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

Xia, Yan; Wang, Cheng Z.; Liu, Jie; Anastasio, Noelle C.; Johnson, Kenneth M.

doi:10.1124/jpet.107.133272

Cited by 24 publications

(25 citation statements)

References 39 publications

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“…The antipsychotic, sertindole, and ampakine CX516 (an AMPA receptor modulator) were able to attenuate these deficits in attentional set-shifting (109). Neonatal PCP administration was also associated with apoptosis of GABAergic interneurons in the primary somatosensory, motor, and retrosplenial cortices as well as neurodegeneration in the striatum and hippocampus, an effect that could be attenuated by treatment with lithium (110, 111). …”

Section: Neurodevelopmental Animal Models Of Schizophreniamentioning

confidence: 99%

Neurodevelopmental Animal Models of Schizophrenia: Role in Novel Drug Discovery and Development

Wilson

Terry

2010

Clinical Schizophrenia & Related Psychoses

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Schizophrenia is a devastating mental illness that is associated with a lifetime of disability. For patients to successfully function in society, the amelioration of disease symptoms is imperative. The recently published results of two large antipsychotic clinical trials (e.g., CATIE, CUtLASS) clearly exemplified the limitations of currently available treatment options for schizophrenia, and further highlighted the critical need for novel drug discovery and development in this field. One of the biggest challenges in schizophrenia-related drug discovery is to find an appropriate animal model of the illness so that novel hypotheses can be tested at the basic science level. A number of pharmacological, genetic, and neurodevelopmental models have been introduced; however, none of these models has been rigorously evaluated for translational relevance or to satisfy requirements of “face,” “construct” and “predictive” validity. Given the apparent polygenic nature of schizophrenia and the limited translational significance of pharmacological models, neurodevelopmental models may offer the best chance of success. The purpose of this review is to provide a general overview of the various neurodevelopmental models of schizophrenia that have been introduced to date, and to summarize their behavioral and neurochemical phenotypes that may be useful from a drug discovery and development standpoint. While it may be that, in the final analysis, no single animal model will satisfy all the requirements necessary for drug discovery purposes, several of the models may be useful for modeling various phenomenological and pathophysiological components of schizophrenia that could be targeted independently with separate molecules or multi-target drugs.

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Section: Neurodevelopmental Animal Models Of Schizophreniamentioning

confidence: 99%

Neurodevelopmental Animal Models of Schizophrenia: Role in Novel Drug Discovery and Development

Wilson

Terry

2010

Clinical Schizophrenia & Related Psychoses

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“…These findings imply that transient disruptions in NMDAR-related signals during this critical period can underpin long-term abnormalities. However, although several studies have suggested possible mechanisms, such as NMDAR antagonist-induced apoptotic neurodegeneration Hansen et al 2004 ;Ikonomidou et al 1999 ;Lei et al 2008 ;Lema Tome et al 2006 ;Xia et al 2008), it still requires further investigation.…”

Section: Introductionmentioning

confidence: 97%

Effects of neonatal MK-801 treatment on p70S6K-S6/eIF4B signal pathways and protein translation in the frontal cortex of the developing rat brain

Kim

Park

Kim

et al. 2010

Int. J. Neuropsychopharm.

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Systemic injections of MK-801, a selective NMDAR antagonist, into neonatal rats induces long-term neurochemical and behavioural changes. It has been suggested that these changes form the neurodevelopmental basis for schizophrenia-like behaviour in rats. In this study, 7-d-old rats were treated with MK-801, and their frontal cortices were examined to investigate the effects on p70S6K-S6 signal pathway and on protein translation, which play crucial roles in the neurodevelopmental process. MK-801, in doses of 0.5 and 1.0 mg/kg, induced a decrease in phosphorylation of p70S6K and its substrates, S6 and eIF4B, in the first 8 h, and no change at 24 and 48 h. These effects were more prominent after two injections of MK-801 than one. Decreased S6 phosphorylation by MK-801 was evident in the prefrontal, cingulate, and insular cortex. In two representative upstream p70S6K-S6 pathways related to ERK1/2 and Akt, changes in ERK1/2-p90RSK phosphorylation were accompanied by changes of p70S6K-S6. Although two MK-801 injections induced a dose-dependent decrease in phosphorylation of Akt and mTOR at 4 and 8 h, a single injection did not produce a significant effect. Protein synthesis rate, measured by [3H]leucine incorporation in frontal cortical tissue, was reduced until 24 h after two MK-801 (1.0 mg/kg) injections. In summary, this study found that neonatal MK-801 treatment induced dysregulation in the p70S6K-S6/eIF4B pathway and protein translation in the frontal cortex of the developing rat brain, which may suggest an important role of protein translation machinery in the MK-801 neurodevelopmental animal model of schizophrenia.

