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PubMed1989

Effects of antidepressant drugs on inositol phospholipid hydrolysis in rat cerebral cortical slices.

The effects of several different types of antidepressant drugs on phosphoinositide hydrolysis by slices of rat cerebral cortex was investigated by prelabeling inositol phospholipids with [3H]inositol and then measuring the formation of [3H]inositol phosphates (a total fraction consisting of the mono- and poly-phosphates was collected) in the presence of 10 mM LiCl. All of the drugs tested (amitriptyline, trimipramine, mianserin, desipramine, tranylcypromine, and citalopram) inhibited NE-stimulated [3H]inositol phosphate formation. This inhibition appeared to be due to antagonism of alpha 1-receptors. In addition to inhibiting the effects of NE, the tricyclic antidepressants themselves were able to stimulate [3H]inositol phosphate formation. This stimulation occurred at drug concentrations higher than that needed to inhibit stimulation by NE. Stimulatory effects of the antidepressants themselves were not blocked by the alpha 1-antagonist, prazosin. An examination of the types of inositol phosphates formed revealed that formation of inositol monophosphate was stimulated, but that inositol biphosphate production was decreased by tricyclic antidepressants compared to control.

Animals↗
PubMed1988

Myo-inositol transport through the blood-brain barrier.

The unidirectional transport of [3H]myo-inositol across cerebral capillaries, the anatomical locus of the blood-brain barrier, was measured using an in situ rat brain perfusion technique. Myo-inositol was transported across the blood-brain barrier by a low capacity, saturable system with a one-half saturation concentration of approximately 0.1 mM. The permeability surface-area product was 6.2 x 10(-5) S-1 with a myo-inositol concentration of 0.02 mM in the perfusate. The myo-inositol stereoisomer scyllo-inositol but not (+)-chiro-inositol (both 1 mM) inhibited myo-inositol transfer through the blood-brain barrier. These observations provide evidence that myo-inositol is transferred through the blood-brain barrier by simple diffusion and a stereospecific, saturable transport system.

Animals↗
PubMed1975

Role of cytidine triphosphate and cytidine diphosphate in promoting inositol entry into microsomal phosphatidylinositol.

The Mn2+ activated incorporation of myo-inositol-3H into subfractions of phosphatidylinositol in rat liver microsomes was studied in the presence and absence of cytidine triphosphate or cytidine diphosphate choline using phosphate buffer. The distribution of labeled inositol among molecular species of microsomal phosphatidylinositol was also investigated in vivo. In other experiments, the release of radioactivity from microsomes labeled with inositol-3H in the phospholipid was measured after the addition of Mn2+, unlabeled inositol, and cytidine nucleotide. Similar chase experiments were conducted with microsomes containing phosphatidylcholine-14C or phosphatidylethanolamine-14C. The addition of cytidine triphosphate or cytidine diphosphate choline stimulated the rate of inositol-3H entry into microsomal phosphatidylinositol by 3.5 to 4-fold and the monoenoic plus dienoic, trienoic, tetraenoic, and polyenoic species contained 6-7, 6, 78-81, and 7-9%, of radioactivity, respectively. These latter patterns were very similar to those observed among the corresponding molecular species when the Mn2+ stimulated entry of free inositol into phospholipid was studied in the absence of added cytidine nucleotide. In chase experiments, the release of radioactivity from phospholipid in the presence of cytidine trephosphate or cytidine diphosphate choline was greatly enhanced by the addition of free inositol when microsomes containing phosphatidylinositol-3H, but not phosphatidylcholine-14C or phosphatidylethanolamine-14C, were employed. Therefore, under the present conditions, cytidine triphosphate and cytidine diphosphate choline appear to stimulate the entry of inositol into phosphatidylinositol by enhancing the Mn2+ activated exchange reaction in rat liver microsomes. The results suggest further that phosphatidylinositol is the preferred substrate when this reaction is stimulated by cytidine nucleotide.

