Abstract
For many decades pharmacological drugs based on lithium salts have been successfully used in psychiatry to treat bipolar disorder, and they remain the “gold standard” of pharmacological therapy of patients with this disease. At the same time, over recent years in experiments in vitro and in vivo a plethora of evidence has accumulated on a positive effect of lithium ions in other areas including their neuro-, cardio-, and nephroprotective properties, regulation of stem cells functions, regulation of inflammation, and others. Numerous studies have shown that the effect of lithium ions involves several mechanisms; however, one of its main targets in the implementation of most of the effects is glycogen synthase kinase 3β, a key enzyme in various pathological and protective signaling pathways in cells. However, one of the main limitations of the use of lithium salts in clinics is their narrow therapeutic window, and the risk of toxic side effects. This review presents the diversity of effects of lithium ions on the organism emphasizing their potential clinical applications with minimal undesirable side effects. In the end, we present a schematic “Lithiometer”, comparing the range of Li+ concentrations that might be used for the treatment of acute pathologies with possible toxic effects of Li+.
Similar content being viewed by others
Abbreviations
- IMP:
-
inositol monophosphatase
- ROS:
-
reactive oxygen species
References
Cade, J. F. (1949) Lithium salts in the treatment of psychotic excitement, Med. J. Aust., 2, 349–352.
Mitchell, P. B., and Hadzi-Pavlovic, D. (2000) Lithium treatment for bipolar disorder, Bull. World Health Org., 78, 515–517.
Schou, M. (2001) Lithium treatment at 52, J. Affect. Disord., 67, 21–32.
Yildiz, A., Vieta, E., Leucht, S., and Baldessarini, R. J. (2011) Efficacy of antimanic treatments: meta-analysis of randomized, controlled trials, Neuropsychopharmacology, 36, 375–389.
Baldessarini, R. J., Tondo, L., Davis, P., Pompili, M., Goodwin, F. K., and Hennen, J. (2006) Decreased risk of suicides and attempts during long-term lithium treatment: a meta-analytic review, Bipolar Disord., 8, 625–639.
Berridge, M. J., Downes, C. P., and Hanley, M. R. (1989) Neural and developmental actions of lithium: a unifying hypothesis, Cell, 59, 411–419.
Harwood, A. J. (2005) Lithium and bipolar mood disorder: the inositol-depletion hypothesis revisited, Mol. Psychiatry, 10, 117–126.
Silverstone, P. H., McGrath, B. M., and Kim, H. (2005) Bipolar disorder and myoinositol: a review of the magnetic resonance spectroscopy findings, Bipolar Disord., 7, 1–10.
Phiel, C. J., and Klein, P. S. (2001) Molecular targets of lithium action, Annu. Rev. Pharmacol. Toxicol., 41, 789–813.
Allison, J. H., and Stewart, M. A. (1971) Reduced brain inositol in lithium-treated rats, Nat. New Biol., 233, 267–268.
Haimovich, A., Eliav, U., and Goldbourt, A. (2012) Determination of the lithium binding site in inositol monophosphatase, the putative target for lithium therapy, by magic-angle-spinning solid-state NMR, J. Am. Chem. Soc., 134, 5647–5651.
Berridge, M. J., and Irvine, R. F. (1989) Inositol phosphates and cell signaling, Nature, 341, 197–205.
Manji, H. K., and Chen, G. (2002) PKC, MAP kinases and the bcl–2 family of proteins as long-term targets for mood stabilizers, Mol. Psychiatry, 7, S46–56.
Klein, P. S., and Melton, D. A. (1996) A molecular mechanism for the effect of lithium on development, Proc. Natl. Acad. Sci. USA, 93, 8455–8459.
Stambolic, V., Ruel, L., and Woodgett, J. R. (1996) Lithium inhibits glycogen synthase kinase-3 activity and mimics wingless signaling in intact cells, Curr. Biol., 6, 1664–1668.
Sutherland, C., Leighton, I. A., and Cohen, P. (1993) Inactivation of glycogen synthase kinase-3β by phosphorylation: new kinase connections in insulin and growth factor signaling, Biochem. J., 296 (Pt. 1), 15–19.
