The protective mechanism(s) of melatonin on MPP+ induced cell death on human U373MG glioma cell

Autor: Chen Tsung Hung, 陳宗鴻
Rok vydání: 2001
Druh dokumentu: 學位論文 ; thesis
Popis: 89
The 1-methyl-4-phenylpyridinium (MPP+) is a neurotoxin that produces Parkinsonism in primate and rodents by specifically destruction the substantial nigra dopaminergic pathway. Oxidative stress and the mitochondrial dysfunction have been linked to the neurotoxicity of MPP+. Our previous results have shown that melatonin can protect neuron from MPP+ toxicity in nigrostriatal pathway in vivo by maintaining the endogenous glutathione (GSH) antioxidant defense system. Therefore, I attempted to investigate the death signaling pathway induced by MPP+ and the underlying protective mechanism(s) of melatonin in human U373MG glioma cells. The results showed that the cell viability decreased in a dose dependent manner at 48h after MPP+ exposure and prevented by co-incubation with melatonin as determined by trypan blue exclusion assay. Furthermore, the results demonstrated the MPP+ (10-4M) induced apoptotic cell death 48 h after treatments by using the MC540 staining and DAPI staining which recognized the typical features of apoptosis, such as PS exposure and chromatin condensation. Subsequently, the ROS generation, GSH defense system impairment and caspase-3 activation were identified and put those temporal molecular events in order in the MPP+ induced death-signaling pathway. In this way, we figured out the sequence of molecular events happened in the MPP+ induced death-signaling pathway: first the reduction of GSH and the increase of GSSG/GSH ratio at 6 h, the increase of ROS levels were revealed at 24 h and the activation of capsase-3 at 36 h after MPP+ exposure. Furthermore our results demonstrate that melatonin significantly attenuates the MPP+-caused apoptotic neuronal loss, the decrease of GSH, and the increase GSSG/GSH ratio, the ROS elevation and caspase-3 activation. The results also imply that melatonin’s neuroprotective action is ascribed to its ability of maintaining the GSH antioxidant system, inhibiting the ROS generation and inhibiting the caspase-3 activation.
Databáze: Networked Digital Library of Theses & Dissertations
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