MELATONIN
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 Melatonin - A Potential Therapeutic Agent For Alzheimer's
Inhibition of Alzheimer-Fibrillogenesis by Melatonin
From the J Biol Chem, Vol. 273, Issue 13, 7185-7188, March 27, 1998 Miguel Pappolla, Peter Bozner, Claudio Soto, Haiyan Shao, Nickolaos
K.Robakis From the University of South Alabama College of Medicine, Mobile, Alabama 36617, New York University, New York, New York 10016, Case Western Reserve University, Cleveland, Ohio 44106, and Mount Sinai Medical School, New York, New York 10029 It is generally postulated that the amyloid protein (A) plays a central role in the progressive neurodegeneration observed in Alzheimer's disease. Important pathologic properties of this protein, such as neurotoxicity and resistance to proteolytic degradation, depend on the ability of A to form -sheet structures or amyloid fibrils. We report that melatonin, a hormone recently found to protect neurons against A toxicity, interacts with A1-40 and A1-42 and inhibits the progressive formation of -sheets and amyloid fibrils. These interactions between melatonin and the amyloid peptides were demonstrated by circular dichroism and electron microscopy for A1-40 and A1-42 and by nuclear magnetic resonance spectroscopy for A1-40. Inhibition of -sheets and fibrils could not be accomplished in control experiments when a free radical scavenger or a melatonin analog were substituted for melatonin under otherwise identical conditions. In sharp contrast with conventional anti-oxidants and available anti-amyloidogenic compounds, melatonin crosses the blood-brain barrier, is relatively devoid of toxicity, and constitutes a potential new therapeutic agent in Alzheimer's disease.
Melatonin-related Indole Structure
Potent Against
Potent Neuroprotective Properties against the Alzheimer Amyloid by an Endogenous Melatonin-related Indole Structure, Indole-3-propionic Acid
J Biol Chem, Vol. 274, Issue 31, 21937-21942, July 30, 1999 Yau-Jan Chyan, Burkhard Poeggeler, Rawhi A. Omar, Daniel G. Chain, From the Departments of Pathology and Neurology, University of South Alabama, Mobile, Alabama 36617, the Department of Pathology, University of Louisville, Louisville, Kentucky 40206, the Department of Pathology, New York University, New York, New York 10016, and Mindset Limited, Jerusalem, Israel Widespread cerebral deposition of a 40-43-amino acid peptide called the amyloid protein (A) in the form of amyloid fibrils is one of the most prominent neuropathologic features of Alzheimer's disease. Numerous studies suggest that A is toxic to neurons by free radical-mediated mechanisms. We have previously reported that melatonin prevents oxidative stress and death of neurons exposed to A. In the process of screening indole compounds for neuroprotection against A, potent neuroprotective properties were uncovered for an endogenous related species, indole-3-propionic acid (IPA). This compound has previously been identified in the plasma and cerebrospinal fluid of humans, but its functions are not known. IPA completely protected primary neurons and neuroblastoma cells against oxidative damage and death caused by exposure to A, by inhibition of superoxide dismutase, or by treatment with hydrogen peroxide. In kinetic competition experiments using free radical-trapping agents, the capacity of IPA to scavenge hydroxyl radicals exceeded that of melatonin, an indoleamine considered to be the most potent naturally occurring scavenger of free radicals. In contrast with other antioxidants, IPA was not converted to reactive intermediates with pro-oxidant activity. These findings may have therapeutic applications in a broad range of clinical situations. |
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