Brain Inositol Levels Research Articles

Acute Intracerebroventricular Inositol Does Not Reverse the Effect of Chronic Lithium Treatment in the Forced Swim Test

Background: Lithium has numerous biochemical effects but it is difficult to dissect which of these is responsible for its therapeutic action in bipolar disorder. In the current study we aimed to address one of the major hypotheses, the inositol depletion hypothesis. This hypothesis postulates that lithium's mood-stabilizing effect is mediated by the depletion of brain inositol levels and the subsequent effect on cellular signaling. Methods: We studied whether acute intracerebroventricular (ICV) administration of myo-inositol could reverse the antidepressant-like effect of chronic lithium treatment in the forced swim test (FST). Results: In contrast with our prediction, acute myo-inositol administration did not reverse the effect of chronic lithium to decrease immobility in the FST. Conclusions: The results of the present study are limited due to the following: (1) inositol was given acutely while possible events downstream of inositol depletion might require a longer period and (2) ICV inositol may not have reached those areas of the brain involved in the FST.

Sodium/myo-Inositol Transporters: Substrate Transport Requirements and Regional Brain Expression in the TgCRND8 Mouse Model of Amyloid Pathology

Inositol stereoisomers, myo- and scyllo-inositol, are known to enter the brain and are significantly elevated following oral administration. Elevations in brain inositol levels occur across a concentration gradient as a result of active transport from the periphery. There are two sodium/myo-inositol transporters (SMIT1, SMIT2) that may be responsible for regulating brain inositol levels. The goals of this study were to determine the effects of aging and Alzheimer's disease (AD)-like amyloid pathology on transporter expression, to compare regional expression and to analyze substrate requirements of the inositol transporters. QPCR was used to examine expression of the two transporters in the cortex, hippocampus and cerebellum of TgCRND8 mice, a mouse model of amyloid pathology, in comparison to non-transgenic littermates. In addition, we examined the structural features of inositol required for active transport, utilizing a cell-based competitive uptake assay. Disease pathology did not alter transporter expression in the cortex or hippocampus (p>0.005), with only minimal effects of aging observed in the cerebellum (SMIT1: F2,26 = 12.62; p = 0.0002; SMIT2: F2,26 = 8.71; p = 0.0015). Overall, brain SMIT1 levels were higher than SMIT2, however, regional differences were observed. For SMIT1, at 4 and 6 months cerebellar SMIT1 levels were significantly higher than cortical and hippocampal levels (p<0.05). For SMIT2, at all three ages both cortical and cerebellar SMIT2 levels were significantly higher than hippocampal levels (p<0.05) and at 4 and 6 months of age, cerebellar SMIT2 levels were also significantly higher than cortical levels (p<0.05). Inositol transporter levels are stably expressed as a function of age, and expression is unaltered with disease pathology in the TgCRND8 mouse. Given the fact that scyllo-inositol is currently in clinical trials for the treatment of AD, the stable expression of inositol transporters regardless of disease pathology is an important finding.

Regulation of Gene Expression by Lithium and Depletion of Inositol in Slices of Adult Rat Cortex

Lithium inhibits inositol monophosphatase at therapeutically effective concentrations, and it has been hypothesized that depletion of brain inositol levels is an important chemical alteration for lithium's therapeutic efficacy in bipolar disorder. We have employed adult rat cortical slices as a model to investigate the gene regulatory consequences of inositol depletion effected by lithium using cytidine diphosphoryl-diacylglycerol as a functionally relevant biochemical marker to define treatment conditions. Genes coding for the neuropeptide hormone pituitary adenylate cyclase activating polypeptide (PACAP) and the enzyme that processes PACAP's precursor to the mature form, peptidylglycine alpha-amidating monooxygenase, were upregulated by inositol depletion. Previous work has shown that PACAP can increase tyrosine hydroxylase (TH) activity and dopamine release, and we found that the gene for GTP cyclohydrolase, which effectively regulates TH through synthesis of tetrahydrobiopterin, was also upregulated by inositol depletion. We propose that modulation of brain PACAP signaling might represent a new opportunity in the treatment of bipolar disorder.

Intracerebroventricular antisense to inositol monophosphatase-1 reduces enzyme activity but does not affect Li-sensitive behavior

Inositol monophosphatase (IMPase) inhibition is a hypothesized mechanism of action of lithium (Li). To test this hypothesis, the authors used the approach of antisense administration. Three days of an intracerebroventricular (icv) administration of 5 μg/20 μl 3′-phosphorothioated IMPA-1 antisense oligonucleotide sequence resulted in 20% reduction of rat periventricular IMPase activity. Li potentiates pilocarpine-induced seizures, because inhibition of IMPase leads to reduction in brain inositol levels. However, antisense-induced reduction in IMPase activity was not followed by seizures induced by subconvulsive pilocarpine doses.

Epi-inositol and inositol depletion: two new treatment approaches in affective disorder.

Inositol is a simple polyol precursor in a second messenger system important in brain myo-insitol, the natural isomer, which has been found to be therapeutically effective in depression, panic disorder, and obsessive-compulsive disorder in double-blind controlled trials. Recently, epi-inositol, an unnatural stereoisomer of myo-inositol, was found to have effects similar to those of myo-inositol to reverse lithium-pilocarpine seizures. We measured the behavior of rats in an elevated plus maze model of anxiety after chronic treatment of 11 daily intraperitoneal injections of epi-inositol, myo-inositol, or control solution. Epi-inositol reduced anxiety levels of rats compared with controls, and its effect was stronger than that of myo- inositol. Lithium has been hypothesized to alleviate mania by reducing brain inositol levels. Inositol in brain derives from the second messenger cycle, from new synthesis, or from diet via transport across the blood brain barrier. Because the first two are inhibited by lithium, we propose that an inositol-free diet will augment lithium action in mania by enhancing restriction of inositol.