Lochhead, P. A., Kinstrie, R., Sibbet, G., Rawjee, T., Morrice, N., and Cleghon, V. (2006) A chaperone-dependent GSK3β transitional intermediate mediates activation-loop autophosphorylation, Mol. Cell, 24, 627–633.
Doble, B. W., and Woodgett, J. R. (2003) GSK-3: tricks of the trade for a multi-tasking kinase, J. Cell Sci., 116, 1175–1186.
Ryves, W. J., and Harwood, A. J. (2001) Lithium inhibits glycogen synthase kinase-3 by competition for magnesium, Biochem. Biophys. Res. Commun., 280, 720–725.
Chiu, C. T., and Chuang, D. M. (2010) Molecular actions and therapeutic potential of lithium in preclinical and clinical studies of CNS disorders, Pharmacol. Ther., 128, 281–304.
Mora, A., Sabio, G., Risco, A. M., Cuenda, A., Alonso, J. C., Soler, G., and Centeno, F. (2002) Lithium blocks the PKB and GSK3 dephosphorylation induced by ceramide through protein phosphatase-2A, Cell Signal., 14, 557–562.
Beaulieu, J. M., Marion, S., Rodriguiz, R. M., Medvedev, I. O., Sotnikova, T. D., Ghisi, V., Wetsel, W. C., Lefkowitz, R. J., Gainetdinov, R. R., and Caron, M. G. (2008) A β-arrestin 2 signaling complex mediates lithium action on behavior, Cell, 132, 125–136.
Zhang, F., Phiel, C. J., Spece, L., Gurvich, N., and Klein, P. S. (2003) Inhibitory phosphorylation of glycogen synthase kinase-3 (GSK-3) in response to lithium. Evidence for autoregulation of GSK-3, J. Biol. Chem., 278, 33067–33077.
Freland, L., and Beaulieu, J. M. (2012) Inhibition of GSK3 by lithium, from single molecules to signaling networks, Front. Mol. Neurosci., 5, 14.
Mendes, C. T., Mury, F. B., de Sa Moreira, E., Alberto, F. L., Forlenza, O. V., Dias-Neto, E., and Gattaz, W. F. (2009) Lithium reduces Gsk3b mRNA levels: implications for Alzheimer disease, Eur. Arch. Psychiatry Clin. Neurosci., 259, 16–22.
Beaulieu, J. M., Sotnikova, T. D., Yao, W. D., Kockeritz, L., Woodgett, J. R., Gainetdinov, R. R., and Caron, M. G. (2004) Lithium antagonizes dopamine-dependent behaviors mediated by an AKT/glycogen synthase kinase 3 signaling cascade, Proc. Natl. Acad. Sci. USA, 101, 5099–5104.
Cole, A. R. (2013) Glycogen synthase kinase 3 substrates in mood disorders and schizophrenia, FEBS J., 280, 5213–5227.
Jope, R. S. (1999) Anti-bipolar therapy: mechanism of action of lithium, Mol. Psychiatry, 4, 117–128.
Malhi, G. S., Tanious, M., Das, P., Coulston, C. M., and Berk, M. (2013) Potential mechanisms of action of lithium in bipolar disorder. Current understanding, CNS Drugs, 27, 135–153.
Dixon, J. F., and Hokin, L. E. (1998) Lithium acutely inhibits and chronically up-regulates and stabilizes glutamate uptake by presynaptic nerve endings in mouse cerebral cortex, Proc. Natl. Acad. Sci. USA, 7, 8363–8368.
Berk, M., Kirchmann, N. H., and Butkow, N. (1996) Lithium blocks 45Ca2+ uptake into platelets in bipolar affective disorder and controls, Clin. Neuropharmacol., 19, 48–51.
Can, A., Schulze, T. G., and Gould, T. D. (2014) Molecular actions and clinical pharmacogenetics of lithium therapy, Pharmacol. Biochem. Behav., doi: 10.1016/j.pbb.2014.02.004.
Brown, K. M., and Tracy, D. K. (2013) Lithium: the pharmacodynamic actions of the amazing ion, Ther. Adv. Psychopharmacol., 3, 163–176.
