Oxidative stress induces a form of programmed cell death with characteristics of both apoptosis and necrosis in neuronal cells

J Neurochem. 1998 Jul;71(1):95-105. doi: 10.1046/j.1471-4159.1998.71010095.x.


Oxidative stress is implicated in a number of neurological disorders including stroke, Parkinson's disease, and Alzheimer's disease. To study the effects of oxidative stress on neuronal cells, we have used an immortalized mouse hippocampal cell line (HT-22) that is particularly sensitive to glutamate. In these cells, glutamate competes for cystine uptake, leading to a reduction in glutathione and, ultimately, cell death. As it has been reported that protein kinase C activation inhibits glutamate toxicity in these cells and is also associated with the inhibition of apoptosis in other cell types, we asked if glutamate toxicity was via apoptosis. Morphologically, glutamate-treated cells underwent plasma membrane blebbing and cell shrinkage, but no DNA fragmentation was observed. At the ultrastructural level, there was damage to mitochondria and other organelles although the nuclei remained intact. Protein and RNA synthesis inhibitors as well as certain protease inhibitors protected the cells from glutamate toxicity. Both the macromolecular synthesis inhibitors and the protease inhibitors had to be added relatively soon after the addition of glutamate, suggesting that protein synthesis and protease activation are early and distinct steps in the cell death pathway. Thus, the oxidative stress brought about by treatment with glutamate initiates a series of events that lead to a form of cell death distinct from either necrosis or apoptosis.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Chloromethyl Ketones / pharmacology
  • Animals
  • Apoptosis / drug effects
  • Apoptosis / physiology*
  • Aurintricarboxylic Acid / pharmacology
  • Buthionine Sulfoximine / pharmacology
  • Cell Line, Transformed / cytology
  • Cell Line, Transformed / enzymology
  • Cell Line, Transformed / ultrastructure
  • Cycloheximide / pharmacology
  • Cysteine Endopeptidases / metabolism
  • Cysteine Proteinase Inhibitors / pharmacology
  • DNA Fragmentation
  • Dactinomycin / pharmacology
  • Enzyme Inhibitors / pharmacology
  • Glutamic Acid / toxicity
  • Glutathione Synthase / metabolism
  • Hippocampus / cytology
  • Mice
  • Microscopy, Electron
  • Necrosis
  • Neurons / enzymology*
  • Neurons / pathology*
  • Neurons / ultrastructure
  • Oxidative Stress / physiology*
  • Protein Kinase C / metabolism
  • Protein Synthesis Inhibitors / pharmacology
  • RNA / metabolism
  • Sulfones / pharmacology
  • Trypsin Inhibitors / pharmacology


  • Amino Acid Chloromethyl Ketones
  • Cysteine Proteinase Inhibitors
  • Enzyme Inhibitors
  • N-acetyl-tyrosyl-valyl-alanyl-aspartyl chloromethyl ketone
  • Protein Synthesis Inhibitors
  • Sulfones
  • Trypsin Inhibitors
  • Dactinomycin
  • 4-(2-aminoethyl)benzenesulfonylfluoride
  • Glutamic Acid
  • Aurintricarboxylic Acid
  • Buthionine Sulfoximine
  • RNA
  • Cycloheximide
  • Protein Kinase C
  • Cysteine Endopeptidases
  • Glutathione Synthase