Cerebellar toxicity of phencyclidine

Abstract

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.

Spatiotemporal Analysis of Purkinje Cell Degeneration Relative to Parasagittal Expression Domains in a Model of Neonatal Viral Infection

“…We found a prominent striped alignment of microglia in the CBLM of PND28 NBD rats, with the highest density of microglia in zebrin II/EAAT4-negative zones. The phenomenon of microglial striping in CBLM was previously reported following phencyclidine injection and traumatic brain injury (21,41). Morphology of PCs.…”

Atypical Antipsychotics and a Src Kinase Inhibitor (PP1) Prevent Cortical Injury Produced by the Psychomimetic, Noncompetitive NMDA Receptor Antagonist MK-801

“…It has been demonstrated in injured, vacuolated neurons and Hsp70 immunostaining has been used as a marker for neuronal injury following administration of MK-801, ketamine and phencyclidine (PCP) (Olney et al, 1991;Sharp et al, 1991Sharp et al, , 1992Sharp et al, , 1994aNakki et al, 1995Nakki et al, , 1996Rajdev et al, 1998;Tomitaka et al, 2000a, b). Hsp70 protein is induced by the presence of denatured proteins in cells and is generally induced in cells that will survive an injury (Sharp et al, 1999).…”

Excitatory Actions of NMDA Receptor Antagonists in Rat Entorhinal Cortex and Cultured Entorhinal Cortical Neurons

“…These effects are characterized by reversible intracellular vacuolization (Olney et al 1989) and induction of mRNAs for c-fos (Dragunow and Faull 1990;Hughes et al 1993;Näkki et al 1996), heat shock protein 70 (HSP70) (Sharp et al 1991(Sharp et al , 1994Näkki et al 1995), and brain-derived neurotrophic factor (BDNF) Hughes et al 1993). Induction of cfos and BDNF is typically observed in activated neurons and we therefore tentatively call these effects "ex- citatory" to distinguish them from the prevention of excitation, which is the typical effect of NMDA receptor antagonists in other brain areas.…”