Epidermal growth factor induces oxidative neuronal injury in cortical culture

J Neurochem. 2000 Jul;75(1):298-303. doi: 10.1046/j.1471-4159.2000.0750298.x.


Recently, we have demonstrated that certain neurotrophic factors can induce oxidative neuronal necrosis by acting at the cognate tyrosine kinase-linked receptors. Epidermal growth factor (EGF) has neurotrophic effects via the tyrosine kinase-linked EGF receptor (EGFR), but its neurotoxic potential has not been studied. Here, we examined this possibility in mouse cortical culture. Exposure of cortical cultures to 1-100 ng/ml EGF induced gradually developing neuronal death, which was complete in 48-72 h; no injury to astrocytes was noted. Electron microscopic findings of EGF-induced neuronal death were consistent with necrosis; severe mitochondrial swelling and disruption of cytoplasmic membrane occurred, whereas nuclei appeared relatively intact. The EGF-induced neuronal death was accompanied by increased free radical generation and blocked by the anti-oxidant Trolox. Suggesting mediation by the EGFR, an EGFR tyrosine kinase-specific inhibitor, C56, attenuated EGF-induced neuronal death. In addition, inhibitors of extracellular signal-regulated protein kinase 1/2 (Erk-1/2) (PD98056), protein kinase A (H89), and protein kinase C (GF109203X) blocked EGF-induced neuronal death. A p38 mitogen-activated protein kinase inhibitor (SB203580) or glutamate antagonists (MK-801 and 6-cyano-7-nitroquinoxaline-2,3-dione) showed no protective effect. The present results suggest that prolonged activation of the EGFR may trigger oxidative neuronal injury in central neurons.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 6-Cyano-7-nitroquinoxaline-2,3-dione / pharmacology
  • Animals
  • Cell Death*
  • Cells, Cultured
  • Cerebral Cortex / cytology*
  • Dizocilpine Maleate / pharmacology
  • Embryo, Mammalian
  • Enzyme Inhibitors / pharmacology
  • Epidermal Growth Factor / administration & dosage
  • Epidermal Growth Factor / toxicity*
  • ErbB Receptors / antagonists & inhibitors
  • ErbB Receptors / physiology
  • Excitatory Amino Acid Antagonists / pharmacology
  • Mice
  • Microscopy, Electron
  • Neurons / cytology*
  • Oxidative Stress*
  • Phosphorylation
  • Protein Kinase Inhibitors
  • Protein Kinases / metabolism
  • Time Factors


  • Enzyme Inhibitors
  • Excitatory Amino Acid Antagonists
  • Protein Kinase Inhibitors
  • Epidermal Growth Factor
  • Dizocilpine Maleate
  • 6-Cyano-7-nitroquinoxaline-2,3-dione
  • Protein Kinases
  • ErbB Receptors