Charney, D. S. (1998) Monoamine dysfunction and the pathophysiology and treatment of depression, J. Clin. Psychiatry, 59, 11–14.
Li, X., Zhu, W., Roh, M. S., Friedman, A. B., Rosborough, K., and Jope, R. S. (2004) In vivo regulation of glycogen synthase kinase-3β (gsk3β) by serotoninergic activity in mouse brain, Neuropsychopharmacology, 29, 1426–1431.
Dunigan, C. D., and Shamoo, A. E. (1995) Li+ stimulates ATP-regulated dopamine uptake in PC12 cells, Neuroscience, 65, 1–4.
Scheuch, K., Holtje, M., Budde, H., Lautenschlager, M., Heinz, A., Ahnert-Hilger, G., and Priller, J. (2010) Lithium modulates tryptophan hydroxylase 2 gene expression and serotonin release in primary cultures of serotoninergic raphe neurons, Brain Res., 1307, 14–21.
Carli, M., and Reader, T. A. (1997) Regulation of central serotonin transporters by chronic lithium: an autoradiographic study, Synapse, 27, 83–89.
Chuang, D. M., Chen, R. W., Chalecka-Franaszek, E., Ren, M., Hashimoto, R., Senatorov, V., Kanai, H., Hough, C., Hiroi, T., and Leeds, P. (2002) Neuroprotective effects of lithium in cultured cells and animal models of diseases, Bipolar Disord., 4, 129–136.
Manji, H. K., Moore, G. J., and Chen, G. (1999) Lithium at 50: have the neuroprotective effects of this unique cation been overlooked? Biol. Psychiatry, 46, 929–940.
Ma, J., and Zhang, G. Y. (2003) Lithium reduced n-methyl-D-aspartate receptor subunit 2a tyrosine phosphorylation and its interactions with src and fyn mediated by psd-95 in rat hippocampus following cerebral ischemia, Neurosci. Lett., 348, 185–189.
Xu, J., Culman, J., Blume, A., Brecht, S., and Gohlke, P. (2003) Chronic treatment with a low dose of lithium protects the brain against ischemic injury by reducing apoptotic death, Stroke, 34, 1287–1292.
Bian, Q., Shi, T., Chuang, D. M., and Qian, Y. (2007) Lithium reduces ischemia-induced hippocampal ca1 damage and behavioral deficits in gerbils, Brain Res., 1184, 270–276.
Chalecka-Franaszek, E., and Chuang, D. M. (1999) Lithium activates the serine/threonine kinase akt-1 and suppresses glutamate-induced inhibition of akt-1 activity in neurons, Proc. Natl. Acad. Sci. USA, 96, 8745–8750.
Roh, M. S., Eom, T. Y., Zmijewska, A. A., De Sarno, P., Roth, K. A., and Jope, R. S. (2005) Hypoxia activates glycogen synthase kinase-3 in mouse brain in vivo: protection by mood stabilizers and imipramine, Biol. Psychiatry, 57, 278–286.
Juhaszova, M., Zorov, D. B., Kim, S. H., Pepe, S., Fu, Q., Fishbein, K. W., Ziman, B. D., Wang, S., Ytrehus, K., Antos, C. L., Olson, E. N., and Sollott, S. J. (2004) Glycogen synthase kinase-3β mediates convergence of protection signaling to inhibit the mitochondrial permeability transition pore, J. Clin. Invest., 113, 1535–1549.
Terashima, Y., Sato, T., Yano, T., Maas, O., Itoh, T., Miki, T., Tanno, M., Kuno, A., Shimamoto, K., and Miura, T. (2010) Roles of phospho-gsk-3β in myocardial protection afforded by activation of the mitochondrial K ATP channel, J. Mol. Cell Cardiol., 49, 762–770.
Faghihi, M., Mirershadi, F., Dehpour, A. R., and Bazargan, M. (2008) Preconditioning with acute and chronic lithium administration reduces ischemia/reperfusion injury mediated by cyclooxygenase not nitric oxide synthase pathway in isolated rat heart, Eur. J. Pharmacol., 597, 57–63.
