文摘
Increasing evidence supports that the mitochondrial dysfunction, mainly caused by abnormal changesin mitochondrial proteins, plays a pivotal role in glutamate-induced excitotoxicity, which is closelyassociated with the pathogenesis of acute and chronic neurodegenerative disorders, such as strokeand Alzheimer's disease. In this study, post-treatment of cerebellar granule neurons with bis(7)-tacrinesignificantly reversed declines in mitochondrial membrane potential, ATP production, and neuronalcell death induced by glutamate. Moreover, this reversal was independent of NMDA antagonism,acetylcholinesterase inhibition, and cholinergic pathways. Using two-dimensional differential in-gelelectrophoresis, we conducted a comparative analysis of mitochondrial protein patterns. In all, 29proteins exhibiting significant differences in their abundances were identified in the glutamate-treatedgroup when compared with the control. The expression patterns in 22 out of these proteins could bereversed by post-treatment with bis(7)-tacrine. Most of the differentially expressed proteins are involvedin energy metabolism, oxidative stress, and apoptosis. In particular, the altered patterns of four ofthese proteins were further validated by Western blot analysis. Our findings suggest that multiplesignaling pathways initiated by the altered mitochondrial proteins may mediate glutamate-inducedexcitotoxicity and also offer potentially useful intracellular targets for the neuroprotection provided bybis(7)-tacrine.
