Valproate decreases inositol biosynthesis

Shaltiel, Galit; Shamir, Alon; Shapiro, Joseph I.; Ding, Daobin; Dalton, Emma; Bialer, Meir; Harwood, Adrian J.; Belmaker, Robert H.; Greenberg, Miriam L.; Agam, Galila

doi:10.1016/j.biopsych.2004.08.027

Cited by 107 publications

(101 citation statements)

References 46 publications

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“…In cytosolic extracts from yeast and the human brain, VPA inhibits inositol synthase/Ino1 activity and hence targets inositol synthesis. 18 Interestingly, VPA does not inhibit purified or bacterially produced inositol synthase, suggesting that either a metabolite of VPA is the true inhibitor or that VPA targets an additional protein required for inositol synthase activity.…”

Section: Vpa and Inositol Depletionmentioning

confidence: 98%

Lithium and bipolar mood disorder: the inositol-depletion hypothesis revisited

2004

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Inositol, a simple six-carbon sugar, forms the basis of a number of important intracellular signaling molecules. Over the last 35 years, a series of biochemical and cell biological experiments have shown that lithium (Li þ ) reduces the cellular concentration of myo-inositol and as a consequence attenuates signaling within the cell. Based on these observations, inositol-depletion was proposed as a therapeutic mechanism in the treatment of bipolar mood disorder. Recent results have added significant new dimensions to the original hypothesis. However, despite a number of clinical studies, this hypothesis still remains to be either proven or refuted. In this review of our current knowledge, I will consider where the inositol-depletion hypothesis stands today and how it may be further investigated in the future.

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Section: Vpa and Inositol Depletionmentioning

confidence: 98%

Lithium and bipolar mood disorder: the inositol-depletion hypothesis revisited

2004

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“…Both valproate and lithium have been shown to interact with the intracellular transport and biosynthesis of myo-inositol in the cell, [45][46][47] possibly explaining the observed decrease. Both also downregulate the inositol triphosphate second messenger system.…”

Section: Post-mortem Brain Tissue Analysismentioning

confidence: 99%

Metabonomic analysis identifies molecular changes associated with the pathophysiology and drug treatment of bipolar disorder

et al. 2008

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Bipolar affective disorder is a severe and debilitating psychiatric condition characterized by the alternating mood states of mania and depression. Both the molecular pathophysiology of the disorder and the mechanism of action of the mainstays of its treatment remain largely unknown. Here, 1 H NMR spectroscopy-based metabonomic analysis was performed to identify molecular changes in post-mortem brain tissue (dorsolateral prefrontal cortex) of patients with a history of bipolar disorder. The observed changes were then compared to metabolic alterations identified in rat brain following chronic oral treatment with either lithium or valproate. This is the first study to use 1 H NMR spectroscopy to study post-mortem bipolar human brain tissue, and it is the first to compare changes in disease brain with changes induced in rat brain following mood stabilizer treatment. Several metabolites were found to be concordantly altered in both the animal and human tissues. Glutamate levels were increased in post-mortem bipolar brain, while the glutamate/glutamine ratio was decreased following valproate treatment, and c-aminobutyric acid levels were increased after lithium treatment, suggesting that the balance of excitatory/inhibitory neurotransmission is central to the disorder. Both creatine and myo-inositol were increased in the post-mortem brain but depleted with the medications. Lastly, the level of N-acetyl aspartate, a clinically important metabolic marker of neuronal viability, was found to be unchanged following chronic mood stabilizer treatment. These findings promise to provide new insight into the pathophysiology of bipolar disorder and may be used to direct research into novel therapeutic strategies.

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“…24 In another study, MTMCD was found to be equipotent to VPA and lithium in various models for bipolar disorders. 41 Thus, the 2,2,3,3-tetramethylcyclopropane amides MTMCD and TMCU have the potential to become new antiepileptics and CNS drugs as the second generation of VPA.…”

Section: Derivatives Of Tmcamentioning

confidence: 99%

Valproic Acid: Second Generation

2007

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Summary:The manuscript focuses on structure-activity relationship studies of CNS-active compounds derived from valproic acid (VPA) that have the potential to become secondgeneration VPA drugs. Valproic acid is one of the four most widely prescribed antiepileptic drugs (AEDs) and is effective (and regularly approved) in migraine prophylaxis and in the treatment of bipolar disorders. Valproic acid is also currently undergoing clinical trials in cancer patients. Valproic acid is the least potent of the established AEDs and its use is limited by two rare but potentially life-threatening side effects, teratogenicity and hepatotoxicity. Because AEDs treat the symptoms (seizure) and not the cause of epilepsy, epileptic patients need to take AEDs for a long period of time. Consequently, there is a substantial need to develop better and safer AEDs. To become a successful second-generation VPA, the new drug should possess the following characteristics: broad-spectrum antiepileptic activity, better potency than VPA, lack of teratogenicity and hepatotoxicity, and a favorable pharmacokinetic profile compared with VPA including a low potential for drug interactions.

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Valproate decreases inositol biosynthesis

Cited by 107 publications

References 46 publications

Lithium and bipolar mood disorder: the inositol-depletion hypothesis revisited

Lithium and bipolar mood disorder: the inositol-depletion hypothesis revisited

Metabonomic analysis identifies molecular changes associated with the pathophysiology and drug treatment of bipolar disorder

Valproic Acid: Second Generation

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