Animals↗
PubMed1999

Inositol reduces depressive-like behaviors in two different animal models of depression.

RATIONALE: Myo-inositol is an isomer of glucose that is a precursor in the phosphatidylinositol (PIP) cycle, a source of two second messengers: diacylglycerol (DAG) and inositol triphosphate (IP3). Clinical studies have reported that inositol is effective in relieving symptoms of depression. OBJECTIVE: The present study examined the effects of inositol on two animal models of depression: the Porsolt forced swim test, a behaviorally based model; and the reserpine-induced immobility model, a pharmacologically based model. METHODS AND RESULTS: Chronic inositol injections (daily for 14 days) of 1.2 g/kg (but not at lower doses) reduced immobility time and increased struggle time in the Porsolt test compared with control animals. The same dose and treatment schedule also reduced complete immobility time but did not affect ambulatory activity in the reserpine test compared with controls. Chronic oral treatment with inositol (10% in food for 14 days) had effects similar to IP inositol in the Porsolt test. CONCLUSIONS: The effect of inositol in animal models of depression supports its possible importance as a new treatment for the disorder, and permits research on its mechanisms of action.

Animals↗
PubMed1999

Effects of fluorinated inositols on the phosphoinositide metabolism and the proliferation of Trypanosoma cruzi.

Inositol has been cited as being essential for the growth of micro-organisms and animals. Its action rests mostly in the formation of a set of inositol-containing lipids, including phosphatidylinositol and its phosphorylated derivatives. To evaluate the functional responses coupled to the phosphoinositide metabolism in Trypanosoma cruzi we used myo-inositol and its six fluorinated analogues. Their uptake into epimastigotes was characterised using tritium-labeled myo-inositol and monodeoxyfluoro-myo-inositols. The analogues were tested for their ability to inhibit [3H]-myo-inositol incorporation into phosphoinositides and the proliferation of epimastigotes and amastigotes. The results showed differences between T. cruzi and mammalian systems in the responses to the fluorinated analogues. We found that the 3-, 5- and 6-fluoro analogues did not enter the cells but had an inhibitory effect on the incorporation of the radioactive inositol into lipids and on the amastigotes' and epimastigotes' replication. The most effective inhibitor, 1-D-6-deoxy-6-myo-inositol, had no effect on mammalian cell division.

Animals↗
PubMed1977

myo-Inositol binding and transport in brush border membranes of rat kidney.

Using hypotonically treated brush border membranes, binding and transport of myo-inositol were examined. By hypotonic treatment, both total and non-specific uptake decreased significantly, but specific uptake was not affected. myo-Inositol release from membranes preloaded by incubation for 2 min was very rapid and about 98% of preloaded myo-inositol was released in 5 min of incubation. However, myo-inositol release from membranes preloaded by incubation for 20 min was fairly slow and 50% of myo-inositol remained in the membranes even after 10 min of incubation. Uptake of myo-inositol decreased by the increase of osmolarity in the medium. However, effect of osmolarity on the uptake was less significant when myo-inositol concentration was lower. Under conditions in which mainly binding occurred, myo-inositol binding to the membranes was measured. Two binding systems were demonstrated and high affinity site could bind 22 pmol/mg protein at most and the apparent Km value was 8.3 muM. Both binding and transport processes were dependent on Na+ and enhanced by Na+-gradient.

Animals↗
PubMed1984

Effect of extracellular myo-inositol on surfactant phospholipid synthesis in the fetal rabbit lung.

