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

Phencyclidine and other N-methyl-D-aspartate receptor antagonists are toxic to pyramidal neurons in the posterior cingulate/retrosplenial cortex of ra t brain. Previous studies have shown induction of heat shock protein 70 in affected neurons, In this study, expression of haem oxygenase-l, a heat sho ck 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 phencyc lidine-treated rats revealed a marked induction of haem oxygenase-l mRNA an d protein, respectively, Immunohistochemistry studies revealed that phencyc lidine increased haem oxygenase-l immunoreactivity primarily in posterior c ingulate/retrosplenial, piriform and entorhinal cortices, striatum and hipp ocampus, Haem oxygenase-1 protein was induced in non-neuronal cells, mainly astrocytes. Some microglia expressing haem oxygenase-l protein were also f ound in the posterior cingulate/retrosplenial cortex. Haem oxygenase-l immu noreactive astrocytes and microglia were present in close proximity to the heat shock protein 70-positive neurons in the posterior cingulate/retrosple nial cortex following phencyclidine. Pretreatment of rats with 1,3-dimethyl thiourea, an antioxidant, significantly reduced haem oxygenase-l protein in duction by phencyclidine. Thus, induction of haem oxygenase-l in glia by ph encyclidine appears to be mediated mostly by oxidative stress, Experiments with the amino cupric silver stain for neuronal degeneration revealed phenc yclidine-induced neurotoxicity in the posterior cingulate/retrosplenial cor tex. The number of affected neurons was significantly reduced after 1,3-dim ethylthiourea pretreatment. This suggests that the neurotoxicity of N-methy l-D-aspartate antagonists is due in part to the oxidative stress and may be amenable to therapeutic interventions.