Gonzalez Arbelaez, L. F., Perez Nunez, I. A., and Mosca, S. M. (2013) Gsk-3β inhibitors mimic the cardioprotection mediated by ischemic pre- and postconditioning in hypertensive rats, Biomed. Res. Int., 2013, 317456.
Yadav, H. N., Singh, M., and Sharma, P. L. (2010) Modulation of the cardioprotective effect of ischemic preconditioning in hyperlipidaemic rat heart, Eur. J. Pharmacol., 643, 78–83.
Plotnikov, E. Y., Kazachenko, A. V., Vyssokikh, M. Y., Vasileva, A. K., Tcvirkun, D. V., Isaev, N. K., Kirpatovsky, V. I., and Zorov, D. B. (2007) The role of mitochondria in oxidative and nitrosative stress during ischemia/reperfusion in the rat kidney, Kidney Int., 72, 1493–1502.
Vasil’eva, A. K., Plotnikov, E. Y., Kazachenko, A. V., Kirpatovsky, V. I., and Zorov, D. B. (2010) GSK-3β inhibition decreases ischemia-induced kidney cell death, Byul. Eksp. Biol. Med., 149, 276–281.
Talab, S. S., Emami, H., Elmi, A., Nezami, B. G., Assa, S., Deroee, A. F., Daneshmand, A., Tavangar, S. M., and Dehpour, A. R. (2010) Chronic lithium treatment protects the rat kidney against ischemia/reperfusion injury: the role of nitric oxide and cyclooxygenase pathways, Eur. J. Pharmacol., 647, 171–177.
Plotnikov, E. Y., Grebenchikov, O. A., Babenko, V. A., Pevzner, I. B., Zorova, L. D., Likhvantsev, V. V., and Zorov, D. B. (2013) Nephroprotective effect of gsk-3β inhibition by lithium ions and δ-opioid receptor agonist dalargin on gentamicin-induced nephrotoxicity, Toxicol. Lett., 220, 303–308.
Wang, Y., Huang, W. C., Wang, C. Y., Tsai, C. C., Chen, C. L., Chang, Y. T., Kai, J. I., and Lin, C. F. (2009) Inhibiting glycogen synthase kinase-3 reduces endotoxaemic acute renal failure by down-regulating inflammation and renal cell apoptosis, Br. J. Pharmacol., 157, 1004–1013.
Zorov, D. B., Sukhikh, G. T., Plotnikov, Ye. Yu., Kirpatovsky, V. I., Kazachenko, A. V., Isaev, N. K., Khryapenkova, T. G., Visilieva, A. K., Zorova, L. D., Pevzner, I. B., and Marey, M. V. (2010) The use of lithium salts for the treatment of acute renal failure, Russian Federtion Patent 2409373.
Liu, A., Fang, H., Dahmen, U., and Dirsch, O. (2013) Chronic lithium treatment protects against liver ischemia/reperfusion injury in rats, Liver Transpl., 19, 762–772.
Patel, S., Doble, B., and Woodgett, J. R. (2004) Glycogen synthase kinase-3 in insulin and wnt signaling: a double-edged sword? Biochem. Soc. Trans., 32, 803–808.
Hill, E. J., Nagel, D. A., O’Neil, J. D., Torr, E., Woehrling, E. K., Devitt, A., and Coleman, M. D. (2013) Effects of lithium and valproic acid on gene expression and phenotypic markers in an NT2 neurosphere model of neural development, PLoS One, 8, e58822.
Huo, K., Sun, Y., Li, H., Du, X., Wang, X., Karlsson, N., Zhu, C., and Blomgren, K. (2012) Lithium reduced neural progenitor apoptosis in the hippocampus and ameliorated functional deficits after irradiation to the immature mouse brain, Mol. Cell Neurosci., 51, 32–42.
Li, H., Li, Q., Du, X., Sun, Y., Wang, X., Kroemer, G., Blomgren, K., and Zhu, C. (2011) Lithium-mediated long-term neuroprotection in neonatal rat hypoxia-ischemia is associated with antiinflammatory effects and enhanced proliferation and survival of neural stem/progenitor cells, J. Cereb. Blood Flow Metab., 31, 2106–2115.
