Biomedical subjects
Publications and source records attributed to G Agam.
1. Two hundred male albino Sprague-Dawley rats were studied for the lithium and/or inositol effect on 5-HTP induced prolactin release. 2. Lithium demonstrated a clear augmentation of 5-HTP induced prolactin levels, however no effect of inositol was demonstrated on lithium augmentation of 5-HTP induced prolactin release.
The inositol depletion hypothesis of lithium (Li) action has been criticized, because depletion of inositol after chronic Li treatment has not been reproducible, effects of inositol to reverse Li-induced behaviors occurred also with epi-inositol, a unnatural isomer, and because inositol is ubiquitous in brain and hard to relate to the pathogenesis of affective disorder. Therefore, we review our studies showing that lithium depletion of brain inositol occurs chronically in the hypothalamus, a region not previously examined; that behavioral effects of four different inositol isomers including epi-inositol correlate perfectly with their biochemical effects; and that inositol in postmortem human brain is reduced by 25% in frontal cortex of bipolars and suicides as compared with controls. Because inositol in postmortem brain is reduced and not increased in bipolar patients, the relationship between inositol, lithium, and affective disorder is complex.
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The influence of acute and chronic lithium administration on inositol content was examined in five different regions of the rat brain: caudate, cerebellum, cortex, hippocampus and hypothalamus. After acute administration of lithium at doses of 3, 6 or 10 mEq kg-1, no significant reductions of inositol were found in any brain region. Also no significant changes were observed in cortex, caudate, hippocampus and cerebellum after chronic treatment with lithium-containing diet, which led to brain concentrations of lithium in the therapeutic range. However, a moderate but significant reduction of inositol was under these conditions observed in the hypothalamus. At basal conditions, ie in control rats not treated with lithium, the inositol content in various brain areas was different, the hypothalamus containing the highest inositol concentration (4.4 mmol kg-1 wet weight) and the cortex the lowest (2.3 mmol kg-1 wet weight). It is concluded that chronic lithium treatment at therapeutically relevant brain concentrations does not evoke major changes in the inositol content of the brain but induces a moderate decrease which is restricted to the hypothalamus. The results are discussed with respect to the potential function of the hypothalamus in affective disorders.
OBJECTIVE: This study aimed to evaluate aspects of second messenger function in the brain of suicide victims and patients with bipolar disorder. METHOD: Inositol and its synthetic enzyme, inositol monophosphatase, were measured in postmortem brain samples of 10 suicide victims, eight patients with bipolar affective disorder, and 10 normal comparison subjects. RESULTS: The frontal cortex inositol levels of the suicide victims and the patients with bipolar disorder were significantly less than those of the normal comparison group. No differences in cerebellum or occipital cortex inositol levels were found among the three groups. The groups also showed no differences in inositol monophosphatase activity in any brain area. CONCLUSIONS: These results could suggest a deficiency of second messenger precursor in patients with bipolar disorder and suicide victims.
Lithium (Li) is an effective drug for prophylaxis and treatment of major affective disorders. It is teratogenic both to animals and human beings. Depletion of inositol is associated both with lithium side effects and teratogenesis. There is no direct evidence showing that in humans Li-teratogenesis is associated with the phosphoinositol (PI) cycle. It is conceivable that the teratogenic effect of Li in humans is also associated with inositol depletion and therefore is amenable to inositol supplementation. To test the hypothesis that oral inositol may cross the placental barrier and may be useful as a protective supplement to lithium therapy during pregnancy, we studied the effect of 2.5% inositol in drinking water on embryonic inositol levels in rats. There was no effect on fetal inositol concentration. However, weight of embryos of mothers receiving inositol was significantly higher. These data do not support the concept that inositol supplementation may be useful in preventing human Li-induced teratogenesis.
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CSF 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.
How lithium works in manic-depressive illness is unknown. Recently, however, a powerful hypothesis has been gaining momentum. Distinguished by its testability and clinical implications, the inositol depletion hypothesis of lithium action is relevant to treatment of lithium side effects, to the development of new compounds with the clinical profile of lithium, and to new experimental treatment of depression.
