Abstract
Regulation of Na+/K+-ATPase in bipolar disorder and lithium therapy has been investigated for more than 40 years. Contradictory results in this area may be caused by the difference between acute and long-term Li effects on cell metabolism and variance in responsiveness of different cell types. We compared the time-course of Li action focusing on Na+/K+-ATPase and lipid peroxidation in two widely different cell models–Jurkat and HEK293. Na+/K+-ATPase expression level was determined in cells cultivated in the absence or presence of 1 mM Li for different time spans (1, 7, and 28 days) using [3H] ouabain binding and immunoblot assay of α-subunit. In parallel samples, the formation of malondialdehyde (MDA) was quantified by HPLC, and 4-hydroxy-2-nonenal (4-HNE) protein adducts were determined by immunoblot. Cultivation of Jurkat cells in 1 mM Li medium resulted in downregulation of Na+/K+-ATPase (decrease of [3H] ouabain-biding sites and intensity of immunoblot signals) in all Li-groups. In HEK293 cells, the decrease of Na+/K+-ATPase was observed after the acute, 1-day exposure only. The long-term treatment with Li resulted in Na+/K+-ATPase upregulation. MDA and 4-HNE modified proteins were decreased in Jurkat cells in all Li-groups. On the other hand, in HEK293 cells, MDA concentration was decreased after the acute, 1-day Li exposure only; the long-term cultivations, for 7 or 28 days, resulted in a significant increase of lipid peroxidation products. The Li-induced decrease of lipid peroxidation products was associated with the decrease of Na+/K+-ATPase level and vice versa.
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References
Alda M (2015) Lithium in the treatment of bipolar disorder: pharmacology and pharmacogenetics. Mol Psychiatry 20:661–670
Alexander MP, Farag YM, Mittal BV, Rennke HG, Singh AK (2008) Lithium toxicity: a double-edged sword. Kidney Int 73:233–237
Antia IJ, Dorkins CE, Wood AJ, Aronson JK (1992) Increase in Na+/K+ pump numbers in vivo in healthy volunteers taking oral lithium carbonate and further upregulation in response to lithium in vitro. Br J Clin Pharmacol 34:535–540
Antia IJ, Smith CE, Wood AJ, Aronson JK (1995) The upregulation of Na+,K(+)-ATPase pump numbers in lymphocytes from the first-degree unaffected relatives of patients with manic depressive psychosis in response to in vitro lithium and sodium ethacrynate. J Affect Disord 34:33–39
Avissar S, Schreiber G (2006) The involvement of G proteins and regulators of receptor-G protein coupling in the pathophysiology, diagnosis and treatment of mood disorders. Clin Chim Acta 366:37–47
Ayala A, Muñoz MF, Argüelles S (2014) Lipid peroxidation: production, metabolism, and signaling mechanisms of malondialdehyde and 4-hydroxy-2-nonenal. Oxidative Med Cell Longev 2014:360438
Baer L (1973) Pharmacology—lithium absorption, distribution, renal handling, and effects on body electrolytes (chapter 3). In: Gershon S, Shopsin B (eds) Lithium: its role in psychiatric research and treatment. Plenum Press, London, p 34
Banerjee U, Dasgupta A, Rout JK, Singh OP (2012) Effects of lithium therapy on Na+-K+-ATPase activity and lipid peroxidation in bipolar disorder. Prog Neuro-Psychopharmacol Biol Psychiatry 37:56–61
Birch NJ (1994) Lithium ions have limited intracellular access: implication for cell regulation and pharmacology. J Trace Microprobe Techn 12:1–16
Can A, Schulze TG, Gould TD (2014) Molecular actions and clinical pharmacogenetics of lithium therapy. Pharmacol Biochem Behav 123:3–16
Catalá A (2009) Lipid peroxidation of membrane phospholipids generates hydroxy-alkenals and oxidized phospholipids active in physiological and/or pathological conditions. Chem Phys Lipids 157:1–11
Cho YW (1995) Lithium-induced inhibition of Na-K ATPase and Ca ATPase activities in rat brain synaptosome. J Korean Med Sci 10:7–13
Chytilová A, Borchert GH, Mandíková-Alánová P, Hlaváčková M, Kopkan L, Khan MA, Imig JD, Kolář F, Neckář J (2015) Tumour necrosis factor-α contributes to improved cardiac ischaemic tolerance in rats adapted to chronic continuous hypoxia. Acta Physiol 214:97–108