Petrini, M., and Azzara, A. (2012) Lithium in the treatment of neutropenia, Curr. Opin. Hematol., 19, 52–57.
Walasek, M. A., Bystrykh, L., van den Boom, V., Olthof, S., Ausema, A., Ritsema, M., Huls, G., de Haan, G., and van Os, R. (2012) The combination of valproic acid and lithium delays hematopoietic stem/progenitor cell differentiation, Blood, 119, 3050–3059.
Eslaminejad, M. B., Karimi, N., and Shahhoseini, M. (2013) Chondrogenic differentiation of human bone marrow-derived mesenchymal stem cells treated by GSK-3 inhibitors, Histochem. Cell Biol., 140, 623–633.
Kim, J. H., Liu, X., Wang, J., Chen, X., Zhang, H., Kim, S. H., Cui, J., Li, R., Zhang, W., Kong, Y., Zhang, J., Shui, W., Lamplot, J., Rogers, M. R., Zhao, C., Wang, N., Rajan, P., Tomal, J., Statz, J., Wu, N., Luu, H. H., Haydon, R. C., and He, T. C. (2013) Wnt signaling in bone formation and its therapeutic potential for bone diseases, Ther. Adv. Musculoskelet. Dis., 5, 13–31.
Satija, N. K., Sharma, D., Afrin, F., Tripathi, R. P., and Gangenahalli, G. (2013) High throughput transcriptome profiling of lithium stimulated human mesenchymal stem cells reveals priming towards osteoblastic lineage, PLoS One, 8, e55769.
Trowbridge, J. J., Xenocostas, A., Moon, R. T., and Bhatia, M. (2006) Glycogen synthase kinase-3 is an in vivo regulator of hematopoietic stem cell repopulation, Nat. Med., 12, 89–98.
Huang, J., Nguyen-McCarty, M., Hexner, E. O., Danet-Desnoyers, G., and Klein, P. S. (2012) Maintenance of hematopoietic stem cells through regulation of Wnt and mTOR pathways, Nat. Med., 18, 1778–1785.
Tsai, L. K., Wang, Z., Munasinghe, J., Leng, Y., Leeds, P., and Chuang, D. M. (2011) Mesenchymal stem cells primed with valproate and lithium robustly migrate to infarcted regions and facilitate recovery in a stroke model, Stroke, 42, 2932–2939.
Plotnikov, E. Y., Pulkova, N. V., Pevzner, I. B., Zorova, L. D., Silachev, D. N., Morosanova, M. A., Sukhikh, G. T., and Zorov, D. B. (2013) Inflammatory pre-conditioning of mesenchymal multipotent stromal cells improves their immunomodulatory potency in acute pyelonephritis in rats, Cytotherapy, 15, 679–689.
Alessandri, A. L., Sousa, L. P., Lucas, C. D., Rossi, A. G., Pinho, V., and Teixeira, M. M. (2013) Resolution of inflammation: mechanisms and opportunity for drug development, Pharmacol. Ther., 139, 189–212.
Beurel, E., Michalek, S. M., and Jope, R. S. (2010) Innate and adaptive immune responses regulated by glycogen synthase kinase-3 (GSK3), Trends Immunol., 31, 24–31.
Rapaport, M. H., and Manji, H. K. (2001) The effects of lithium on ex vivo cytokine production, Biol. Psychiatry, 50, 217–224.
Knijff, E. M., Breunis, M. N., Kupka, R. W., de Wit, H. J., Ruwhof, C., Akkerhuis, G. W., Nolen, W. A., and Drexhage, H. A. (2007) An imbalance in the production of IL-1β and IL-6 by monocytes of bipolar patients: restoration by lithium treatment, Bipolar Disord., 9, 743–753.
Tickenbrock, L., Schwable, J., Strey, A., Sargin, B., Hehn, S., Baas, M., Choudhary, C., Gerke, V., Berdel, W. E., Muller-Tidow, C., and Serve, H. (2006) Wnt signaling regulates transendothelial migration of monocytes, J. Leukoc. Biol., 79, 1306–1313.
