Lithium but not cholinergic ligands influence guanylate cyclase activity in intact human lymphocytes

Schubert, Thomas; Müller, Wernér E.G.

doi:10.1016/0006-2952(90)90048-p

Cited by 13 publications

(5 citation statements)

References 16 publications

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“…78 Similar to other regulatory systems, the effect of lithium on cGMP/NO pathway does not work in isolation, and it likely affects monoaminergic signalling, adding to its neuroprotective role. 79,80 In several studies the effects of lithium were discrepant (increase in NO and cGMP production under chronic treatment).…”

Section: Mechanismsmentioning

confidence: 99%

Lithium in the treatment of bipolar disorder: pharmacology and pharmacogenetics

2015

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After decades of research, the mechanism of action of lithium in preventing recurrences of bipolar disorder remains only partially understood. Lithium research is complicated by absence of suitable animal models of bipolar disorder and by having to rely on in vitro studies of peripheral tissues. A number of distinct hypotheses emerged over the years, but none has been conclusively supported or rejected. The common theme emerging from pharmacological and genetic studies is that lithium affects multiple steps in cellular signalling, usually enhancing basal and inhibiting stimulated activities. Some of the key nodes of these regulatory networks include GSK3, CREB, and Na+-K+ ATPase. Genetic and pharmacogenetic studies are starting to generate promising findings, but remain limited by small sample sizes. As full responders to lithium seem to represent a unique clinical population, there is inherent value and need for studies of lithium responders. Such studies will be an opportunity to uncover specific effects of lithium in those individuals who clearly benefit from the treatment.

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Section: Mechanismsmentioning

confidence: 99%

Lithium in the treatment of bipolar disorder: pharmacology and pharmacogenetics

2015

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“…Lithium is a potent inhibitor of guanylate cyclase in intact human lymphocytes (262). Exposing human lymphocytes for 72 h to lithium markedly increased Na/K pump numbers (138) and this can be prevented by adding myoinositol.…”

Section: Lithium Mechanismsmentioning

confidence: 99%

Review of Lithium Effects on Brain and Blood

2009

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Clinicians have long used lithium to treat manic depression. They have also observed that lithium causes granulocytosis and lymphopenia while it enhances immunological activities of monocytes and lymphocytes. In fact, clinicians have long used lithium to treat granulocytopenia resulting from radiation and chemotherapy, to boost immunoglobulins after vaccination, and to enhance natural killer activity. Recent studies revealed a mechanism that ties together these disparate effects of lithium. Lithium acts through multiple pathways to inhibit glycogen synthetase kinase-3β (GSK3β). This enzyme phosphorylates and inhibits nuclear factors that turn on cell growth and protection programs, including the nuclear factor of activated T cells (NFAT) and WNT/β-catenin. In animals, lithium upregulates neurotrophins, including brain-derived neurotrophic factor (BDNF), nerve growth factor, neurotrophin-3 (NT3), as well as receptors to these growth factors in brain. Lithium also stimulates proliferation of stem cells, including bone marrow and neural stem cells in the subventricular zone, striatum, and forebrain. The stimulation of endogenous neural stem cells may explain why lithium increases brain cell density and volume in patients with bipolar disorders. Lithium also increases brain concentrations of the neuronal markers n-acetyl-aspartate and myoinositol. Lithium also remarkably protects neurons against glutamate, seizures, and apoptosis due to a wide variety of neurotoxins. The effective dose range for lithium is 0.6-1.0 mM in serum and >1.5 mM may be toxic. Serum lithium levels of 1.5-2.0 mM may have mild and reversible toxic effects on kidney, liver, heart, and glands. Serum levels of >2 mM may be associated with neurological symptoms, including cerebellar dysfunction. Prolonged lithium intoxication >2 mM can cause permanent brain damage. Lithium has low mutagenic and carcinogenic risk. Lithium is still the most effective therapy for depression. It "cures" a third of the patients with manic depression, improves the lives of about a third, and is ineffective in about a third. Recent studies suggest that some anticonvulsants (i.e., valproate, carbamapazine, and lamotrigene) may be useful in patients that do not respond to lithium. Lithium has been reported to be beneficial in animal models of brain injury, stroke, Alzheimer's, Huntington's, and Parkinson's diseases, amyotrophic lateral sclerosis (ALS), spinal cord injury, and other conditions. Clinical trials assessing the effects of lithium are under way. A recent clinical trial suggests that lithium stops the progression of ALS.

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“…Briefly, [3H]inositol-labelled lymphocytes, separated from extracellular [3H]inositol, were suspended in a modified Hank's balanced salt solution. 0.18 ml of the cell suspension, about 3 x 10 6 cells, were incubated at 37 ~ with the various drugs or saline (as control) for three hours, a time period that yields maximal intracellular lithium levels (Schubert and Mfiller, 1990). Subsequently fMLP was added (final concentration 0.1 pM) and after 1 minute the incubation was stopped by the addition of ice cold trichloroacetic acid.…”

Section: Evaluation Of Inositol Phosphate Turnovermentioning

confidence: 99%

Levoprotiline ((?)-oxaprotiline) effects on inositol phosphate generation in human peripheral lymphocytes

Schubert

Müller

1991

J. Neural Transmission

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The effects of the atypical antidepressant levoprotiline (LPT) on inositol phosphate metabolism were investigated in N-formyl-methionyl-leucylphenylalanine (fMLP) activated human lymphocytes. In the presence of LPT, stimulation of phosphoinositide hydrolysis by fMLP lead to an increased accumulation of inositol bisphosphates, an effect which could be detected within the range of therapuetic plasma concentrations and which is exerted by lithium in a similar way. Furthermore, incubation of lymphocytes with LPT and subsequent stimulation with fMLP lead to a pronounced decrease in the level of free intracellular [3H]inositol. Both LPT effects, the increased accumulation of inositol bisphosphates and the reduction of free intracellular [3H]inositol, were found to be more pronounced for LPT than for its enantiomer (+)-oxaprotiline. The results are discussed in view of a possible biochemical mechanism which may contribute to the antidepressive activity of LPT.

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Lithium but not cholinergic ligands influence guanylate cyclase activity in intact human lymphocytes

Cited by 13 publications

References 16 publications

Lithium in the treatment of bipolar disorder: pharmacology and pharmacogenetics

Lithium in the treatment of bipolar disorder: pharmacology and pharmacogenetics

Review of Lithium Effects on Brain and Blood

Levoprotiline ((?)-oxaprotiline) effects on inositol phosphate generation in human peripheral lymphocytes

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