Cerebellar toxicity of phencyclidine.
Phencyclidine (PCP), dizocilpine maleate (MK801), and other NMDA antagonists are toxic to neurons in the posterior cingulate and retrosplenial cortex. To determine if additional neurons are damaged, the distribution of microglial activation and 70 kDa heat shock protein (HSP70) induction was studied following the administration of PCP and MK801 to rats. PCP (10-50 mg/kg) induced microglial activation and neuronal HSP70 mRNA and protein expression in the posterior cingulate and retrosplenial cortex. In addition, coronal sections of the cerebellar vermis of PCP (50 mg/kg) treated rats contained vertical stripes of activated microglial in the molecular layer. In the sagittal plane, the microglial activation occurred in irregularly shaped patches, suggesting damage to Purkinje cells. In accord with this finding, PCP induced HSP70 protein and mRNA expression in Purkinje cells. Although there were relatively few foci of microglial activation and cells with HSP70 protein induction, HSP70 mRNA was detected in many Purkinje cells located throughout the cerebellar hemispheres as well as the vermis. MK801, at doses of 5-10 mg/kg, induced microglial activation and neuronal HSP70 mRNA and protein expression in the cingulate and retrosplenial cortex but not in the cerebellum. At the dose of 1 mg/kg MK801 induced HSP70 but did not consistently activate microglia. These data suggest that microglia are activated by MK801 doses that kill or severely damage neurons, whereas HSP70 is induced in "stressed" neurons at MK801 doses well below those that produce severe neurotoxicity. These observations suggest that PCP, but not MK801, is toxic to Purkinje cells and raise the question of whether NMDA antagonists or sigma ligands other than PCP are toxic to the cerebellum. Moreover, this study illustrates the usefulness of microglial activation and HSP70 induction as markers of neurotoxicity.
Näkki
R
R
Department of Neurology, University of California, San Francisco 94121.
Koistinaho
J
J
Sharp
F R
FR
Sagar
S M
SM
D000818:Animals; D001483:Base Sequence; D002531:Cerebellum / Q000187:drug effects*; D016291:Dizocilpine Maleate / Q000494:pharmacology / Q000633:toxicity*; D005786:Gene Expression Regulation / Q000187:drug effects; D006179:Gyrus Cinguli / Q000187:drug effects; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D017628:Microglia / Q000187:drug effects; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics; D010296:Parietal Lobe / Q000187:drug effects; D010622:Phencyclidine / Q000633:toxicity*; D011689:Purkinje Cells / Q000187:drug effects; D017966:Pyramidal Cells / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000502:physiology; D017480:Receptors, sigma / Q000187:drug effects / Q000502:physiology
D018840:HSP70 Heat-Shock Proteins; D009419:Nerve Tissue Proteins; D016194:Receptors, N-Methyl-D-Aspartate; D017480:Receptors, sigma; D016291:Dizocilpine Maleate; D010622:Phencyclidine