Melatonin reduces amyloid beta-induced apoptosis in pheochromocytoma (PC12) cells.
The finding that the amyloid beta protein (Abeta) has neurotoxic properties and that such effects are partly mediated by free radicals has provided insights into the mechanisms of cell death in Alzheimer's disease (AD) and an avenue to explore new therapeutic approaches. Melatonin is a potent antioxidant and free radical scavenger. Previously, we showed that long-term application of melatonin alleviated the learning and memory deficits in the APP695 transgenic mouse model of AD. In this study, the importance of melatonin in the management of Abeta-induced apoptosis was investigated. Rat pheochromocytoma (PC12) cells treated with either Abeta25-35 or Abeta1-42 underwent apoptosis. Melatonin pretreatment at 10(-5), 10(-6) and 10(-7) m significantly attenuated Abeta25-35- or Abeta1-42-induced apoptosis in PC12 cells. The anti-apoptotic effects of melatonin were highly reproducible and corroborated by multiple quantitative methods, including MTT cell viability assay, Hoechst 33342 nuclei staining, DNA fragmentation analysis, and flow cytometric analysis. In addition, melatonin effectively suppressed Abeta1-42-induced nitric oxide formation, potently prevented Abeta1-40-induced intracellular calcium overload and significantly alleviated Abeta1-40-induced membrane rigidity. These results suggest that the mechanism of Abeta neurotoxicity involves oxidative stress, and the neuroprotective effects of melatonin are, at least in part, associated with its antioxidant properties. The use of melatonin or its derived analogs should be explored as a therapeutic approach in AD.
Department of Pharmacology, Institute of Materia Medica Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Xiannong Tan Street, Beijing, 10050, P.R. China. zhengfengcns@hotmail.com
Zheng
Z
Feng
Jun-Tian
JT
Zhang
D016229:Amyloid beta-Peptides / Q000633:toxicity; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D005434:Flow Cytometry; D008550:Melatonin / Q000494:pharmacology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D016716:PC12 Cells; D051381:Rats; D015203:Reproducibility of Results
D016229:Amyloid beta-Peptides; D000975:Antioxidants; D018696:Neuroprotective Agents; D008550:Melatonin