Green tea extract modulates lithium-induced thyroid follicular cell damage in rats.

BACKGROUND: The aim of the current work was to clarify the modulation role of green tea extract (GTE) over structural and functional affection of the thyroid gland after long term use of lithium carbonate (LC). The suggested underlying mechanisms participating in thyroid affection were researched. MATERIALS AND METHODS: Twenty-four Sprague-Dawley adult albino rats were included in the work. They were divided into three groups (control, LC, and concomitant LC + GTE). The work was sustained for 8 weeks. Biochemical assays were performed (thyroid hormone profile, interleukin 6 [Il-6]). Histological, histochemical (Periodic Acid Schiff [PAS]) and immunohistochemical (caspase-3, tumour necrosis factor alpha [TNF-α], proliferating cell nuclear antigen [PCNA]) evaluations were done. Oxidative/antioxidative markers (malondialdehyde [MDA]/gluthathione [GSH], superoxide dismutase [SOD]) and Western blot evaluation of the Bcl2 family were done. RESULTS: Lithium carbonate induced hypothyroidism (decreased T3, T4/increased thyroid-stimulating hormone [TSH]). The follicles were distended, others were involuted. Some follicles were disorganised, others showed detached follicular cells. Apoptotic follicular cells were shown (BAX and caspase-3 increased, Bcl2 decreased, BAX/Bcl2 ratio increased). The collagen fibres' content and proinflammatory markers (TNF-α and IL-6) increased. The proliferative nuclear activity was supported by increased expression of PCNA. Oxidative stress was established (increased MDA/decreased GSH, SOD). With the use of GTE, the thyroid hormone levels increased, while the TSH level decreased. Apoptosis was improved as BAX decreased, Bcl2 increased, and BAX/Bcl2 ratio was normal. The collagen fibres' content and proinflammatory markers (TNF-α and IL-6) decreased. The expression of PCNA and caspase-3 were comparable to the control group. The oxidative markers were improved (decreased MDA/increased GSH, SOD). CONCLUSIONS: In conclusion, prolonged use of LC results in hypothyroidism, which is accompanied by structural thyroid damage. LC induced thyroid damage through oxidative stress that prompted sterile inflammation and apoptosis. With the use of GTE, the thyroid gland regained its structure and function. The protecting role of GTE is through antioxidant, antifibrotic, anti-inflammatory, and antiproliferative effects.

Effect of a New Lithium Preparation on the Behavior of CBA/CaLac Mice in an Experimental Conflict Model.

The use of lithium drugs in clinical practice requires constant monitoring of lithium plasma concentration, because toxicity is sometimes observed at therapeutic concentrations of lithium. This is often associated with fluctuations of plasma concentration of lithium ions after intake of individual doses. Therefore, the use of a porous carrier providing a stable blood level of the drug is extremely promising and important for clinical practice. We studied activity of a new lithium drug (lithium complex) consisting of aluminum-silicon base and lithium citrate immobilized on its surface. Lithium carbonate served as the reference drug. It was shown that lithium carbonate and lithium complex exhibited no anxiolytic activity in the conflict model, but produced an antidepressant effect and improved exploratory behavior of animals.

Effect of Lithium Preparations on Cerebral Electrophysiological Activity in Rats.

The study examined the effects of a novel neurotropic medication based on a lithium complex composed of lithium citrate, polymethylsiloxane, and aluminum oxide on electrophysiological parameters of the rat brain. In contrast to lithium carbonate (the reference drug), the novel preparation resulted in a wave-like dynamics of electrical activity in the visual cortex. Rhythmic photic stimulation of the rats treated with lithium carbonate resulted in appearance of the signs attesting to up-regulation of excitability of cerebral cortex in all examined ranges. In contrast, the complex lithium preparation diminished the delta power spectrum, which was the only affected frequency band. It is hypothesized that the complex lithium medication induces milder activation of the cerebral cortex in comparison with lithium carbonate. The novel medication composed of lithium citrate, aluminum oxide, and polymethylsiloxane, is characterized by greater efficacy and safety than the preparation based on inorganic lithium salt (lithium carbonate).

The Influence of Lithium and/or Selenium Treatment on Homeostasis of Chosen Bioelements in Rats.