In the present investigation, myo-inositol was elevated in fetal serum by dietary manipulation. The myo-inositol-containing diet doubled the already high fetal serum myo-inositol between fetal days 26 and 28 but had no detectable effects on the lung. However, myo-inositol decreased betamethasone-induced (0.2 mg/kg, days 26.3 and 27.3, to the doe) inhibition in lung growth and potentiated the hormone-induced increase in alveolar space saturated phosphatidylcholine. This effect could not be explained by alteration of glucocorticoid-stimulated enzyme activity (phosphatidate cytidylyltransferase, phosphatidic acid phosphohydrolase, choline phosphate cytidylyltransferase) in the lung. Lung explants from 26-day-old fetuses were grown in a serum-free medium for 4 days. myo-Inositol (1.5 mM) had only a small effect on the phospholipid incorporation. Dexamethasone and thyroxine increased the incorporation of the precursors into surfactant phosphatidylglycerol and saturated phosphatidylcholine. myo-Inositol, in the presence of the hormones, switched the acidic surfactant phospholipid from phosphatidylglycerol to phosphatidylinositol and further increased the incorporation of surfactant-associated saturated phosphatidylcholine. myo-Inositol-excess preferentially increased the incorporation of NADPH (derived from glucose) and acetate into the fatty acid moiety of surfactant phosphatidylcholine. It is proposed that the high extracellular myo-inositol in immature fetuses provides an environment that promotes both the hormone-stimulated differentiation and the growth.

Animals↗
PubMed1996

Chronic lithium does not alter human myo-inositol or phosphomonoester concentrations as measured by 1H and 31P MRS.

Lithium may act by decreasing intracellular concentrations of myo-inositol. The present study measured the effects of chronic lithium on myo-inositol concentrations in volunteers. Eleven subjects received either lithium (n = 7) or placebo (n = 4) for 7 days in a double-blind study. Myo-inositol concentrations at baseline and day 8 were measured in vivo using 1H magnetic resonance spectroscopy (MRS). The results showed that lithium did not alter brain myo-inositol concentrations compared to placebo. In 5 other subjects we used 1H MRS and 31P MRS to measure changes in both myo-inositol and phosphomonoester concentrations. This second study showed that lithium did not alter myo-inositol or phosphomonoester concentrations. Thus, the present studies do not support the hypothesis that lithium significantly affects the brain concentrations of myo-inositol or phosphomonoesters; however, it is possible these findings represent an inability to detect the changes in myo-inositol and phosphomonoester concentrations that may have occurred following lithium administration.

Brain↗
PubMed1988

Dopamine D2 receptor stimulation inhibits inositol phosphate generating system in rat striatal slices.

Previous studies on the transduction mechanisms triggered by dopamine receptor stimulation have established that both D1 and D2 subtypes of dopamine receptors are linked to the adenylate cyclase system, the former in a stimulatory and the latter in an inhibitory manner. The present report provides the first evidence that stimulation of D2 receptors in rat brain tissue affects the turnover of polyphosphoinositides, as revealed by changes of the content of inositol phosphates. We found that the basal level of [3H]inositol trisphosphate, [3H]inositol bisphosphate and [3H]inositol monophosphate decreased following the stimulation of the D2 receptor. The rank order of potency was quinpirole (IC50 5 nM) greater than lisuride (IC50 8 nM) greater than RU 24213 (IC50 50 nM) greater than dopamine (IC50 200 nM). In contrast, selective D1 receptor stimulation by fenoldopam did not alter the inositol monophosphate, inositol bisphosphate and inositol trisphosphate content. The quinpirole effect was prevented by selective D2 antagonists, such as domperidone and L-sulpiride (both 5 microM) while it was unaffected by the selective D1 antagonist SCH 23390 (100 nM) and by the pharmacologically inactive D-isomer of sulpiride. Our data indicate that the activation of striatal D2 receptors leads to the inhibition of inositol phosphate production.

Animals↗
PubMed1990

The synthesis and resolution of (+/-)-1,5,6-tri-O-benzyl-myo-inositol.

Racemic 1,5,6-tri-O-benzyl-myo-inositol was prepared by five routes and converted into 1,5,6-tri-O-benzyl-2,3-O-isopropylidene-myo-inositol, the camphanates of which were readily separated by chromatography. The absolute configurations of the chiral derivatives were established by their conversion into the known chiral 1,4,5,6-tetra-O-benzyl-myo-inositols. 1D-1,5,6-Tri-O-benzyl-2,3-O-isopropylidene-myo-inositol was converted into 1D-1,3,5,6-tetra-O-benzyl-myo-inositol and thence into 1D-2,4-di-O-methyl-myo-inositol. 1D-1,5,6-Tri-O-benzyl-myo-inositol was converted into 1D-1,2,5,6-tetra-O-benzyl-myo-inositol, the diacetate of which is a chiral analogue of "thermosalient crystals". The potential of the above compounds for the synthesis of natural products is surveyed.

