Effects of lithium on the membrane composition and on intracellular levels of free magnesium and calcium: A multinuclear NMR and fluorescence study

Bipolar disorder is a psychiatric disorder in which patients experience uncontrollable episodes of mania and depression. Lithium salts are the most widely used drugs for treatment of bipolar disorder. To date, the exact mechanism of action is not known. An understanding of the bioactivity of Li+ salts may lead to the development of less toxic drugs.; Previous studies have shown that acute incubation with Li+ in neuroblastoma cells over time resulted in an increase of free intracellular magnesium concentrations, [Mg2+]f. We demonstrated the effects of therapeutic Li+ levels on neuroblastoma cells under chronic loading conditions. We also found that chronic Li+ incubation resulted in a larger change in the percentage of [Mg2+] f as compared to acute loading conditions.; Under physiological conditions, the concentrations of unbound, free metal ions, such as Mg2+ and Ca2+ are strictly regulated. Competition between Li+ and Mg2+ for Mg-binding sites has been demonstrated in Mg2+-regulated biomolecules, such as adenosine triphosphate and guanine nucleotide binding proteins. Furthermore, Ca2+ acts as a second messenger in response to Mg2+ -regulated proteins. In neuroblastoma cells under similar conditions of perfusion, we observed by both fluorescence spectroscopy and microscopy, and upon the addition of Li+ to the perfusate that intracellular [Mg2+]f rose prior to [Ca2+] f.; Bipolar patients are thought to suffer from a membrane abnormality, which affects the composition and chemical properties of plasma membranes. To test this hypothesis, we measured the phospholipid composition of plasma membranes purified from neuroblastoma cells before and after chronic Li+ incubation. We found that chronic Li+ incubation with therapeutically relevant intracellular [Li+] resulted in altered phospholipid levels as compared to Li+-free samples.; In order to study how Li+ affects patients who suffer from this disease, we conducted a clinical study in which we measured biochemical parameters of erythrocytes isolated from the blood of bipolar patients who were not on Li+-therapy and compared our results to those from a previous study in which all the patients were on Li +-therapy. Our preliminary results indicated that significant differences in some biochemical parameters existed between both types of patients.