abeta-containing culture media. This study demonstrates that the neuroprotective properties of melatonin against Abeta-mediated toxicity does not require binding of melatonin to a membrane receptor and is likely the result of the antioxidant and antiamyloidogenic features of the agent.
authors.affiliation: Department of Pathology, University of South Alabama, Mobile 36617, USA. memorycenter@aol.com
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Pappolla
authors.forename: Marcia J
authors.initials: MJ
authors.lastname: Simovich
authors.forename: Tara
authors.initials: T
authors.lastname: Bryant-Thomas
authors.forename: Yau-Jan
authors.initials: YJ
authors.lastname: Chyan
authors.forename: Burkhard
authors.initials: B
authors.lastname: Poeggeler
authors.forename: Margarita
authors.initials: M
authors.lastname: Dubocovich
authors.forename: Roger
authors.initials: R
authors.lastname: Bick
authors.forename: George
authors.initials: G
authors.lastname: Perry
authors.forename: Felix
authors.initials: F
authors.lastname: Cruz-Sanchez
authors.forename: Mark A
authors.initials: MA
authors.lastname: Smith
mesh_terms: D008735:5-Methoxytryptamine / Q000494:pharmacology; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D000975:Antioxidants / Q000378:metabolism / Q000494:pharmacology; D002478:Cells, Cultured; D003497:Cyclic N-Oxides; D016166:Free Radical Scavengers / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D008550:Melatonin / Q000378:metabolism / Q000494:pharmacology*; D009447:Neuroblastoma / Q000188:drug therapy / Q000473:pathology; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009589:Nitrogen Oxides / Q000494:pharmacology; D051381:Rats; D011956:Receptors, Cell Surface / Q000819:agonists / Q000187:drug effects / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000187:drug effects / Q000378:metabolism; D044094:Receptors, Melatonin; D012701:Serotonin / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D016229:Amyloid beta-Peptides; D000975:Antioxidants; D003497:Cyclic N-Oxides; D016166:Free Radical Scavengers; D018696:Neuroprotective Agents; D009589:Nitrogen Oxides; D011956:Receptors, Cell Surface; D018160:Receptors, Cytoplasmic and Nuclear; D044094:Receptors, Melatonin; D012701:Serotonin; C029217:phenyl-N-tert-butylnitrone; D008735:5-Methoxytryptamine; D008550:Melatonin; C006389:N-acetylserotonin