Abstract
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)-3β was also dephosphorylated at serine 9 and thus activated. Lithium prevented PCP-induced inhibition of the two pathways and activation of GSK-3β. Furthermore, blocking either PI-3K/Akt or MEK/ERK pathway abolished the protective effect of lithium, whereas inhibiting GSK-3β activity mimicked the protective effect of lithium. However, no cross-talk between the two pathways was found. Finally, specific GSK-3β 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-3β activity.
Footnotes
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This work was supported by National Institutes of Health Grant DA-02073 (to K.M.J.).
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.107.133272.
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ABBREVIATIONS: NMDA, N-methyl-d-aspartate; MK-801, 5H-dibenzo[a,d]cyclohepten-5,10-imine (dizocilpine maleate); PCP, phencyclidine; BDNF, brain-derived neurotrophin factor; NMDAR, N-methyl-d-aspartate receptor; ERK, extracellular signal-regulated kinase; PI-3K, phosphotydylinositide-3 kinase; GSK, glycogen synthase kinase; AFC, 7-amino-4-trifluorocumarin; ANOVA, analysis of variance; TdT, deoxynucleotidyl transferase; TUNEL, terminal deoxynucleotidyl transferase dUTP nick-end labeling; LY294002 (LY), 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; AR-A014418 (AR-A), N-(4-methoxybenzyl)-N′-(5-nitro-1,3-thiazol-2-yl)urea; PD98059 (PD), 2′-amino-3′-methoxyflavone; MEK, mitogen-activated protein kinase kinase; TCN, triciribine; DIV, day in vitro; CHAPS, 3-[(3-cholamidopropyl)dimethylammonio]propanesulfonate; PBS, phosphate-buffered saline; p-, phosphorylated; SB216763, 3-(2,4-dichlorophenyl)-4-(1-methyl-1H-indol-3-yl)-1H-pyrrole-2.5-dione; U0126, 1,4-diamino-2,3-dicyano-1,4-bis(methylthio)butadiene; CTRL, control.
- Received October 24, 2007.
- Accepted June 9, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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