The possible role of the Akt signaling pathway in schizophrenia

Zheng, Wenhua; Wang, Haitao; Zeng, Zhiwen; Lin, Jun; Little, Peter J.; Srivastava, Lalit K.; Quirion, Rémi

doi:10.1016/j.brainres.2012.06.032

Cited by 113 publications

(84 citation statements)

References 171 publications

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“…Like resveratrol in the present study, high frequency stimulation can induce AKT Thr308 phosphorylation, without affecting total protein levels (Tsokas et al, 2007; though see Sui et al, 2008). AKT function has been associated with prefrontal cortex structural alterations in both humans and mice (Lai et al, 2006;Tan et al, 2008), together with alterations in social information processing and mental health conditions associated with disordered mood, such as depression, autism, bipolar disorder and schizophrenia (De Lacy and King, 2013;Ebert and Greenberg, 2013;Emamian, 2012;Kitagishi et al, 2012;Marsden, 2013;Zheng et al, 2012). Resveratrol increased Thr308 phosphorylation of AKT, noteworthy as the brains of depressed (suicide and non-suicide) subjects exhibit prefrontal cortex reductions in AKT enzymatic activity, including Thr308 phosphorylation, and also in the absence of protein level changes (Dwivedi et al, 2010;Kar ege et al, 2011Kar ege et al, , 2007.…”

Section: Discussionmentioning

confidence: 61%

Social deficits induced by peripubertal stress in rats are reversed by resveratrol

Poirier

Imamura

Zanoletti

et al. 2014

Journal of Psychiatric Research

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a b s t r a c tAdolescence is increasingly recognized as a critical period for the development of the social system, through the maturation of social competences and of their underlying neural circuitries. The present study sought to test the utility of resveratrol, a dietary phenol recently reported to have mood lifting properties, in modulating social interaction that is deficient following early life adversity. The main aims were to 1) pharmacologically restore normative social investigation levels dampened by peripubertal stress in rats and 2) identify neural pathways engaged by this pharmacological approach. Following peripubertal (P28e42) stress consisting of unpredictable exposures to fearful experiences, at adulthood the subjects' propensity for social exploration was examined in the three-chamber apparatus, comparing time invested in social or non-social investigation. Administered intraperitoneally 30 min before testing, resveratrol (20 mg/kg) normalized the peripubertal stress-induced social investigation deficit seen in the vehicle group, selectively altering juvenile but not object exploration. Examination of prefrontal cortex subregion protein samples following acute resveratrol treatment in a separate cohort revealed that while monoamine oxidase A (MAOA) enzymatic activity remained unaltered, nuclear AKT activation was selectively increased in the infralimbic cortex, but not in the prelimbic or anterior cingulate cortex. In contrast, androgen receptor nuclear localization was increased in the prelimbic cortex, but not in the infralimbic or anterior cingulate cortex. This demonstration that social contact deficits are reversed by resveratrol administration emphasizes a prosocial role for this dietary phenol, and evokes the possibility of developing new treatments for social dysfunctions.

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Section: Discussionmentioning

confidence: 61%

Social deficits induced by peripubertal stress in rats are reversed by resveratrol

Poirier

Imamura

Zanoletti

et al. 2014

Journal of Psychiatric Research

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“…For instance, the brain and lymphocytes from schizophrenic patients contain low levels of Akt1 protein and its substrate, GSK3β, has reduced phosphorylation (Emamian et al, 2004). In addition, mutation of AKT1 has been suggested as a susceptibility gene for schizophrenia (Emamian et al, 2004;Zheng et al, 2012) and APDs enhance phosphorylation of Akt1 and GSK3β in vitro and in vivo (Emamian et al, 2004;Park et al, 2011;Deslauriers et al, 2013). As Akt and GSK3 responses are mediated through ligands that are biased for βArr signaling, this may represent a novel approach to treat schizophrenia.…”

Section: Introductionmentioning

confidence: 99%

Effects of β-Arrestin-Biased Dopamine D2 Receptor Ligands on Schizophrenia-Like Behavior in Hypoglutamatergic Mice

Park

Chen

Schmerberg

et al. 2015

Neuropsychopharmacol

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Current antipsychotic drugs (APDs) show efficacy with positive symptoms, but are limited in treating negative or cognitive features of schizophrenia. Whereas all currently FDA-approved medications target primarily the dopamine D2 receptor (D2R) to inhibit G i/omediated adenylyl cyclase, a recent study has shown that many APDs affect not only G i/o -but they can also influence β-arrestin-(βArr)-mediated signaling. The ability of ligands to differentially affect signaling through these pathways is termed functional selectivity. We have developed ligands that are devoid of D2R-mediated G i/o protein signaling, but are simultaneously partial agonists for D2R/βArr interactions. The purpose of this study was to test the effectiveness of UNC9975 or UNC9994 on schizophrenia-like behaviors in phencyclidinetreated or NR1-knockdown hypoglutamatergic mice. We have found the UNC compounds reduce hyperlocomotion in the open field, restore PPI, improve novel object recognition memory, partially normalize social behavior, decrease conditioned avoidance responding, and elicit a much lower level of catalepsy than haloperidol. These preclinical results suggest that exploitation of functional selectivity may provide unique opportunities to develop drugs with fewer side effects, greater therapeutic selectivity, and enhanced efficacy for treating schizophrenia and related conditions than medications that are currently available.

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“…The Akt kinase regulates processes of cellular proliferation and survival and is activated by growth factors, hormones, and chemical drugs [20]. The forkhead transcription factor family, FoxO (forkhead box, O class), including FoxO1, 3, 4, and 6, are downstream targets of Akt.…”

Section: Introductionmentioning

confidence: 99%

Huang Qi Huai Granules Induce Apoptosis in Acute Lymphoblastic Leukemia Cells through the Akt/FoxO1 Pathway

Han¹,

Lin²,

Zeng³

et al. 2016

Cell Physiol Biochem

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Background/Aims: In recent years, a traditional Chinese medicine named Huang Qi Huai (HQH) has been frequently used in China for solid tumor therapy. However, the role of HQH on leukemia cells and its underlying mechanisms have not been elucidated. In this study, we investigated the effect of HQH on the proliferation and apoptosis of acute lymphoblastic leukemia (ALL) cell lines. Methods: Sup-B15 and Nalm-6 cells were treated with gradient doses of HQH for 24, 48 or 72 h. Cell viability was measured using a CCK8 assay and cell cycle distribution and apoptosis levels were analyzed using flow cytometry. Western blotting was used to assess the levels of proteins associated with the apoptotic pathway. Results: The results revealed that cell survival decreased significantly with increasing concentrations of HQH. HQH induced G2 cell-cycle arrest and cell apoptosis in a dose-dependent manner. HQH inhibited phosphorylated-Akt, phosphorylated- FoxO1 and Bcl2 expression and upregulated Bim, cleaved-caspase-3 and Bax expression in a dose-dependent manner, which suggests that HQH induces the apoptosis of ALL cells via the Akt/FoxO1 pathway. Conclusion: HQH is a potential complementary agent for the treatment of acute lymphoblastic leukemia.

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The possible role of the Akt signaling pathway in schizophrenia

Cited by 113 publications

References 171 publications

Social deficits induced by peripubertal stress in rats are reversed by resveratrol

Social deficits induced by peripubertal stress in rats are reversed by resveratrol

Effects of β-Arrestin-Biased Dopamine D2 Receptor Ligands on Schizophrenia-Like Behavior in Hypoglutamatergic Mice

Huang Qi Huai Granules Induce Apoptosis in Acute Lymphoblastic Leukemia Cells through the Akt/FoxO1 Pathway

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