Lithium is widely used in medicine and the therapy is often long term. Apart from beneficial effects, its application can cause diverse side effects. The current study was performed with the aim of the evaluation of the effect of lithium and/or selenium administration on magnesium, calcium and silicon levels in rats. The study was performed on rats divided into four groups (six animals each): control-received saline, Li-received Li2CO3 (2.7 mg Li/kg b.w.), Se-received Na2SeO3·H2O (0.5 mg Se/kg b.w.), and Li+Se-received simultaneously Li2CO3 and Na2SeO3·H2O (2.7 and 0.5 mg Se/kg b.w.). The administration was performed in form of water solutions by a stomach tube once a day for 6 weeks. In the organs (liver, kidney, brain, spleen, heart, lung and femoral muscle), the concentrations of magnesium, calcium and silicon were determined. Lithium significantly increased Ca in the kidney, brain and spleen. Coadministration of selenium reversed this effect. No changes of magnesium in organs were observed. Silicon was affected only in spleen-an increase vs. control was observed in all studied groups. The beneficial influence of coadministration of selenium in case of calcium lets us suggest that an issue of its possible use as an adjuvant alleviating side effects in lithium-treated subjects is worth being continued.

Could selenium administration alleviate the disturbances of blood parameters caused by lithium administration in rats?

Lithium is widely used in medicine, but its administration can cause numerous side effects. The present study aimed at the evaluation of the possible application of selenium, an essential and antioxidant element, as a protective agent against lithium toxicity. The experiment was performed on four groups of Wistar rats: I (control)-treated with saline, II (Li)-treated with lithium (Li2CO3), III (Se)-treated with selenium (Na2SeO3) and IV (Li + Se)-treated with lithium and selenium (Li2CO3 and Na2SeO3) in the form of water solutions by stomach tube for 6 weeks. The following biochemical parameters were measured: concentrations of sodium, potassium, calcium, magnesium, phosphorus, iron, urea, creatinine, cholesterol, glucose, total protein and albumin and activities of alkaline phosphatase, aspartate aminotransferase and alanine aminotransferase in serum as well as whole blood superoxide dismutase and glutathione peroxidase. Morphological parameters such as red blood cells, haemoglobin, haematocrit, mean corpuscular volume, mean corpuscular haemoglobin, mean corpuscular haemoglobin concentration, platelets, white blood cells, neutrophils as well as lymphocytes were determined. Lithium significantly increased serum calcium and glucose (2.65 ± 0.17 vs. 2.43 ± 0.11; 162 ± 31 vs. 121 ± 14, respectively), whereas magnesium and albumin were decreased (1.05 ± 0.08 vs. 1.21 ± 0.15; 3.85. ± 0.12 vs. 4.02 ± 0.08, respectively). Selenium given with lithium restored these parameters to values similar to those observed in the control (Ca-2.49 ± 0.08, glucose-113 ± 26, Mg-1.28 ± 0.09, albumin-4.07 ± 0.11). Se alone or co-administered with Li significantly increased aspartate aminotransferase and glutathione peroxidase. The obtained outcomes let us suggest that the continuation of research on the application of selenium as an adjuvant in lithium therapy seems warranted.

IMPA1 is essential for embryonic development and lithium-like pilocarpine sensitivity.

Lithium has been the standard pharmacological treatment for bipolar disorder over the last 50 years; however, the molecular targets through which lithium exerts its therapeutic effects are still not defined. We characterized the phenotype of mice with a dysfunctional IMPA1 gene (IMPA1-/-) to study the in vivo physiological functions of IMPA1, in general, and more specifically its potential role as a molecular target in mediating lithium-dependent physiological effects. Homozygote IMPA1-/- mice died in utero between days 9.5 and 10.5 post coitum (p.c.) demonstrating the importance of IMPA1 in early embryonic development. Intriguingly, the embryonic lethality could be reversed by myo-inositol supplementation via the pregnant mothers. In brains of adult IMPA1-/- mice, IMPase activity levels were found to be reduced (up to 65% in hippocampus); however, inositol levels were not found to be altered. Behavioral analysis of the IMPA1-/- mice indicated an increased motor activity in both the open-field test and the forced-swim test as well as a strongly increased sensitivity to pilocarpine-induced seizures, the latter supporting the idea that IMPA1 represents a physiologically relevant target for lithium. In conclusion the IMPA1-/- mouse represents a novel model to study inositol homeostasis, and indicates that genetic inactivation of IMPA1 can mimic some actions of lithium.

