Lithium salts continue to be one of the most promising drugs in the treatment of acute episodes and the prevention of relapses in patients suffering from manic depression or bipolar illness. Even though lithium salts have been used clinically in the treatment of bipolar patients for more than forty years, their pharmacologic mode of action is unclear. In particular, a detailed understanding of the biological action of lithium is lacking. The main goals of the research proposed in this application are: (i) to advance the understanding at the molecular and cellular levels of the pharmacologic action of the Li+ ion in the treatment of bipolar disorder by analyzing the binding and transport properties of Li+ and Mg2+ ions in human red blood cells (RBCs), in human nerve cells, and in purified guanine nucleotide-binding (G) protein preparations by nuclear magnetic resonance (NMR) and fluorescence spectroscopies; and (ii) to test the application of these spectroscopic methods to the identification of bipolar patients who are most likely to respond to lithium treatment or are most susceptible to experiencing lithium toxicity. The proposed spectroscopic methods will test two interrelated mechanisms of action of Li+: a cell membrane abnormality, and a competition mechanism between Li+ and Mg2+ ions for membrane binding sites (in particular, anionic phospholipids and the metal-binding domain of G proteins). Our RBC studies completed in the previous grant period as well as our preliminary studies with nerve cells and G proteins indicate that the spectroscopic methods proposed in this study provide new information on Li+ interactions with cell components; this new information could not have been obtained with other techniques routinely used for Li+ analysis. In addition to contributing to an advancement of the understanding at the molecular and cellular levels of the pharmacologic action of the Li+ ion in the treatment of bipolar illness, the results of this study may also be useful in the diagnosis and prognosis of bipolar patients. More precisely defined molecular parameters, such as Li+ binding constants to the RBC membranes from bipolar patients and their phospholipid composition, may be useful for predicting the success of Li+ therapy and the likelihood of Li+ toxicity. We believe that our proposed research endeavor will also address a broad range of fundamental questions in the fields of neurochemistry, biophysics, bioinorganic chemistry, and physiology.
| Layden, Brian T; Minadeo, Nicole; Suhy, Joyce et al. (2004) Biochemical and psychiatric predictors of Li(+) response and toxicity in Li(+)-treated bipolar patients. Bipolar Disord 6:53-61 |