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“…In support of this, it has been shown that postnatal PCP injections resulted in lower levels of phosphorylated ERK1/2 in the hippocampus of juvenile rats compared to controls 49,50 . Furthermore PCP treatment in organotypic brain slice culture from rats showed decreased phosphorylation levels of MEK1/2 and ERK1/2, both downstream signaling partners of p75 cell survival pathways, suggesting that PCP may induce cell death through the inhibition of the MEK/ERK/1/2 prosurvival pathways 51 ( Figure 2). The expression pattern of p75 and TROY seems to recover over time, normalizing around adolescence as there are no significant differences in either p75 or TROY expression in the 5 week old rats (p>0.05).…”

Section: Alterations Of P75 Troy and Myt1 In A Pcp Induced Neurodevementioning

confidence: 99%

Alterations of p75 neurotrophin receptor and Myelin transcription factor 1 in the hippocampus of perinatal phencyclidine treated rats

Andrews

Newell

Matosin

et al. 2015

Progress in Neuro-Psychopharmacology and Biological Psychiatry

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(2015). Alterations of p75 neurotrophin receptor and Myelin transcription factor 1 in the hippocampus of perinatal phencyclidine treated rats. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 63 91-97.Alterations of p75 neurotrophin receptor and Myelin transcription factor 1 in the hippocampus of perinatal phencyclidine treated rats AbstractPostnatal administration of phencyclidine (PCP) in rodents causes major disturbances to neurological processes resulting in severe modifications to normal behavioral traits into adulthood. It is routinely used to model psychiatric disorders such as schizophrenia, producing many of the dysfunctional processes in the brain that are present in this devastating disorder, including elevated levels of apoptosis during neurodevelopment and disruptions to myelin and plasticity processes. Lingo-1 (or Leucine-rich repeat and immunoglobulin domain-containing protein) is responsible for negatively regulating neurite outgrowth and the myelination of axons. Recent findings using a postmortem human brain cohort showed that Lingo-1 signaling partners in the Nogo receptor (NgR)/p75/TNF receptor orphan Y (TROY) signaling complex, and downstream signaling partners With No Lysine (K) (WNK1) and Myelin transcription factor 1 (Myt1), play a significant part in schizophrenia pathophysiology. Here we have examined the implication of Lingo-1 and its signaling partners in a neurodevelopmental model of schizophrenia using PCP to determine if these pathways are altered in the hippocampus throughout different stages of neurodevelopment. Male Sprague-Dawley rats were injected subcutaneously with PCP (10 mg/kg) or saline solution on postnatal days (PN) 7, 9, and 11. Rats (n = 6/group) were sacrificed at PN12, 5 weeks, or 14 weeks. Relative expression levels of Lingo-1 signaling proteins were examined in the hippocampus of the treated rats. p75 and Myt1 were decreased (0.001 ≤ p ≤ 0.011) in the PCP treated rats at PN12. There were no significant changes in any of the tested proteins at 5 weeks (p > 0.05). At 14 weeks, p75, TROY, and Myt1 were increased in the PCP treated rats (0.014 ≤ p ≤ 0.022). This is the first report of an alteration in Lingo-1 signaling proteins in the rat hippocampus, both directly after PCP treatment in early development and in adulthood. Based on our results, we propose that components of the Lingo-1 signaling pathways may be involved in the acute neurotoxicity induced by perinatal administration of PCP in rats early in development and suggest that this may have implications for the hippocampal deficits seen in schizophrenia. Male Sprague Dawley rats were injected subcutaneously with PCP (10mg/kg) or saline solution on postnatal days (PN)7, 9 and 11. Rats (n=6/group) were sacrificed at PN12, 5 weeks or 14 weeks. Relative expression levels of Lingo-1 signaling proteins were examined in the hippocampus of the treated rats. p75 and Myt1 were decreased (0.001≤p≤0.011) in the PCP treated rats at PN12. There were no significant changes in any of the tested proteins at 5 we...

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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

Cited by 24 publications

References 39 publications

Neurodevelopmental Animal Models of Schizophrenia: Role in Novel Drug Discovery and Development

Neurodevelopmental Animal Models of Schizophrenia: Role in Novel Drug Discovery and Development

Effects of neonatal MK-801 treatment on p70S6K-S6/eIF4B signal pathways and protein translation in the frontal cortex of the developing rat brain

Alterations of p75 neurotrophin receptor and Myelin transcription factor 1 in the hippocampus of perinatal phencyclidine treated rats

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