Inositol deficiency diet and lithium effects.

OBJECTIVES: A major hypothesis explaining the therapeutic effect of lithium (Li) in mania is depletion of inositol via inhibition of inositol monophosphatase. However, inositol is also present in the diet. Restriction of dietary inositol could theoretically enhance the effects of Li. METHODS: We used dietary inositol restriction in animal studies and also devised a palatable diet for humans that is 90% free of inositol. RESULTS: Dietary inositol restriction significantly augmented the inositol-reducing effect of Li in rat frontal cortex. Li reduced inositol levels by 4.7%, inositol-deficient diet by 5.1%, and Li plus inositol-deficient diet by 10.8%. However, feeding with the inositol-deficient diet did not enhance the behavioral effect of Li in the Li-pilocarpine seizure model. Fifteen patients participated in an open clinical study of the inositol-deficient diet: six rapid cycling bipolar patients responding inadequately to Li or valproate in different phases of illness; two Li-treated bipolar outpatients with residual symptomatology, and seven inpatient Li-treated bipolar patients in non-responding acute mania. The diet had a major effect in reducing the severity of affective disorder in 10 of the patients within the first 7-14 days of treatment. CONCLUSION: These results suggest that dietary inositol restriction may be useful in some bipolar patients, but controlled replication is necessary.

Interaction of calbindin D28k and inositol monophosphatase in human postmortem cortex: possible implications for bipolar disorder.

OBJECTIVES: Therapeutically relevant concentrations of lithium (Li) exert an uncompetitive inhibition on inositol monophosphatase (IMPase). It has recently been shown that calbindin D28k (calbindin) activates IMPase. Purified calbindin attaches to a specific amino acid sequence on purified IMPase enhancing its activity by several hundred fold. We studied whether calbindin activates IMPase in postmortem human brain crude homogenate, whether differences in calbindin levels between lymphocytes and brain may be responsible for our previous finding of reduced IMPase activity in lymphocytes but not brain of bipolar patients, and whether calbindin protein levels are altered in postmortem brain from bipolar patients versus control subjects and schizophrenic and major depressive patients. METHODS: IMPase activity in human postmortem brain specimens with or without 10 microM human recombinant calbindin was quantified spectrophotometrically in an enzyme-linked immunosorbent assay (ELISA) reader. Calbindin protein levels in postmortem brain were determined using Western blot analysis. RESULTS: Supplementation of human recombinant calbindin to postmortem human brain crude homogenate enhanced IMPase activity by 3.5-fold. No difference in postmortem temporal cortex calbindin protein levels was found between bipolar patients versus comparison groups. Two-fold higher calbindin protein levels were found in Li-treated bipolar patients compared with other bipolar patients. Subchronic Li treatment in mice did not affect brain calbindin protein levels significantly. Chronic Li treatment reduced calbindin protein levels in the frontal cortex but not in the hippocampus. CONCLUSIONS: Calbindin is a physiological activator of IMPase in human brain. Protein levels of calbindin are not altered in postmortem temporal cortex of bipolar patients.

Lithium alters measures of auditory gating in two strains of mice.

BACKGROUND: There are similarities between schizophrenia and bipolar disorder, especially during the psychotic phase. Auditory gating deficits are common in both schizophrenia (does not remit postpsychotic event) and bipolar disorder (only during the manic phase). Lithium has been used to treat psychosis acutely in both bipolar disorder and schizophrenia. An animal model was used to assess the effects of lithium treatment on normal and deficient auditory gating. METHODS: Mice of the DBA/2 (deficient gating) and C3H (normal gating) strains were treated for 6 weeks with either standard rodent chow or rodent chow supplemented with 2.55g/kg lithium carbonate. After 6 weeks of treatment, auditory evoked potentials were recorded under anesthesia. Differences between the groups and treatments were determined using analysis of variance. RESULTS: The normally impaired DBA/2 mice showed improved auditory gating following lithium treatment, while the C3H mice, the benchmark "normal" mouse strain, were impaired after lithium treatment. CONCLUSIONS: C3H mice treated with lithium had significantly impaired auditory gating as a result of treatment. This may be due to norepinephrine facilitation, through a blockade of presynaptic alpha(2) autoreceptors. DBA/2 mice had improved gating as a result of treatment with lithium, likely due to improved functioning of the gamma-aminobutyric acid system.

