Inositol depletion, GSK3 inhibition and bipolar disorder

Yu, Wenxi; Greenberg, Miriam L.

doi:10.2217/fnl-2016-0003

Cited by 42 publications

(42 citation statements)

References 166 publications

(156 reference statements)

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“…Although the inositol depletion and GSK3 inhibition hypotheses of mood stabilization have been suggested independently based on seemingly unrelated studies, our findings suggest that they may be linked by a common mechanism [ 40 ]. In light of published findings that VPA causes inositol depletion by indirectly inhibiting MIPS [ 18 ], that VPA inhibits GSK3 (23–26), and that yeast cells lacking all four GSK3 homologs ( MCK1 , MDS1 , MRK1 and YGK3 ) exhibit inositol depletion [ 41 ], we hypothesized that VPA inhibits MIPS by a mechanism involving negative regulation of one or more GSK3 homologs, thereby causing inositol depletion.…”

Section: Introductionmentioning

confidence: 71%

MCK1 is a novel regulator of myo-inositol phosphate synthase (MIPS) that is required for inhibition of inositol synthesis by the mood stabilizer valproate

Yu¹,

Daniel²,

Mehta³

et al. 2017

PLoS ONE

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Myo-inositol, the precursor of all inositol compounds, is essential for the viability of eukaryotes. Identifying the factors that regulate inositol homeostasis is of obvious importance to understanding cell function and the pathologies underlying neurological and metabolic resulting from perturbation of inositol metabolism. The current study identifies Mck1, a GSK3 homolog, as a novel positive regulator of inositol de novo synthesis in yeast. Mck1 was required for normal activity of myo-inositol phosphate synthase (MIPS), which catalyzes the rate-limiting step of inositol synthesis. mck1Δ cells exhibited a 50% decrease in MIPS activity and a decreased rate of incorporation of [13C6]glucose into [13C6]-inositol-3-phosphate and [13C6]-inositol compared to WT cells. mck1Δ cells also exhibited decreased growth in the presence of the inositol depleting drug valproate (VPA), which was rescued by supplementation of inositol. However, in contrast to wild type cells, which exhibited more than a 40% decrease in MIPS activity in the presence of VPA, the drug did not significantly decrease MIPS activity in mck1Δ cells. These findings indicate that VPA-induced MIPS inhibition is Mck1-dependent, and suggest a model that unifies two current hypotheses of the mechanism of action of VPA—inositol depletion and GSK3 inhibition.

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Section: Introductionmentioning

confidence: 71%

MCK1 is a novel regulator of myo-inositol phosphate synthase (MIPS) that is required for inhibition of inositol synthesis by the mood stabilizer valproate

Yu¹,

Daniel²,

Mehta³

et al. 2017

PLoS ONE

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“…The mechanism of action of VPA as a mood stabilizer is not well understood. VPA has been shown to affect the serotonergic [4,5], dopaminergic [6], GABAergic [7] and glutamatergic [8][9][10] pathways as well as intracellular signalling pathways such as those mediated by phosphoinositol [11,12], glycogen kinase-3β/Wnt [13], protein kinase C [14], and ERK/MAPK [15,16] among others [17][18][19].…”

Section: Introductionmentioning

confidence: 99%

Transcriptional analysis of sodium valproate in a serotonergic cell line reveals gene regulation through both HDAC inhibition-dependent and independent mechanisms

Sinha

Cree

Miller

et al. 2019

Preprint

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Sodium valproate (VPA) is a histone deacetylase (HDAC) inhibitor, widely prescribed in the treatment of bipolar disorder, and yet the precise modes of therapeutic action for this drug are not fully understood.After exposure of the rat serotonergic cell line RN46A to VPA, RNA-sequencing (RNA-Seq) analysis showed widespread changes in gene expression. Analysis by multiple pipelines revealed as many as 230 genes were significantly upregulated and 72 genes were significantly downregulated. A subset of 23 differentially expressed genes was selected for validation using the nCounter® platform, and of these we obtained robust validation for ADAM23, LSP1, MAOB, MMP13, PAK3, SERPINB2, SNAP91, WNT6, and ZCCHC12. We investigated the effect of lithium on this subset and found four genes, CDKN1C, LSP1, SERPINB2 and WNT6 co-regulated by lithium and VPA. We also explored the effects of other HDAC inhibitors and the VPA analogue valpromide on the subset of 23 selected genes. Expression of eight of these genes, CDKN1C, MAOB, MMP13, NGFR, SHANK3, VGF, WNT6 and ZCCHC12, was modified by HDAC inhibition, whereas others did not appear to respond to several HDAC inhibitors tested. These results suggest VPA may regulate genes through both HDAC-dependent and independent mechanisms. Understanding the broader gene regulatory effects of VPA in this serotonergic cell model should provide insights into how this drug works and whether other HDACi compounds may have similar gene regulatory effects, as well as highlighting molecular processes that may underlie regulation of mood.

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“…Inositol is a less used sugar alcohol, similar to the structure of glucose, present in a variety of foods, but at a lower concentration [4]. Theoretically, inositol may have 9 isomers, but now only four species are found in nature.…”

Section: Introductionmentioning

confidence: 99%

Effects of Muscle Inositol on Fasting Blood Glucose in Patients with type 2 Diabetes, Blood Glucose 2 h after Meal, and Glycosylated Hemoglobin

Yin¹,

Guo²,

Sun³

et al. 2018

ijSciences

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Objective: To investigate the effects of muscle inositol on fasting blood glucose (FBG), postprandial 2 h blood glucose (2 h PG) and glycosylated hemoglobin (HbAlc) in patients with type 2 diabetes. Methods: Ninety patients with type 2 diabetes were divided into observation group and control group, 45 cases each. In the observation group, muscle myo-inositol was added to the conventional treatment of diabetes, and the control group was treated with conventional diabetes. The clinical efficacy of FBG in 2 groups was compared between the two groups. The proportion of adverse reactions in the two groups was compared. The changes of FBG, 2 h PG, HbAlc, adiponectin and serum inflammatory factors were compared before and after treatment. Results: The effective rate of FBG and 2 h PG in the observation group was significantly higher than that in the control group (P < 0.05). There was no significant difference in the number of patients with adverse reactions in the two groups (P > O.05). After treatment, 2 The FBG, 2 h PG and HbAlc were significantly lower than those before treatment, and the FBG, 2 h PG and HbAlC decreased significantly in the observation group than in the control group (P < 0.05). The level was significantly higher than that before treatment. The indexes of serum inflammatory factors such as TNF-α and IL-6 were significantly lower than those before treatment. The increase of adiponectin and the decrease of serum inflammatory factor index in the observation group were significantly greater than those in the control group. (P < 0.05). Conclusion: Muscle inositol is effective in the treatment of type 2 diabetes, which can reduce serum inflammatory factors, FBG, 2 hPG and HbAlc.

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Inositol depletion, GSK3 inhibition and bipolar disorder

Cited by 42 publications

References 166 publications

MCK1 is a novel regulator of myo-inositol phosphate synthase (MIPS) that is required for inhibition of inositol synthesis by the mood stabilizer valproate

MCK1 is a novel regulator of myo-inositol phosphate synthase (MIPS) that is required for inhibition of inositol synthesis by the mood stabilizer valproate

Transcriptional analysis of sodium valproate in a serotonergic cell line reveals gene regulation through both HDAC inhibition-dependent and independent mechanisms

Effects of Muscle Inositol on Fasting Blood Glucose in Patients with type 2 Diabetes, Blood Glucose 2 h after Meal, and Glycosylated Hemoglobin

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