Kainate excitotoxicity in organotypic hippocampal slice cultures: evidence for multiple apoptotic pathways.

  • Liu W
  • Liu R
  • Chun J
 et al. 
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The mechanisms underlying kainate (KA) neurotoxicity are still not well understood. We previously reported that KA-mediated neuronal damage in organotypic cultures of hippocampal slices was associated with p53 induction. Recently, both bax and caspase-3 have been demonstrated to be key components of the p53-dependent neuronal death pathway. Caspase activation has also been causally related to the release of mitochondrial cytochrome c (Cyto C) in the cytoplasm as a result of the collapse of the mitochondrial membrane potential (Deltapsi(M)) and the opening of mitochondrial permeability transition pores (mPTP). In the present study, we observed a rapid induction of bax in hippocampal slice cultures after KA treatment. In addition, the levels of Cyto C and caspase-3 were increased in the cytosol while the level of the caspase-9 precursor was decreased. There was also a complete reduction of Rhodamine 123 fluorescence after KA treatment, an indication of Deltapsi(M) dissipation. Furthermore, inhibition of mPTP opening by cyclosporin A partially prevented Cyto C release, caspase activation and neuronal death. These data suggest the involvement of bax, several caspases, as well as Cyto C release in KA-elicited neuronal death. Finally, inhibition of caspase-3 activity by z-VAD-fmk only partially protected neurons from KA toxicity, implying that multiple mechanisms may be involved in KA excitotoxicity.

Author-supplied keywords

  • Amino Acid Chloromethyl Ketones
  • Amino Acid Chloromethyl Ketones: pharmacology
  • Animals
  • Apoptosis
  • Apoptosis: drug effects
  • Apoptosis: physiology
  • Brain Diseases
  • Brain Diseases: metabolism
  • Brain Diseases: physiopathology
  • Caspase Inhibitors
  • Caspases
  • Caspases: metabolism
  • Cells
  • Cultured
  • Cultured: drug effects
  • Cultured: enzymology
  • Cyclosporine
  • Cyclosporine: pharmacology
  • Cytochrome c Group
  • Cytochrome c Group: drug effects
  • Cytochrome c Group: metabolism
  • Cytosol
  • Cytosol: drug effects
  • Cytosol: enzymology
  • Enzyme Inhibitors
  • Enzyme Inhibitors: pharmacology
  • Excitatory Amino Acid Agonists
  • Excitatory Amino Acid Agonists: pharmacology
  • Hippocampus
  • Hippocampus: drug effects
  • Hippocampus: enzymology
  • Hippocampus: physiopathology
  • Immunohistochemistry
  • Kainic Acid
  • Kainic Acid: pharmacology
  • Membrane Potentials
  • Membrane Potentials: drug effects
  • Membrane Potentials: physiology
  • Messenger
  • Messenger: metabolism
  • Mitochondria
  • Mitochondria: drug effects
  • Mitochondria: enzymology
  • Mitochondria: pathology
  • Nerve Degeneration
  • Nerve Degeneration: enzymology
  • Nerve Degeneration: physiopathology
  • Neurons
  • Neurons: drug effects
  • Neurons: enzymology
  • Neurons: pathology
  • Neuroprotective Agents
  • Neuroprotective Agents: pharmacology
  • Neurotoxins
  • Neurotoxins: pharmacology
  • Newborn
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Proto-Oncogene Proteins: genetics
  • Proto-Oncogene Proteins: metabolism
  • Pyramidal Cells
  • Pyramidal Cells: drug effects
  • Pyramidal Cells: enzymology
  • Pyramidal Cells: pathology
  • RNA
  • Rats
  • bcl-2-Associated X Protein

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  • W Liu

  • R Liu

  • J T Chun

  • R Bi

  • W Hoe

  • S S Schreiber

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