The role of the extracellular signal-regulated kinase signaling pathway in mood modulation.

The neurobiological underpinnings of mood modulation, molecular pathophysiology of manic-depressive illness, and therapeutic mechanism of mood stabilizers are largely unknown. The extracellular signal-regulated kinase (ERK) pathway is activated by neurotrophins and other neuroactive chemicals to produce their effects on neuronal differentiation, survival, regeneration, and structural and functional plasticity. We found that lithium and valproate, commonly used mood stabilizers for the treatment of manic-depressive illness, stimulated the ERK pathway in the rat hippocampus and frontal cortex. Both drugs increased the levels of activated phospho-ERK44/42, activated phospho-ribosomal protein S6 kinase-1 (RSK1) (a substrate of ERK), phospho-CREB (cAMP response element-binding protein) and phospho-B cell lymphoma protein-2 antagonist of cell death (substrates of RSK), and BDNF. Inhibiting the ERK pathway with the blood-brain barrier-penetrating mitogen-activated protein kinase (MAP kinase)/ERK kinase (MEK) kinase inhibitor SL327, but not with the nonblood-brain barrier-penetrating MEK inhibitor U0126, decreased immobility time and increased swimming time of rats in the forced-swim test. SL327, but not U0126, also increased locomotion time and distance traveled in a large open field. The behavioral changes in the open field were prevented with chronic lithium pretreatment. SL327-induced behavioral changes are qualitatively similar to the changes induced by amphetamine, a compound that induces relapse in remitted manic patients and mood elevation in normal subjects. These data suggest that the ERK pathway may mediate the antimanic effects of mood stabilizers.

Lithium regulates PKC-mediated intracellular cross-talk and gene expression in the CNS in vivo.

It has become increasingly appreciated that the long-term treatment of complex neuropsychiatric disorders like bipolar disorder (BD) involves the strategic regulation of signaling pathways and gene expression in critical neuronal circuits. Accumulating evidence from our laboratories and others has identified the family of protein kinase C (PKC) isozymes as a shared target in the brain for the long-term action of both lithium and valproate (VPA) in the treatment of BD. In rats chronically treated with lithium at therapeutic levels, there is a reduction in the levels of frontal cortical and hippocampal membrane-associated PKC alpha and PKC epsilon. Using in vivO microdialysis, we have investigated the effects of chronic lithium on the intracellular cross-talk between PKC and the cyclic AMP (cAMP) generating system in vivo. We have found that activation of PKC produces an increase in dialysate cAMP levels in both prefrontal cortex and hippocampus, effects which are attenuated by chronic lithium administration. Lithium also regulates the activity of another major signaling pathway the c-Jun N-terminal kinase pathway--in a PKC-dependent manner. Both Li and VPA, at therapeutically relevant concentrations, increase the DNA binding of activator protein 1 (AP-1) family of transcription factors in cultured cells in vitro, and in rat brain ex vivo. Furthermore, both agents increase the expression of an AP-1 driven reporter gene, as well as the expression of several endogenous genes known to be regulated by AP-1. Together, these results suggest that the PKC signaling pathway and PKC-mediated gene expression may be important mediators of lithium's long-term therapeutic effects in a disorder as complex as BD.

Utilización del carbonato de litio en el Instituto Psiquiátrico de Santiago: comparación entre dos servicios clínicos, variación estacional / Use of lithium carbonate at Instituto Psiquiátrico, Santiago: comparison of 2 clinical services, seasonal variation

