Protective effect of melatonin on beta-amyloid-induced apoptosis in rat astroglioma C6 cells and its mechanism.
Astrocytosis is a common feature of amyloid plaques. The Abeta-astrocyte interaction produces a detrimental effect on neurons, which may contribute to neurodegeneration in Alzheimer disease (AD). The regulation of astrocyte apoptosis is essential to physiological and pathological processes in the CNS. Melatonin is a potent antioxidant and free radical scavenger. Previously, we showed that melatonin alleviated the learning and memory deficits in the APP 695 transgenic mouse model of AD. In this study, the importance of melatonin in the management of Abeta-induced apoptosis in an astrocyte-like cell is discussed. We found that rat astroglioma C6 cells treated with Abeta25-35 or Abeta1-42 undergo apoptosis and that melatonin pretreatment at 10(-5), 10(-6), and 10(-7) M significantly attenuates Abeta25-35- or Abeta1-42-induced apoptosis. The antiapoptotic effects of melatonin were extremely reproducible and corroborated by multiple quantitative methods, including an 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, remarkably prevented Abeta1-40-induced intracellular calcium overload, and significantly alleviated Abeta1-40-induced membrane rigidity. Our results demonstrate that, in addition to the beneficial effects of providing direct antioxidant protection to neurons, melatonin may enhance neuroprotection against Abeta-induced neurotoxicity by promoting the survival of glial cells.
Feng
Zheng
Z
Department of Pharmacology, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 10050, People's Republic of China. zhengfengCNS@hotmail.com
Zhang
Jun-Tian
JT
D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001253:Astrocytes / Q000187:drug effects*; D001254:Astrocytoma; D002118:Calcium / Q000378:metabolism; D002467:Cell Nucleus / Q000187:drug effects / Q000648:ultrastructure; D015227:Lipid Peroxidation / Q000187:drug effects; D008550:Melatonin / Q000494:pharmacology* / Q000627:therapeutic use; D008560:Membrane Fluidity / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism; D010446:Peptide Fragments / Q000037:antagonists & inhibitors*; D051381:Rats
D016229:Amyloid beta-Peptides; D018696:Neuroprotective Agents; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); C113041:amyloid beta-protein (35-25); D009569:Nitric Oxide; D008550:Melatonin; D002118:Calcium