Benzyl Compounds↗
PubMed1995

Ion specificity and stoichiometry of the cardiac inositol transporter.

Cardiac myocytes have a high affinity. Mg(2+)-dependent, electrogenic, Na-inositol co-transporter on the plasma or sarcolemma (SL) membrane (Rubin and Hale, 1993). The ion specificity and stoichiometry of this transport process is unknown. Using bovine cardiac SL vesicles, we have determined that transmembrane movement of myo-[3H]inositol requires Na+ and is not supported by K+ or Li+. Furthermore, replacing Cl- with a non-permeant anion has no effect on inositol transport. Carrier-mediated inositol efflux indicated that efflux was Na(+)-dependent and electrogenic but independent of extravesicular Mg2+ in the efflux media. The transport stoichiometry of 1 Na+ for one inositol was derived by determining the null point of myo-[3H]inositol flux under conditions where the inside and outside concentration (ratio) of myoinositol and Na+ were controlled. The results suggest that Na+, inositol, and Mg2+ bind to the same side of the membrane for transport to occur and that the stoichiometry of Na+ and inositol transport is 1:1.

Animals↗
PubMed1986

Myo-inositol enhances the proliferation of human endothelial cells in culture but fails to prevent the delay induced by high glucose.

Evidence is accumulating, indicating that the abnormal metabolic milieu of diabetes might interfere with orderly replication of some cellular systems and in vitro studies point to a causal contribution of elevated glucose. We had previously shown that human umbilical vein endothelial cells cultured in 20 mmol/L glucose are delayed in achieving saturation density primarily as a consequence of decreased cellular proliferation. We have now addressed whether depletion of myo-inositol--a prevailing consequence of hyperglycemia in other tissues and overcome by provision of supplemental inositol--might play a role in the observed replicative abnormality. Control cultures (5 mmol/L glucose) displayed a dose-dependent response to myo-inositol supplementation that was maximal at concentrations (40 mumol/L) matching physiologic serum levels. The increment in cell number was (mean +/- SD) 141 +/- 20% of control (P less than 0.001), and saturation density was achieved at a cell number 160% higher than in nonsupplemented cultures. Thymidine incorporation and cell cycle studies documented that myo-inositol increased the number of cells cycle studies documented that myo-inositol increased the number of cells engaged in DNA synthesis. These effects of myo-inositol, as well as the dose-response relationship between ambient inositol levels and increments in cell number, were not significantly modified by 20 mmol/L glucose with the exceptions of a transient lesser effect of the physiologic doses during rapid proliferation (day 6) and a larger effect of all doses of myo-inositol in later stages of growth curve (day 12).(ABSTRACT TRUNCATED AT 250 WORDS)

Cell Count↗
PubMed1988

Formation of inositol phosphates in synaptoneurosomes of guinea pig brain: stimulatory effects of receptor agonists, sodium channel agents and sodium and calcium ionophores.

