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)

TCHQ is a major carcinogenic metabolite of the widely used wood preservative PCP. Recently, we found that TCHQ was a promoter in a mouse skin carcinogenesis model. However, the mechanism is still not clear. In this study, we showed that overexpression of Bcl-2 effectively suppressed TCHQ-induced apoptosis in NIH3T3 cells, as evidenced by morphological changes and DNA fragmentation. Although production of ROS contributes to TCHQ-induced apoptosis, Bcl-2 failed to attenuate TCHQ-elicited increase of intracellular ROS level. In addition, overexpressed Bcl-2 provides only partial protection against TCHQ-induced cellular DNA damage. We also found that TCHQ induced a change in mitochondrial transmembrane potential, and that caspase-9 and subsequent caspase-3 can be activated during TCHQ-induced acute apoptosis. Interestingly, TCHQ induced a significant upregulation of Bcl-2 expression, and over-expressed Bcl-2 can dramatically inhibit the change of mitochondria membrane potential and activation of both caspase-9 and -3. Thus, our results suggest TCHQ-induced tumor promotion may be through a mechanism of upregulation of Bcl-2 protein and subsequent apoptosis inhibition.
 ...
PMID:Bcl-2 overexpression inhibits tetrachlorohydroquinone-induced apoptosis in NIH3T3 cells: a possible mechanism for tumor promotion. 1510 27

This study determined the role of caspase-3 in phencyclidine (PCP)-induced neurodegeneration in postnatal rats. PCP administration to postnatal day 7 rats induced a dose-dependent increase in caspase-3 enzymatic activity in frontal cortex, striatum, and hippocampus. Enzymatic activation was present at 4 h, peaked between 6 and 12 h, and disappeared by 24 h. Further, cleaved caspase-3-immunoreactive neurons were detected as early as 2 h in the cortex, and were found throughout the brain, including, in addition, the thalamus and striatum. Within the cingulate, frontal, parietal, and retrosplenial cortices, immunoreactivity was specific for layers II-IV (especially layer II). Neurons positive for both silver staining and terminal deoxynucleotidyl transferase biotin-d-UTP nick-end labeling (TUNEL) were found in the same brain regions and subregions. Double labeling experiments confirmed that cleaved caspase-3 and TUNEL were coexpressed in many neurons in all brain regions and subregions studied. Temporal studies revealed that procaspase-3 cleavage preceded TUNEL staining by about 3 h, with many neurons being positive for both caspase-3 and TUNEL 9 h after PCP treatment. In organotypic corticostriatal slices, PCP caused a concentration- and time-dependent cleavage of procaspase-3 that was also colocalized with TUNEL staining in layers II-IV of the parietal cortex. Caspase-3 activation again preceded PCP-induced DNA damage assessed by TUNEL. PCP-induced neuronal death in vitro as measured by TUNEL staining was blocked 85% by Ac-AAVALLPAVLLALLAPDEVD-CHO, a cell-permeable selective caspase-3 inhibitor. These data demonstrate that caspase-3 activation plays a necessary role in the regionally selective neuronal death induced by PCP in the developing rat brain.
 ...
PMID:The role of caspase-3 activation in phencyclidine-induced neuronal death in postnatal rats. 1698 4

N-methyl-D-aspartate (NMDA) receptor antagonists such as phencyclidine (PCP) can induce positive and negative symptoms of schizophrenia in humans and related effects in rodents. PCP treatment of developing rats induces apoptotic neurodegeneration and behavioral deficits later in life that mimic some symptoms of schizophrenia. The precise mechanism of PCP-induced neural degeneration is unknown. This study used selective antagonists, siRNA, and Western analysis to investigate the role of the Akt-glycogen synthase kinase-3beta (GSK-3beta) pathway in PCP-induced neuronal apoptosis in both neuronal culture and postnatal day 7 rats. PCP administration in vivo and in vitro reduced the phosphorylation of Akt Ser427 and GSK-3beta Ser9, decreasing Akt activity and increasing GSK-3beta activity. The alteration of Akt-GSK-3beta signaling parallels the temporal profile of caspase-3 activation by PCP. Reducing GSK-3beta activity by application of selective inhibitors or depletion of GSK-3beta by siRNA attenuates caspase-3 activity and blocks PCP-induced neurotoxicity. Moreover, increasing synaptic strength by either activation of L-type calcium channels with BAY K8644 or potentiation of synaptic NMDA receptors with either a low concentration of NMDA or bicuculline plus 4-aminopyridine completely blocks PCP-induced cell death by increasing Akt phosphorylation. These neuroprotective effects are associated with activation of phosphoinositide-3-kinase-Akt signaling, and to a lesser extent, the MAPK signaling pathway. Overall, these data suggest that PCP-induced hypofunction of synaptic NMDA receptors impairs the Akt-GSK-3beta cascade, which is necessary for neuronal survival during development, and that interference with this cascade by PCP or natural factors may contribute to neural pathologies, perhaps including schizophrenia.
 ...
PMID:The role of Akt-GSK-3beta signaling and synaptic strength in phencyclidine-induced neurodegeneration. 1763 6

