Haloperidol disrupts Akt signalling to reveal a phosphorylation-dependent regulation of pro-apoptotic Bcl-XS function

Wei, Zhao; Qi, Ji; Dai, Yunxiu; Bowen, Wayne D.; Mousseau, Darrell D.

doi:10.1016/j.cellsig.2008.10.005

Cited by 22 publications

(11 citation statements)

References 51 publications

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“…Pragmatically, the psychotic episodes may be correlated with metastasis in cancers. 36 Typical antipsychotic medications may have protective effects against cancer, 37 consistent also with our connectivity map results identifying fluphenazine as having an opposite gene expression profile to that of high delusions (Table 8). Lastly, the involvement of interleukin signaling canonical pathways suggests that anti-inflammatory and immune-modulating medications should to be more systematically evaluated for prevention and early intervention in psychotic disorders, consistent with some emerging clinical data.…”

Section: From Biomarkers To Biologysupporting

confidence: 82%

Identification of blood biomarkers for psychosis using convergent functional genomics

et al. 2009

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There are to date no objective clinical laboratory blood tests for psychotic disease states. We provide proof of principle for a convergent functional genomics (CFG) approach to help identify and prioritize blood biomarkers for two key psychotic symptoms, one sensory (hallucinations) and one cognitive (delusions). We used gene expression profiling in whole blood samples from patients with schizophrenia and related disorders, with phenotypic information collected at the time of blood draw, then cross-matched the data with other human and animal model lines of evidence. Topping our list of candidate blood biomarkers for hallucinations, we have four genes decreased in expression in high hallucinations states (Fn1, Rhobtb3, Aldh1l1, Mpp3), and three genes increased in high hallucinations states (Arhgef9, Phlda1, S100a6). All of these genes have prior evidence of differential expression in schizophrenia patients. At the top of our list of candidate blood biomarkers for delusions, we have 15 genes decreased in expression in high delusions states (such as Drd2, Apoe, Scamp1, Fn1, Idh1, Aldh1l1), and 16 genes increased in high delusions states (such as Nrg1, Egr1, Pvalb, Dctn1, Nmt1, Tob2). Twenty-five of these genes have prior evidence of differential expression in schizophrenia patients. Predictive scores, based on panels of top candidate biomarkers, show good sensitivity and negative predictive value for detecting high psychosis states in the original cohort as well as in three additional cohorts. These results have implications for the development of objective laboratory tests to measure illness severity and response to treatment in devastating disorders such as schizophrenia.

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Section: From Biomarkers To Biologysupporting

confidence: 82%

Identification of blood biomarkers for psychosis using convergent functional genomics

et al. 2009

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“…Our results appear to suggest similar apoptosis regulation mechanisms since we found higher levels of IL-1β and caspases, along with Bcl-2/BAX imbalance, in cells exposed to haloperidol and risperidone. In addition, findings yielded by studies in which other cells were used as experimental models suggest that cytotoxicity induced by haloperidol involves modulation of proteins that are members of the Bcl-2 family, such as Bcl-XS (Wei et al 2009).…”

Section: Discussionmentioning

confidence: 99%

Haloperidol and Risperidone at high concentrations activate an in vitro inflammatory response of RAW 264.7 macrophage cells by induction of apoptosis and modification of cytokine levels

et al. 2015

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Antipsychotic drugs, such as haloperidol and risperidone, are used in long-term treatment of psychiatric patients and thus increase the risk of obesity and other metabolic dysfunctions. Available evidence suggests that these drugs have pro-inflammatory effect, which contributes to the establishment of endocrine disturbances. However, results yielded by extant studies are inconsistent. Therefore, in this work, we tested the in vitro effects of different high concentrations of haloperidol and risperidone on the activation of isolated macrophages (RAW 264.7 cell line). The results indicated that macrophages were activated by both drugs. In addition, the activation involved an increase in nitric oxide levels and apoptosis events by modulation of caspases 8 and 3 levels and a decrease of the Bcl-2/BAX gene expression ratio. Cells treated with haloperidol and risperidone also presented higher concentrations of inflammatory cytokines (IL-1β, IL-6, TNFα) and low levels of IL-6 anti-inflammatory cytokine in a dose-dependent manner. Despite the limitation of cell line studies based solely on macrophages cells, we suggest that antipsychotic drugs could potentially exacerbate inflammatory processes in peripheral tissues (blood and fat). The continued activation of macrophages could contribute to the development of obesity and other endocrine disturbances caused by the use of antipsychotic drugs.

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“…Vojtek, University of Michigan, Ann Arbor, MI, USA; refs. 25,26). The Akt1 cDNA (without the myristoylation sequence) was subcloned in frame with an N-terminal triple-FLAG epitope in pFLAG3 vector (a gift from Dr. D. H. Anderson, University of Saskatchewan).…”

Section: Plasmid Construction and Stable Expression Of Akt1 Variants mentioning

confidence: 99%

Modification of Akt1 by methylglyoxal promotes the proliferation of vascular smooth muscle cells

et al. 2011

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Methylglyoxal (MG), a reactive dicarbonyl molecule, can modify protein to form advanced glycation endproducts. Increased MG level has been implicated in proliferative vascular diseases, but the underlying mechanisms are not clear yet. The serine/threonine kinase, Akt, regulates multiple signaling pathways that control cell proliferation. Using mass spectrometric analysis, we have detected the modification of Akt1 by MG at Cys(77). This structural modification increased Akt1 phosphorylation at Ser(473) and Thr(308). Akt1 phosphorylation and activity were also increased by MG treatment (<50 μM) in cultured vascular smooth muscle cells (VSMCs). MG treatment of VSMCs led to increased DNA synthesis (EC(50)=5.8 μM), cell proliferation, phosphorylation of p21 and glycogen synthase kinase-3α/β (GSK-3α/β), and increased cyclin-dependent kinase 2 (CDK2) activity. These effects of MG were significantly inhibited by silencing Akt1 or by an Akt inhibitor. Overexpression of Akt1 Cys(77)Ser mutant in HEK-293 cells increased cell proliferation and DNA synthesis, concurrent with an increase in Akt1 activity, which could not be further augmented by MG treatment. It is concluded that MG-induced VSMC proliferation is mediated by the activation of Akt1 via the modification of Akt1 at Cys(77).

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Haloperidol disrupts Akt signalling to reveal a phosphorylation-dependent regulation of pro-apoptotic Bcl-XS function

Cited by 22 publications

References 51 publications

Identification of blood biomarkers for psychosis using convergent functional genomics

Identification of blood biomarkers for psychosis using convergent functional genomics

Haloperidol and Risperidone at high concentrations activate an in vitro inflammatory response of RAW 264.7 macrophage cells by induction of apoptosis and modification of cytokine levels

Modification of Akt1 by methylglyoxal promotes the proliferation of vascular smooth muscle cells

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