Carbamylcholine, norepinephrine, histamine and glutamate stimulated the formation of [3H]inositol phosphates in [3H]inositol-labelled synaptoneurosomes obtained from the cortex, striatum and hippocampus of the guinea pig. Synaptoneurosomes prepared from the cerebellum did not respond to receptor agonists. Agents that enhance the influx of sodium ions through voltage-sensitive channels, such as batrachotoxin, scorpion venom and pumiliotoxin B, or a sodium ionophore, monensin, stimulated the formation of [3H]inositol phosphates in synaptoneurosomes from all four regions of the brain. Neither calcium channel blockers nor receptor antagonists reduced the responses to batrachotoxin. Ionomycin, a calcium ionophore, also stimulated the formation of [3H]inositol phosphates in synaptoneurosomes from all four regions of the brain. A phorbol ester inhibited the formation of [3H]inositol phosphates, elicited by either receptor agonists or by sodium channel agents. The major [3H]inositol-labelled lipid in the synaptoneurosomes was phosphatidylinositol as analyzed by thin layer chromatography. While the hydrolysis of phosphatidylinositol elicited by carbamylcholine resulted in an increase of lipid-labelling with [3H]inositol, sodium channel agents caused a decrease in the incorporation of [3H]inositol. The results indicate that intracellular sodium may have a regulatory role in the turnover of phosphatidylinositol, and that, unlike the receptor-mediated responses, this regulation is present in all regions of the brain.

Adenosine Triphosphate↗
PubMed1990

The effect of tityustoxin in the turnover of inositol phosphates in crude synaptosomes.

The formation of inositol phosphates in response to stimulation by tityustoxin was studied in crude synaptosomes (P2). Phosphoinositides were labelled by incubation in the presence of [3H]inositol. Tityustoxin stimulated the turnover of inositol phosphate (PI). Tityustoxin specifically stimulated the turnover of glycerophosphoinositol (GP1), inositol 1-monophosphate (IP1), inositol 1,4-biphosphate (IP2) and inositol 1,4,5-triphosphate (IP3). The tityustoxin-stimulated turnover of water-soluble inositol phosphates was inhibited by tetrodotoxin, atropine and phorbol myristate acetate. It is suggested that the stimulatory effect of tityustoxin on the turnover of inositol phosphates might be mediated by increases in the release of acetylcholine, caused by the depolarizing effect of tityustoxin.

Animals↗
PubMedDate not supplied

Angiotensin II-induced inositol phosphate production in isolated rat zona glomerulosa and fasciculata/reticularis cells.

Angiotensin II (2.5 to 250nM) induced, within 60 sec, a significant increase in [3H]inositol-labeled inositol phosphate, inositol bisphosphate, and inositol trisphosphate in rat zona glomerulosa cells. Neither ACTH (3nM) nor K+ (8.4mM) had any effect, although aldosterone and corticosterone were significantly stimulated by all three agonists (after 30 min incubation). A similar significant dose-dependent increase in the inositol phosphates was observed with angiotensin II in zona fasciculata/reticularis cells after 30 min, but without any effect on corticosterone. In contrast ACTH significantly increased corticosterone with only a small although highly significant increase in inositol trisphosphate and inositol bisphosphate at 0.03nM ACTH. However at the higher dose (3.0nM) only inositol bisphosphate was significantly increased. These results indicate the presence on both zona glomerulosa and zona fasciculata/reticularis cells of AII receptors, which were linked to the formation of the secondary messenger, but only in the zona glomerulosa cells are associated with steroidogenesis.

Adrenal Cortex↗
PubMed1985

The effects of gamma-hexachlorocyclohexane on amylase secretion and inositol phospholipid metabolism in mouse pancreatic acini.

Dispersed mouse and guinea-pig pancreatic acini were used to examine the effects of the inositol analogue, gamma-hexachlorocyclohexane (lindane) on agonist-stimulated amylase secretion. Secretion from mouse acini in response to carbachol and cholecystokinin octapeptide (CCK-8) was reduced by lindane. Similarly, amylase release from guinea-pig acini stimulated by carbachol was abolished by lindane. These acini, however, still remained responsive to dibutyryl-cAMP with only a slightly diminished secretion to this agent. Inositol phospholipid synthesis and hydrolysis was stimulated in mouse acini by both carbachol and CCK-8. Although hydrolysis of these lipids in response to CCK-8 was reduced by only 18%, stimulation of inositol phospholipid synthesis by either agonist was abolished by lindane. Dose-response curves for inositol phospholipid synthesis stimulated by carbachol and CCK-8 in mouse acini were biphasic and superimposable with those of amylase secretion. In contrast, the dose-response curve for phosphoinositide hydrolysis was sigmoid and clearly separable from that of synthesis. Reducing the external Ca2+ concentration caused the dose-response curves for carbachol- and CCK-8-induced inositol phospholipid synthesis to be displaced to the right, as has been observed for amylase secretion. A23187 was also found to induce amylase secretion and inositol phospholipid synthesis, and both of these responses were inhibited by lindane. Amylase secretion and inositol phospholipid synthesis may, therefore, be closely related events in the exocrine pancreas. Lindane may provide a valuable tool with which to determine the role of inositol phospholipid metabolism in stimulus-response coupling.