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

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.

Effect of inositol treatment on the behavior of rhesus monkeys: Preliminary results

1. 1. The effects of inositol (20 g/day, oral) on spatial learning and spontaneous home-cage behavior of four Rhesus monkeys, were studied in a crossover design. 2. 2. Results indicate no marked inositol effect on learning, memory, or behavior. There was a suggestion of an effect of chronic inositol in reducing cage-induced repetitive behavior as indicated by increased switching between modes of behavior, and reduction in length of longest behavioral bout. Furthermore inositol may increase time spent in environmentally- rather than self-oriented behavior. 3. 3. Previous behavioral studies of inositol were performed in rats, which maintain low brain inositol levels compared to primates, including humans. The present study demonstrates the feasibility of primate behavioral studies with inositol, and shows the need for longer time experiments and increased variety of behavioral tests.

Plasma inositol is not elevated in Alzheimer's disease

Brain inositol levels have been previously reported as elevated in Alzheimer's disease (AD) in brain. Brain inositol levels may be reflected in plasma levels. We therefore studied plasma inositol levels in 20 AD patients and 20 controls. Plasma inositol levels in the AD patients did not differ from values found in the controls. © 1998 John Wiley & Sons, Ltd.

Plasma inositol is not elevated in Alzheimer's disease

Brain inositol levels have been previously reported as elevated in Alzheimer's disease (AD) in brain. Brain inositol levels may be reflected in plasma levels. We therefore studied plasma inositol levels in 20 AD patients and 20 controls. Plasma inositol levels in the AD patients did not differ from values found in the controls. © 1998 John Wiley & Sons, Ltd.

Lack of effect of ECS on rat brain inositol monophosphatase activity and inositol levels and of i.c.v. inositol on ictal and post-ictal length

Lithium (Li) has often been compared to ECT in therapeutic spectrum and mechanism. Inhibition of inositol monophosphatase and reduction of brain inositol are major mechanisms of Li action. Many Li effects in animals and humans are reversible by inositol. We therefore studied interactions of ECS and inositol. ECS in rats did not reduce brain inositol monophosphatase activity or brain inositol levels. Intracerebroventricular injection of 10 mg inositol, a dose that reverses Li effects, had no effect on seizure length or post-ictal length.

Behavioral evidence for the existence of two pools of cellular inositol

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 Pl synthesis and inositol for osmotic function are sequestered in different cellular pools.

High-dose peripheral inositol raises brain inositol levels and reverses behavioral effects of inositol depletion by lithium

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.

TCDD decreases brain inositol concentrations in the rat

A single dose of 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD) reduced significantly brain regional inositol levels in both the most TCDD-susceptible (Long-Evans; LD 509.8 μg/ kg) and the most TCDD-resistant (Han/Wistar; LD 50 > 7200 μg/ kg) rat strain. The decrease emerged earlier in Long-Evans rats but was similar in magnitude at 8 days in both strains. There were some inconsistent and largely dose-independent changes in inositol-1- and inositol-4-monophosphate concentrations at 2 days. On day 8, a tendency towards reduced levels was seen especially in H/W rats. We conclude that TCDD reduces brain inositol levels presumably by inhibiting its synthesis by way of substrate deficit (hypoglycemia), but this effect does not appear to be causally related to the lethal action of TCDD.

Biochemical, behavioral, and clinical studies of the role of inositol in lithium treatment and depression

Lithium (Li) reduces brain inositol levels by inhibiting the enzyme inositol monophosphatase. The enzyme inositol-1-phosphatase was measured in human erd blood cells of controls, Li-free bipolar patients, and Li-treated bipolar patients and was found to be reduced by 80% in Li-treated bipolars, thus supporting the concept that chronic Li at therapeutic concentrations inhibits this enzyme. Two behaviors in rats caused by Li, reduction of rearing, and Li-pilocarpine seizures, are reversed by intracerebroventricular replenishment of inositol. The reversal is stereospecific to the naturally occurring myo-inositol; whereas the stereoisomer L- chiro-inositol is ineffective. The reversal is dose-dependent, requiring a dose consistent with known quantities of brain inositol depletion; and is time-dependent, as inositol must be given 1–8 h before stimulation. High-dose peripheral inositol also reverses limbic seizures induced by Li-pilocarpine, and using gas chromatography was shown to increase brain inositol levels that had been reduced by Li treatment. Low-dose inositol could be shown to reverse a peripheral Li-induced side effect, polyuria/polydipsia, in rats and in patients treated with Li. A higher dose of inositol markedly reduced Hamilton Depression Ratings in 9 of 11 unipolar major depressive disorder patients previously unresponsive to tricyclics, in an open design, but had no effect on chronic schizophrenics in a controlled double-blind randomized crossover trial. A new inositol monophosphatase inhibitor, a fungal product originally discovered as a complement inhibitor, was found to act like Li and lower the seizure threshold for subconvulsant doses of pilocarpine. These data suggest that inositol monophosphatase inhibition is a key mechanism of Li's therapeutic action and that design of new inositol monophosphatase inhibitors may be a practical strategy to create new compounds with Li-like therapeutic effects.