Phencyclidine (PCP) and other N-methyl-D-aspartate (NMDA) receptor antagonists have been shown to be neurotoxic to developing brains and to result in schizophrenia-like behaviors later in development. Prevention of both effects by antischizophrenic drugs suggests the validity of PCP neurodevelopmental toxicity as a heuristic model of schizophrenia. Lithium is used for the treatment of bipolar and schizoaffective disorders and has recently been shown to have neuroprotective properties. The present study used organotypic corticostriatal slices taken from postnatal day 2 rat pups to investigate the protective effect of lithium and the role of the phosphatidylinositol-3 kinase (PI-3K)/Akt and mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK/ERK) pathways in PCP-induced cell death. Lithium pretreatment dose-dependently reduced PCP-induced caspase-3 activation and DNA fragmentation in layers II to IV of the cortex. PCP elicited time-dependent inhibition of the MEK/ERK and PI-3K/Akt pathways, as indicated by dephosphorylation of ERK1/2 and Akt. The proapoptotic factor glycogen synthase kinase (GSK)-3beta was also dephosphorylated at serine 9 and thus activated. Lithium prevented PCP-induced inhibition of the two pathways and activation of GSK-3beta. Furthermore, blocking either PI-3K/Akt or MEK/ERK pathway abolished the protective effect of lithium, whereas inhibiting GSK-3beta activity mimicked the protective effect of lithium. However, no cross-talk between the two pathways was found. Finally, specific GSK-3beta inhibition did not prevent PCP-induced dephosphorylation of Akt and ERK. These data strongly suggest that the protective effect of lithium against PCP-induced neuroapoptosis is mediated through independent stimulation of the PI-3K/Akt and ERK pathways and suppression of GSK-3beta activity.
 ...
PMID:Lithium protection of phencyclidine-induced neurotoxicity in developing brain: the role of phosphatidylinositol-3 kinase/Akt and mitogen-activated protein kinase kinase/extracellular signal-regulated kinase signaling pathways. 1854 76

The mechanism underlying phencyclidine (PCP)-induced apoptosis in perinatal rats and the development of schizophrenia-like behaviors is incompletely understood. We used antagonists for N-methyl-D-aspartate (NMDA) receptor subunit NR2A- and NR2B-containing NMDA receptor to test the hypothesis that the behavioral and apoptotic effects of PCP are mediated by blockade of NR1/NR2A-containing receptors, rather than NR1/NR2B-containing receptors. Sprague-Dawley rats were treated on PN7, PN9, and PN11 with PCP (10 mg/kg), PEAQX (NR2A-preferring antagonist; 10, 20, or 40 mg/kg), or ifenprodil (selective NR2B antagonist; 1, 5, or 10 mg/kg) and sacrificed for measurement of caspase-3 activity (an index of apoptosis) or allowed to age and tested for locomotor sensitization to PCP challenge on PN28-PN35. PCP or PEAQX on PN7, PN9, and PN11 markedly elevated caspase-3 activity in the cortex; ifenprodil showed no effect. Striatal apoptosis was evident only after subchronic treatment with a high dose of PEAQX (20 mg/kg). Animals treated with PCP or PEAQX on PN7, PN9, and PN11 showed a sensitized locomotor response to PCP challenge on PN28-PN35. Ifenprodil treatment had no effect on either measure. Therefore, PCP blockade of cortical NR1/NR2A, rather than NR1/NR2B, appears to be responsible for PCP-induced apoptosis and the development of long-lasting behavioral deficits.
 ...
PMID:Differential role of N-methyl-D-aspartate receptor subunits 2A and 2B in mediating phencyclidine-induced perinatal neuronal apoptosis and behavioral deficits. 1965 40