Joseph Shapiro

Valproate decreases inositol biosynthesis.

BACKGROUND Lithium and valproate (VPA) are used for treating bipolar disorder. The mechanism of mood stabilization has not been elucidated, but the role of inositol has gained substantial support. Lithium inhibition of inositol monophosphatase, an enzyme required for inositol recycling and de novo synthesis, suggested the hypothesis that lithium depletes brain inositol and attenuates phosphoinositide signaling. Valproate also depletes inositol in yeast, Dictyostelium, and rat neurons. This raised the possibility that the effect is the result of myo-inositol-1-phosphate (MIP) synthase inhibition. METHODS Inositol was measured by gas chromatography. Human prefrontal cortex MIP synthase activity was assayed in crude homogenate. INO1 was assessed by Northern blotting. Growth cones morphology was evaluated in cultured rat neurons. RESULTS We found a 20% in vivo reduction of inositol in mouse frontal cortex after acute VPA administration. As hypothesized, inositol reduction resulted from decreased MIP synthase activity: .21-.28 mmol/LVPA reduced the activity by 50%. Among psychotropic drugs, the effect is specific to VPA. Accordingly, only VPA upregulates the yeast INO1 gene coding for MIP synthase. The VPA derivative N-methyl-2,2,3,3,-tetramethyl-cyclopropane carboxamide reduces MIP synthase activity and has an affect similar to that of VPA on rat neurons, whereas another VPA derivative, valpromide, poorly affects the activity and has no affect on neurons. CONCLUSIONS The rate-limiting step of inositol biosynthesis, catalyzed by MIP synthase, is inhibited by VPA; inositol depletion is a first event shown to be common to lithium and VPA.

Inositol treatment raises CSF inositol levels.

Inositol is a key precursor for synthesis of phosphatidylinositol in a major second messenger signalling system. It is biologically active in syndromes such as respiratory distress syndrome but has been thought to be excluded from CNS by the blood-brain barrier. Oral inositol treatment of 8 patients is shown to significantly increase CSF inositol by almost 70%, suggesting possible CNS therapeutic applications of this compound and possible CNS side-effects of systemic therapy.

Lack of Lithium-Like Behavioral and Molecular Effects in IMPA2 Knockout Mice

Lithium is a potent mood-stabilizing medication in bipolar disorder. Despite 50 years of clinical use, the mechanism of action is unknown. Multiple effects have been attributed to lithium including the uncompetitive inhibition of inositol monophosphatase (IMPase). IMPA2, one of the genes that encode IMPase, is located in a region with linkage to bipolar disorder. Owing to the role of IMPase in cell signaling and the possibility that this enzyme is a target for mood-stabilizing drugs, we generated IMPA2−/− mice. Possible involvement of IMPase in complex behaviors related to affective disorders was assessed by monitoring the behavior of the IMPA2−/− mice in the forced swim test, the tail suspension test (TST), the elevated zero-maze and open field test. It has been described that chronically lithium-treated mice exhibit reduced immobility time in the forced swim test and decreased exploratory behavior. We found increased rearing of IMPA2−/− mice in the open field, suggesting an increased exploratory behavior. Although immobility time of IMPA2−/− female but not male mice in the forced swim test was reduced, no difference was found between male and female IMPA2−/− and IMPA2+/+ mice in the TST and overall there was no clear effect of the deletion of IMPA2 on depression-like behavior. Frontal cortex IMPase activity and inositol levels in the IMPA2−/− mice did not differ from IMPA2+/+ mice, but kidney inositol levels were reduced. In conclusion, phenotypic characterization of the IMPA2−/− mouse indicates that deleting IMPA2 does not mimic the effects of lithium treatment.

Scyllo-inositol in post-mortem brain of bipolar, unipolar and schizophrenic patients.

