Mitochondrial proteomic analysis and characterization of the intracellular mechanisms of bis(7)-tacrine in protecting against glutamate-induced excitotoxicity in primary cultured neurons

Hongjun Fu, Wenming Li, Yulin Liu, Yuanzhi Lao, Wei Liu, Cheng Chen, Hua Yu, Nelson T.K. Lee, Donald C. Chang, Peng Li, Yuanping Pang, Karl W.K. Tsim, Mingtao Li, Yifan Han

Research output: Contribution to journalArticle

27 Scopus citations

Abstract

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

Original languageEnglish (US)
Pages (from-to)2435-2446
Number of pages12
JournalJournal of Proteome Research
Volume6
Issue number7
DOIs
StatePublished - Jul 2007

Keywords

  • Bis(7)-tacrine
  • Cerebellar granule neurons
  • Glutamate
  • MALDI-TOF/MS
  • Mitochondria
  • Two-dimensional differential in-gel electrophoresis

ASJC Scopus subject areas

  • Biochemistry
  • Chemistry(all)

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