Yu, F., Wang, Z., Tchantchou, F., Chiu, C. T., Zhang, Y., and Chuang, D. M. (2012) Lithium ameliorates neurodegeneration, suppresses neuroinflammation, and improves behavioral performance in a mouse model of traumatic brain injury, J. Neurotrauma, 29, 362–374.
Hofmann, C., Dunger, N., Scholmerich, J., Falk, W., and Obermeier, F. (2010) Glycogen synthase kinase 3β: a master regulator of toll-like receptor-mediated chronic intestinal inflammation, Inflamm. Bowel Dis., 16, 1850–1858.
Albayrak, A., Halici, Z., Polat, B., Karakus, E., Cadirci, E., Bayir, Y., Kunak, S., Karcioglu, S. S., Yigit, S., Unal, D., and Atamanalp, S. S. (2013) Protective effects of lithium: a new look at an old drug with potential antioxidative and anti-inflammatory effects in an animal model of sepsis, Int. Immunopharmacol., 16, 35–40.
Bertsch, S., Lang, C. H., and Vary, T. C. (2011) Inhibition of glycogen synthase kinase 3β activity with lithium in vitro attenuates sepsis-induced changes in muscle protein turnover, Shock, 35, 266–274.
Nahman, S., Belmaker, R. H., and Azab, A. N. (2012) Effects of lithium on lipopolysaccharide-induced inflammation in rat primary glia cells, Innate Immun., 18, 447–458.
Malhi, G. S., Adams, D., and Berk, M. (2009) Is lithium in a class of its own? A brief profile of its clinical use, Aust. NZ J. Psychiatry, 43, 1096–1104.
McKnight, R. F., Adida, M., Budge, K., Stockton, S., Goodwin, G. M., and Geddes, J. R. (2012) Lithium toxicity profile: a systematic review and meta-analysis, Lancet, 379, 721–728.
Pilcher, H. R. (2003) Drug research: the ups and downs of lithium, Nature, 425, 118–120.
Tredget, J., Kirov, A., and Kirov, G. (2010) Effects of chronic lithium treatment on renal function, J. Affect. Disord., 126, 436–440.
Coresh, J., Astor, B. C., Greene, T., Eknoyan, G., and Levey, A. S. (2003) Prevalence of chronic kidney disease and decreased kidney function in the adult US population: Third National Health and Nutrition Examination Survey, Am. J. Kidney Dis., 41, 1–12.
Coppen, A., Abou-Saleh, M., Milln, P., Bailey, J., and Wood, K. (1983) Decreasing lithium dosage reduces morbidity and side-effects during prophylaxis, J. Affect. Disord., 5, 353–362.
Khasraw, M., Ashley, D., Wheeler, G., and Berk, M. (2012) Using lithium as a neuroprotective agent in patients with cancer, BMC Med., 10, 131.
Kishore, B. K., and Ecelbarger, C. M. (2013) Lithium: a versatile tool for understanding renal physiology, Am. J. Physiol. Renal. Physiol., 304, F1139–1149; doi: 10.1152/ajprenal.00718.2012; Epub 2013 Feb 13.
Chiu, C. T., Wang, Z., Hunsberger, J. G., and Chuang, D. M. (2013) Therapeutic potential of mood stabilizers lithium and valproic acid: beyond bipolar disorder, Pharmacol. Rev., 65, 105–142.
Author information
Authors and Affiliations
Corresponding authors
Additional information
Original Russian Text © E. Y. Plotnikov, D. N. Silachev, L. D. Zorova, I. B. Pevzner, S. S. Jankauskas, S. D. Zorov, V. A. Babenko, M. V. Skulachev, D. B. Zorov, 2014, published in Biokhimiya, 2014, Vol. 79, No. 8, pp. 932–943.
Rights and permissions
About this article
Cite this article
Plotnikov, E.Y., Silachev, D.N., Zorova, L.D. et al. Lithium salts — Simple but magic. Biochemistry Moscow 79, 740–749 (2014). https://doi.org/10.1134/S0006297914080021
Received:
Revised:
Published:
Issue Date:
DOI: https://doi.org/10.1134/S0006297914080021