Amylases↗
PubMed1990

Competitive inhibition by glucose of myo-inositol incorporation into cultured porcine aortic endothelial cells.

To explore the significance of hyperglycaemia as a causal factor for the appearance of diabetic angiopathies we investigated aspects of myo-inositol metabolism in porcine aortic endothelial cells. myo-Inositol was shown to be a long-living metabolite. Its uptake into the cells was mediated by a high-affinity, Na(+)-dependent uptake system inhibitable by ouabain with an apparent KM of 18.6 mumols/l, which was responsible for more than 80% of total uptake at physiological myo-inositol concentrations. Inhibition of inositol uptake by D-glucose was exclusively competitive with an apparent Ki of 24 mmol/l as shown by Lineweaver-Burk- and Dixon-plot analysis. The specificity of competitive inhibition was studied. L-Glucose which is stereochemically related to myo-inositol in the same way as the D-isomer proved to be an equally potent inhibitor. The hexoses D-galactose, D-mannose and D-fructose inhibited myo-inositol uptake to a minor extent. D-allose and 3-O-methyl-D-glucose had no inhibitory effect indicating that the OH-group of the carbon atom in 3 position is essential for the interaction with the carrier. The acyclic hexitol sorbitol also did not compete. As expected, the aldose reductase blocker sorbinil did not influence the carrier since there is no polyol pathway operating in porcine aortic endothelial cells. In accordance with the results of the uptake experiments, the incorporation of exogenous myo-inositol into membrane phosphatidylinositol was reduced at elevated extracellular glucose levels. The results raise the possibility that hyperglycaemia impairs endothelial inositol supply.

Aldehyde Reductase↗
PubMed1990

Local anesthetics: stimulation of incorporation of inositol into phosphoinositides in guinea pig cerebral cortical synaptoneurosomes.

Various local anesthetics enhanced the incorporation of [3H]inositol into phosphoinositides in guinea pig cerebral cortical synaptoneurosomes. Dibucaine, QX-572 and dimethisoquin showed maximum stimulation at 100 microM, tetracaine and diphenhydramine at 300 microM, and QX-314 at 1 mM, while quinacrine, lidocaine and cocaine showed no or only slight stimulation. There was no correlation between local anesthetic activity, estimated by inhibition of the 22Na+ flux elicited by the sodium channel activator batrachotoxin, and the potency for stimulation of inositol incorporation. A quaternary, relatively weak, local anesthetic, QX-572, was the most potent agent in stimulation of inositol incorporation, while the next most potent agent was dibucaine, a tertiary, very potent, local anesthetic. Dibucaine did not affect the uptake of [3H]inositol by synaptoneurosomes. The incorporation of [3H]inositol into phosphoinositides was increased in calcium-free buffer. The presence of dibucaine resulted in further stimulation of [3H]inositol incorporation in calcium-free buffer. Although dibucaine and QX-572 markedly stimulated incorporation of [3H]inositol into phosphoinositides, only QX-572 significantly enhanced the incorporation of 32PO4(3-) into phosphoinositides. The results suggest that certain local anesthetics enhance a pathway involving an exchange reaction between inositol and the phosphoinositol ester bond of phosphatidylinositol, but do not markedly affect the de novo pathway of phosphoinositide synthesis.

Anesthetics, Local↗