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Aims: To screen for inositol-depleting valproate-like compounds as potential mood stabilizing drugs., Main Methods: We exploited the yeast Saccharomyces cerevisiae, as a model in which inositol de novo synthesis has been extensively characterized, to test the effects of ethyl butyrate (EB), 2-ethyl-butyric acid, sodium butyrate, and n-propyl hexanoate on inositol biosynthesis. Cell growth was followed by measuring the optical density of the cultures (spectrophotometrically), RNA abundance was determined by Northern blot analysis, intracellular inositol was measured by a fluorometric assay, and 1-d-myo-inositol-3-phosphate synthase activity was examined using a chromatographic method., Key Findings: Of the tested compounds, only EB exhibited an inositol-depleting effect. The inositol-depleting effect of EB was achieved without significant adverse effect on cell growth, pointing to lesser toxicity compared to valproate., Significance: These results indicate that EB is a potential candidate for mood-stabilizing therapy.

Bipolar affective disorder is a chronic, severe, debilitating illness affecting 1-2% of the population. Valproate, along with lithium and carbamazepine, are the only drugs for which long-term efficacy has been established. However, these drugs are ineffective for, and not well tolerated by, a large number of patients and are also associated with teratogenicity and reproductive defects. Therefore, there is a substantial need to develop more effective anti-bipolar drugs. We have previously shown that valproate, like lithium, decreases intracellular inositol, which supports the inositol depletion hypothesis. We employed inositol depletion in yeast as a screening tool to identify potential new anti-bipolar medications. We show here that hexanoic acid, heptanoic acid, octanoic acid, nonanoic acid, decanoic acid, ethylhexanoate, and methyloctanoate decrease intracellular inositol levels and increase the expression of INO1, the gene encoding myo-inositol-3-phosphate synthase (MIPS). Similar to valproate, these inositol-depleting carboxylic acids inhibited MIPS indirectly. A correlation was shown between cell growth inhibition and the increase in INO1 expression by the carboxylic acids, factors that were reversed in the presence of inositol. Inositol depletion in yeast may be exploited as an easy and inexpensive screening test for potential new inositol depleting anti-bipolar drugs.

Studies have shown that the inositol biosynthetic pathway and the enzyme glycogen synthase kinase-3 (GSK-3) are targets of the mood-stabilizing drugs lithium and valproate. However, a relationship between these targets has not been previously described. We hypothesized that GSK-3 may play a role in inositol synthesis, and that loss of GSK-3 may lead to inositol depletion, thus providing a mechanistic link between the two drug targets. Utilizing a yeast Saccharomyces cerevisiae gsk-3Delta quadruple-null mutant, in which all four genes encoding homologues of mammalian GSK-3 are disrupted, we tested the hypothesis that GSK-3 is required for de novo inositol biosynthesis. The gsk-3Delta mutant exhibited multiple features of inositol depletion, including defective growth in inositol-lacking medium, decreased intracellular inositol, increased INO1 and ITR1 expression, and decreased levels of phosphatidylinositol. Treatment of wild-type cells with a highly specific GSK-3 inhibitor led to a significant increase in INO1 expression. Supplementation with inositol alleviated the temperature sensitivity of gsk-3Delta. Activity of myo-inositol-3 phosphate synthase, the rate-limiting enzyme in inositol de novo biosynthesis, was decreased in gsk-3Delta. These results demonstrate for the first time that GSK-3 is required for optimal myo-inositol-3 phosphate synthase activity and de novo inositol biosynthesis, and that loss of GSK-3 activity causes inositol depletion.

Valproate is the most widely prescribed antiepileptic drug worldwide, and it is also used in the treatment of bipolar affective disorder, migraine headache and cancer. However, the therapeutic mechanism of action of valproate in these illness states is not understood. This article reviews the pharmacological effects of valproate that may explain its therapeutic efficacy. It focuses on the hypothesis that inhibition of glycogen synthase kinase-3 by valproate is a crucial therapeutic mechanism of this drug in the treatment of bipolar affective disorder. Other cellular pathways and signaling molecules that are targets of valproate (such as inositol de novo biosynthesis, histone deacetylase, protein kinase C, γ-aminobutyric acid, the extracellular signal-regulated kinase pathway and others) are also discussed. [ABSTRACT FROM AUTHOR]

Bipolar affective disorder is a severe and chronic disabling illness affecting 1.5% of the general population. Lithium, valproate and other mood stabilizers are used to treat bipolar disorder; however, these are ineffective for, and not tolerated by, a significant percentage of patients, underscoring the urgent need for better medications. Although not universally accepted, the inositol-depletion hypothesis is one of the main hypotheses suggested to explain the therapeutic mechanism of mood-stabilizing drugs. This paper reviews the relevance of the inositol-depletion hypothesis, paying special attention to the inhibition of inositol de novo synthesis by valproate. It also discusses inositol supplementation as a treatment strategy for multiple neurological disorders, including prophylactic use against valproate-induced neural tube defects. [ABSTRACT FROM AUTHOR]