Cystic fibrosis has been characterized as a defect in the regulation of cyclic AMP-dependent transepithelial chloride transport. The activation of cyclic AMP-dependent protein kinase A by cyclic AMP occurs normally in cystic fibrosis cells, but they fail to transport chloride ions in response to protein kinase A stimulation. Defective chloride secretion and abnormal electrolyte transport occurs in several organs including the lung, sweat glands, intestine and pancreas. The present work was aimed at exploring whether the same or similar regulatory systems are functional in platelets, and if they are altered or deficient in individuals with cystic fibrosis. Chloride transport in platelets from normal subjects and from cystic fibrosis patients was measured by cell sizing techniques where chloride permeability is the limiting factor. In platelets from healthy volunteers, the chloride channel blocker, 5-nitro-2-(3-phenylpropylamino) benzoic acid, inhibits the transport in a dose-dependent manner. The preservation of chloride transport capability is shown to be dependent upon the presence of either Ca2+ or two divalent cation substitutes, Cd2+ or Cu2+. It is also shown that in normal subjects 0.1 mumol/l prostaglandin E1, which elevates cyclic AMP 6 times and abolishes platelet aggregation, significantly enhances the rate constant of the transport. Furthermore, in five out of nine cystic fibrosis patients studied, platelet chloride transport did not respond to stimulation by prostaglandin E1.
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Inositol, a naturally occurring isomer of glucose, is a key intermediate of the phosphatidyl-inositol (PI) cycle, a second-messenger system used by several noradrenergic, serotonergic and cholinergic receptors. The suggestion that lithium might treat mania via its reduction of inositol levels led to experiments showing that pharmacological doses of peripheral inositol reverse behavioral effects of lithium in animals and side effects of lithium in man. Cerebrospinal fluid (CSF) levels of inositol are low in depression. An open-label, add-on trial of inositol in depression suggested a beneficial effect. In a subsequent 1-month, parallel-groups, double-blind, placebo-controlled study of 28 patients, inositol was effective as sole therapy for depression (p = .043). Inositol was also effective for panic disorder in a double-blind, random-assignment, placebo-controlled crossover study of 21 patients, with 4 weeks in each phase (p = .02); the effect was comparable to that of imipramine in recent studies.
Lithium (Li) reduces brain inositol levels. Berridge has suggested that this effect is related to Li's mechanism of action. It had previously been shown that pilocarpine causes a limbic seizure syndrome in lithium treated rats, and that these lithium-pilocarpine seizures are reversible by intracerebroventricular inositol administration to rats. We now show that although inositol passes the blood-brain barrier poorly, large doses of intraperitoneal (IP) inositol can also reverse Li-pilocarpine seizures. Using gas chromatography, IP inositol can raise brain inositol levels. Demonstration that inositol enters brain after peripheral administration provides a basis for possible pharmacological intervention in psychiatric disorders at the level of second messengers linked to the phosphatidylinositol cycle.
Lithium reduces brain inositol levels by inhibiting inositol monophosphatase. In a previous study it was found that administration of pilocarpine to Li-treated rats causes limbic seizure behavior which can be reversed by i.c.v. myo-inositol but not chiro-inositol, suggesting that this behavior is related to inositol depletion in the PI cycle. Hyponatremia can lower brain inositol and hypernatremia can raise brain inositol. We now report that induction of low brain inositol by hyponatremia followed by pilocarpine did not cause limbic seizures. Induction of high brain inositol using hypernatremia followed by Li-pilocarpine administration did not reverse limbic seizures. These data support the concept that inositol available for P1 synthesis and inositol for osmotic function are sequestered in different cellular pools.
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.
Human erythrocytes suspended in plasma, or in phosphate buffered saline (PBS), were exposed to ionizing radiation. Potassium leakage from irradiated erythrocytes is significantly higher in PBS than in plasma. The potassium leakage decreases when PBS is gradually replaced by plasma. These findings suggest that some of the plasma constituents have radioprotective properties. The potassium leakage per cell is independent of the hematocrit, Hct. The potassium leakage is attributed to the formation of radiation defects in the membrane. Analysis of the effect of radiation dose, plasma and cell concentrations on the product of the number and surface area of the radiation defects indicates that the radiation damage is mainly due to the direct formation of free radicals in the cell membrane. The radioprotective effect of plasma is attributed to surface reactions of these free radicals with plasma constituents adsorbed on the membrane.
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.
OBJECTIVE: Our purpose was to examine the temporal relationship between maternal blood and amniotic fluid levels. STUDY DESIGN: Glucose levels were measured on 158 paired samples from maternal plasma and amniotic fluid obtained from healthy women undergoing genetic amniocentesis at 15 to 20 weeks of gestation. The samples of venous blood and amniotic fluid were drawn at different time intervals, randomly assigned from 0 to 200 minutes. Linear regression analysis was used to test the relationship. The significance was tested by two-tailed t test. RESULTS: A good significant correlation (r = 0.78, p < 0.01 and r = 0.67, p < 0.05) was found at 21- to 40- and 121- to 140-minute intervals, respectively. CONCLUSION: The amniotic fluid glucose level reflects the maternal blood glucose levels at specific lag times.