Acute phencyclidine neurotoxicity in rat forebrain: Induction of haem oxygenase-1 and attenuation by the antioxidant dimethylthiourea

Sunita Rajdev, Andrew S. Fix, Frank R Sharp

Research output: Contribution to journalArticle

29 Scopus citations

Abstract

Phencyclidine and other N-methyl-D-aspartate receptor antagonists are toxic to pyramidal neurons in the posterior cingulate/retrosplenial cortex of rat brain. Previous studies have shown induction of heat shock protein 70 in affected neurons. In this study, expression of haem oxygenase-1, a heat shock protein induced by oxidative stress, was examined in rat forebrain after administration of a single intraperitoneal dose of phencyclidine (50 mg/kg). Northern and Western blot analyses of brain tissue extracts from phencyclidine-treated rats revealed a marked induction of haem oxygenase-1 mRNA and protein, respectively. Immunohistochemistry studies revealed that phencyclidine increased haem oxygenase-1 immunoreactivity primarily in posterior cingulate/retrosplenial, piriform and entorhinal cortices, striatum and hippocampus. Haem oxygenase-1 protein was induced in non-neuronal cells, mainly astrocytes. Some microglia expressing haem oxygenase-1 protein were also found in the posterior cingulate/retrosplenial cortex. Haem oxygenase-1 immunoreactive astrocytes and microglia were present in close proximity to the heat shock protein 70-positive neurons in the posterior cingulate/retrosplenial cortex following phencyclidine. Pretreatment of rats with 1,3-dimethylthiourea, an antioxidant, significantly reduced haem oxygenase-1 protein induction by phencyclidine. Thus, induction of haem oxygenase-1 in glia by phencyclidine appears to be mediated mostly by oxidative stress. Experiments with the amino cupric silver stain for neuronal degeneration revealed phencyclidine-induced neurotoxicity in the posterior cingulate/retrosplenial cortex. The number of affected neurons was significantly reduced after 1,3-dimethylthiourea pretreatment. This suggests that the neurotoxicity of N-methyl-D-aspartate antagonists is due in part to the oxidative stress and may be amenable to therapeutic interventions.

Original languageEnglish (US)
Pages (from-to)3840-3852
Number of pages13
JournalEuropean Journal of Neuroscience
Volume10
Issue number12
DOIs
StatePublished - Dec 1998
Externally publishedYes

Keywords

  • Dopamine
  • Haem oxygenase
  • Heat shock proteins
  • Neurodegeneration
  • NMDA receptor antagonists
  • Oxidative stress
  • Schizophrenia
  • Stress proteins

ASJC Scopus subject areas

  • Neuroscience(all)

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