Role of the PI-3K/Akt and ERK pathways in phencyclidine-induced neurotoxicity in neonatal rats and the protection by lithium and BDNF
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Phencyclidine is an N-methyl-D-aspartate receptor (NMDAR) open channel blocker that causes schizophrenia-like symptoms in healthy humans and exacerbates psychoses in schizophrenics. In animals, PCP administration to immature rats causes wide spread neuronal death during brain development and results in behavioral deficits that resemble those observed in schizophrenic patients in later life. The purpose of this study was to investigate the mechanisms of PCP-induced neurotoxicity as well as the protection by lithium and brain-derived neurotrophic factor (BDNF). In corticostriatal slice cultures, we found that lithium and BDNF, inhibited PCP-induced caspase-3 activation and DNA fragmentation in a concentration-dependent manner, respectively. Lithium and BDNF also prevented the inhibitory action of PCP on the phosphatidylinositol-3 kinase (PI-3K)/Akt and extracellular regulated kinase (ERK) pathways and suppressed activation of the pro-apoptotic factor, glycogen synthase kinase-3â (GSK-3â), evoked by PCP. Furthermore, blocking either the PI-3K/Akt or the ERK pathway abolished the protective effects of lithium and BDNF. Western blot analysis revealed that the PI-3K/Akt and ERK pathways were stimulated by lithium and BDNF in parallel; however, inhibition of ERK and PI-3K cooperatively regulated GSK-3â activity by reducing its phosphorylation at serine 9. In vivo, acute PCP administration to rats on postnatal day (PN) 7 caused inhibition of Akt and ERK and activation of GSK-3â in the three brain regions examined (frontal cortex, striatum, and hippocampus). After the last dose of subchronic PCP administration on PN 7, 9, 11, inhibition of ERK was still found in the three regions, though it lasted for a much shorter period than after administration on PN 7 only; Inhibition of Akt was only observed in the frontal cortex; GSK-3â activity was not affected in any of the regions. Finally, subchronic PCP administration during brain development resulted in dysregulation of the PI-3K/Akt and ERK pathways upon PCP challenge in adolescence (PN 35). These studies strongly suggest that the PI-3K/Akt and ERK pathways are two important signaling transductions implicated in PCP-induced neurotoxicity in developing brains and in the protection of lithium and BDNF.