Summary. Inositol levels measured in postmortem brain of unipolar, bipolar and schizophrenic patients, suicide victims and normal controls showed no difference in scyllo-inositol levels in frontal or occipital cortex between any of the groups. We could not replicate previous reports of low myo-inositol levels in the frontal cortex of unipolar, bipolar and schizophrenic patients and suicide victims. There was no correlation between myo-inositol levels and estimated chlorpromazine equivalents in neuroleptic-treated subjects, and no effect of chronic haloperidol treatment on rat brain myo-inositol levels.

CSF inositol does not predict antidepressant response to inositol

SummaryCSF inositol was reported to be reduced in depression and inositol has been reported to be effective in treatment of depression. We studied CSF inositol in 18 drug-free depressed patients and 36 normal controls; the depressed patients then participated in an open trial of 18 gm daily inositol treatment for 4 weeks. There was no difference in pre-treatment CSF inositol between depressed patients and controls. CSF inositol levels did not predict response on the Hamilton Depression Scale to 4 weeks of inositol treatment.

Chronic dietary inositol enhances locomotor activity and brain inositol levels in rats

Abstract myo-Inositol has been found to be clinically effective in depression, obsessive compulsive disorder (OCD) and panic disorder when given chronically per os. The present study examined the effects of chronic dietary inositol in rats on locomotor behaviour. Regional brain levels of inositol were analyzed by gas chromatography. Chronic dietary inositol significantly enhanced locomotion and rearing in rats and elevated inositol levels by 36% in the cortex and 27% in hippocampus. No differences in inositol levels were found in the striatum or cerebellum. The stimulatory effects of inositol may be related to its effects as an atypical antidepressant in depressed patients.

CSF inositol in schizophrenia and high-dose inositol treatment of schizophrenia

Inositol is a key metabolite in the phosphatidylinositol cycle, which is a second messenger system for serotonin-2 receptors that have been implicated in the pathophysiology of schizophrenia. Cerebrospinal fluid inositol levels were measured in 20 schizophrenic patients and 19 age- and sex-matched controls and no difference was found. However, the patients were all neuroleptic-treated. A controlled double-blind crossover trial of 12 g daily of inositol for a month in 12 anergic schizophrenic patients, twice the dose given before in schizophrenia, did not show any beneficial effects. However, the number of patients studied was small and the length of time of inositol administration may not have been sufficient.

No Differences Between Bipolar Patients and Normal Controls in Inositol Levels and Inositol Monophosphatase Activity in Postmortem Brain

The discovery of inositol monophosphatase (IMPase) activity inhibition by lithium (Li) ions led to Berridge’s inositol depletion hypothesis, and brain inositol levels have been studied in relation to psychiatric disorders. We have previously reported low myo-inositol levels in the frontal cortex of bipolar and schizophrenic patients and low IMPase activity in lymphocyte-derived cell lines from this group of patients. In the present study, myo- and scyllo-inositol levels and IMPase activity were measured in the Stanley Brain Consortium postmortem brain specimens from bipolar patients and normal controls. No differences were found between the diagnostic groups in any parameter in any brain area studied. There was a positive correlation between myo- and scyllo-inositol in frontal and occipital cortex. We could not replicate our previous report of low myo-inositol levels in the frontal cortex of bipolar patients. In subjects treated with neuroleptic drugs, there was no correlation between myo-inositol levels and estimated chlorpromazine equivalents administered peri mortem.

Inositol levels in post mortem brain samples of Alzheimer's patients

Abstract 1. 1. Free inositol levels in occipital and parietal cortex of Alzheimers Disease (AD) patients were reported to be significantly elevated by 10–35% compared with matched controls, studied by magnetic resonance spectroscopy (MRS) during life. 2. 2. An MRS study of post mortem samples failed to demonstrate a significant difference between AD and controls. 3. 3. The present study shows non-significant trends of 13% increase in frontal cortex and 5% and 21% decrease in occipital cortex and cerebellum respectively, in post mortem brain specimens of AD patients measured gas chromatographically (GC).