Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.16.2 (PCP)
 3,761 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chronic administration of phencyclidine (PCP) to rats has been demonstrated to produce a sensitized locomotor response to PCP challenge that is associated with apoptotic cell death and an up-regulation of the N-methyl-D-aspartate (NMDA) receptor. To determine the underlying mechanisms, dissociated forebrain cultures were treated for 2 days with 3 microM PCP. After washout of PCP, NMDA was added (in the presence of Mg(2+)) for 20 h. The uptake of a vital dye and the release of lactate dehydrogenase measured cell viability. Apoptosis was assessed by an enzyme-linked immunosorbent assay that was specific for fragmented (histone-associated) DNA and an in situ assay for nicked DNA, terminal dUTP nick-end labeling. These assays showed that the effect of a nontoxic concentration of NMDA (30 microM) became lethal to approximately one-third of the neurons after chronic (48-h) PCP treatment. This treatment also resulted in a 47% increase in NR1 subunit mRNA, suggesting that NMDA-induced neuronal cell death after chronic PCP is due to NMDA receptor up-regulation. Furthermore, exposure of PCP-treated cultures to NMDA led to increased expression of Bax and decreased expression of Bcl-X(L). The Bcl-X(L)/Bax ratio was markedly decreased by 30 microM NMDA in the PCP-treated, but not control, cultures. Addition of superoxide dismutase and catalase prevented the decrease in Bcl-X(L)/Bax. This study suggests that NMDA-induced changes in Bax and/or Bcl-X(L) involve the formation of reactive oxygen species. By extrapolation, these data suggest that PCP-induced apoptosis in vivo may involve similar mechanisms and that cultured neurons may be a suitable model for the mechanistic study PCP toxicity in vivo.
 ...
PMID:Mechanisms of N-methyl-D-aspartate-induced apoptosis in phencyclidine-treated cultured forebrain neurons. 1087 24

Repetitive administration of phencyclidine (PCP) in the perinatal period results in cortical apoptosis and a long-lasting deficit in sensorimotor gating. Because these changes are olanzapine-sensitive, we have suggested that the effects of perinatal PCP could be used to model certain aspects of schizophrenia. Studies of PCP and N-methyl-D-aspartate-induced cell death suggested that superoxide could play a role in the pathway leading to death after PCP administration. The purpose of the current study was to determine whether the in vivo administration of M40403, a superoxide dismutase mimetic, could prevent PCP-induced cortical apoptosis and/or deficits in prepulse inhibition. Perinatal rat pups were administered 10 mg/kg PCP on postnatal (PN) days 7, 9, and 11 with or without treatment with 10 mg/kg M40403. Pups were either killed on PN 12 for analysis of various apoptotic markers or they were assessed for prepulse inhibition on PN 24 to 26. Treatment with M40403 2 and 24 h after each PCP treatment prevented PCP-induced increases in two measures of apoptosis in the dorsolateral frontal cortex and in the olfactory cortex. PCP-induced proapoptotic changes in Bax and Bcl-X(L) were also prevented by M40403 treatment. This regimen did not prevent the deficit in prepulse inhibition caused by PCP treatment, but when the treatment regimen was extended through PN 23, M40403 completely prevented the PCP-induced deficit in prepulse inhibition. These data suggest that perinatal PCP treatment leads to long-lasting changes in the pathway(s), leading to cell death and behavioral deficits, and that the superoxide radical plays a critical role in the underlying mechanism.
 ...
PMID:Blockade of phencyclidine-induced cortical apoptosis and deficits in prepulse inhibition by M40403, a superoxide dismutase mimetic. 1249 Jun