El objetivo de este estudio es analizar el uso del carbonato de litio en pacientes hospitalizados en sectores de agudos en el Instituto Psiquiátrico de Santiago, desde 1985 a 1990, y comparar su uso en los dos servicios clínicos existentes en ese período. El estudio se llevó a cabo en los Servicios A y B del Instituto que tenían características similares en cuanto a tipo de pacientes. El instrumento usado para hacer las comparaciones fue la DDD (dosis diaria definida), fórmula que hace posible comparar el uso de fármacos entre distintos centros. Se buscó también variaciones estacionales en su utilización. Un masivo incremento en el uso del Carbonato de Litio se aprecia en los primeros seis años, el que se estabiliza en los últimos dos. Este hecho puede atribuirse a un menor diagnóstico de los trastornos afectivos y a una progresiva aceptación del uso del medicamento. También se encontró una gran diferencia en el uso del medicamento entre los dos servicios (A y B) lo que resulta difícil de explicar y podría estar relacionado con la aplicación de criterios diagnósticos diferentes en trastornos del ánimo versus esquizofrenia. En relación a la variación estacional se encontró un incremento mayor en primavera

Influence of streptozotocin-induced diabetes in rats on the lithium content of tissue and the effect of dietary lithium supplements on this diabetic condition.

To study the effects of lithium supplementation on the diabetic condition, we measured the lithium concentration in the liver, kidney, and muscle from streptozotocin (STZ)-induced diabetic male Sprague-Dawley (SD) rats that were either treated or untreated with peroral lithium carbonate (0.3 mg/mL). The data showed that the lithium content of the liver and muscle was significantly lower in STZ rats than in normal control rats (0.22 +/- 0.05 v 1.30 +/- 0.15, P < .01, and 0.79 +/- 0.30 v 2.48 +/- 2.00 microg/g, respectively). After 4 weeks of lithium carbonate supplementation, we found that (1) the lithium content of the liver and muscle returned to the normal range, (2) the extent of STZ-mediated destruction of beta cells in the pancreas decreased, (3) fasting blood glucose (FBG) and 2-hour postprandial blood glucose (PBG) decreased (P < .05), (4) among the indicators of oxidative stress and antioxidant defenses, blood lipid peroxidate (LPO) decreased and erythrocyte superoxide dismutase (RBC-SOD) and glutathione (GSH) returned to normal, and (5) hepatic LPO decreased and glutathione peroxidase (GSH-Px) increased. These results suggest that the restoration of lithium to control levels in the liver and muscle of diabetic animals is associated not only with decreased blood glucose but also with reduced oxidative stress, and consequently with the protection of insulin-secreting pancreatic islet cells.

Trace element distribution in rat brain following lead and lithium supplementation--a study using an EDXRF spectrometer.

Distribution of K, Fe, Cu, Zn, Br and Rb in whole brain samples following combined Pb and Li administration to female Porton rats has been investigated by using the Energy Dispersive x-Ray Fluorescence (EDXRF) technique. Brain K, Cu and Rb levels are diminished, whereas Fe and Br levels are enhanced significantly following short-term (1 month) and long-term (4 months) combined treatment with Li (1.1 g/kg diet) and two doses of Pb (50 and 100 mg/kg body weight). The Zn levels are lowered following combined treatment with Li and both the doses of Pb given for short-term only.

Daidzin and daidzein suppress free-choice ethanol intake by Syrian golden hamsters.

Syrian Golden hamsters prefer and consume large and remarkably constant amounts of ethanol in a simple two-bottle free-choice regimen. Ethanol intake is significantly suppressed by zimelidine, bromocriptine, buspirone, and lithium carbonate, pharmacological agents that have been shown to be beneficial in controlling ethanol intake in alcohol-dependent humans. These results suggest that this ethanol-drinking animal model has high "predictive validity" and can be used effectively in the search for and identification of new agents for the treatment of alcohol abuse. The model has enabled us to confirm the putative antidipsotropic effect of Radix puerariae (RP), an herb long used in traditional Chinese medicine for the treatment of patients who abuse alcohol. A crude extract of RP at a dose of 1.5 g.kg-1 x day-1 significantly suppresses (> 50%) the free-choice ethanol intake of Golden hamsters. Moreover, two major constituents of RP, daidzein (4',7-dihydroxyisoflavone) and daidzin (the 7-glucoside of daidzein), were also shown to suppress free-choice ethanol intake. Daidzin and daidzein, at doses of 150 and 230 mg.kg-1 x day-1, respectively, suppress ethanol intake by > 50%. RP, daidzein, and daidzin treatment do not significantly affect the body weight and water or food intake of the hamsters. These findings identify a class of compounds that offer promise as safe and effective therapeutic agents for alcohol abuse.