de Vasconcellos AP, Zugno AI, Dos Santos AH, Nietto FB, Crema LM, Gonçalves M, Franzon R, de Souza Wyse AT, da Rocha ER, Dalmaz C (2005) Na+,K(+)-ATPase activity is reduced in hippocampus of rats submitted to an experimental model of depression: effect of chronic lithium treatment and possible involvement in learning deficits. Neurobiol Learn Mem 84:102–110
El-Mallakh RS (1983a) The Na,K-ATPase hypothesis for manic-depression. I. General considerations. Med Hypotheses 12:253–268
El-Mallakh RS (1983b) The Na,K-ATPase hypothesis for manic-depression. II. The mechanism of action of lithium. Med Hypotheses 12:269–282
Fisar Z, Anders M, Tvrzicka E, Stankova B (2005) Effect of long-term administration of antidepressants on the lipid composition of brain plasma membranes. Gen Physiol Biophys 24:221–236
Gawlik-Kotelnicka O, Mielicki W, Rabe-Jabłońska J, Lazarek J, Strzelecki D (2016) Impact of lithium alone or in combination with haloperidol on oxidative stress parameters and cell viability in SH-SY5Y cell culture. Acta Neuropsychiatr 28:38–44
Gioia L, Siddique A, Head SR, Salomon DR, Su AI (2018) A genome-wide survey of mutations in the Jurkat cell line. BMC Genomics 19:334
Guerri C, Ribelles M, Grisolía S (1981) Effects of lithium, and lithium and alcohol administration on (Na + K)-ATPase. Biochem Pharmacol 30:25–30
Gutman Y, Hochman S, Wald H (1973) The differential effect of Li + on microsomal ATPase in cortex, medulla and papilla of the rat kidney. Biochim Biophys Acta 298:284–290
He B, Soderlund DM (2010) Human embryonic kidney (HEK293) cells express endogenous voltage-gated sodium currents and Na v 1.7 sodium channels. Neurosci Lett 469:268–272
He B, Soderlund DM (2014) Functional expression of rat Nav1.6 voltage-gated sodium channels in HEK293 cells: modulation by the auxiliary β1 subunit. PLoS One 9:e85188
Hesketh JE, Glen AI, Reading HW (1977a) Membrane ATPase activities in depressive illness. J Neurochem 28:1401–1402
Hesketh JE, Kinloch N, Reading HW (1977b) The effects of lithium on ATPase activity in subcellular fractions from rat brain. J Neurochem 29:883–894
Hillert M, Zimmermann M, Klein J (2012) Uptake of lithium into rat brain after acute and chronic administration. Neurosci Lett 521:62–66
Jakobsson E, Argüello-Miranda O, Chiu SW, Fazal Z, Kruczek J, Nunez-Corrales S, Pandit S, Pritchet L (2017) Towards a unified understanding of lithium action in basic biology and its significance for applied biology. J Membr Biol 250:587–604
Jenkins RJ, Aronson JK, Brearley CJ (1991) Increases in Na/K pump numbers in isolated human lymphocytes exposed to lithium in vitro. Reversal by myo-inositol and by inhibitors of protein kinase C and the Na/H antiport. Biochim Biophys Acta 1092:138–144
Johnston BB, Naylor GJ, Dick EG, Hopwood SE, Dick DA (1980) Prediction of clinical course of bipolar manic depressive illness treated with lithium. Psychol Med 10:329–334
Joshi YB, Praticò D (2014) Lipid peroxidation in psychiatric illness: overview of clinical evidence. Oxidative Med Cell Longev 2014:828702
Khairova R, Pawar R, Salvadore G, Juruena MF, de Sousa RT, Soeiro-de-Souza MG, Salvador M, Zarate CA, Gattaz WF, Machado-Vieira R (2012) Effects of lithium on oxidative stress parameters in healthy subjects. Mol Med Rep 5:680–682
Khoubnasabjafari M, Ansarin K, Jouyban A (2015) Reliability of malondialdehyde as a biomarker of oxidative stress in psychological disorders. Bioimpacts 5:123–127
Kim Y, Santos R, Gage FH, Marchetto MC (2017) Molecular mechanisms of bipolar disorder: progress made and future challenges. Front Cell Neurosci 11:30
Komoroski RA, Pearce JM (2008) Estimating intracellular lithium in brain in vivo by localized 7Li magnetic resonance spectroscopy. Magn Reson Med 60:21–26
Komoroski RA, Lindquist DM, Pearce JM (2013) Lithium compartmentation in brain by 7Li MRS: effect of total lithium concentration. NMR Biomed 26:1152–1157
Lai JS, Zhao C, Warsh JJ, Li PP (2006) Cytoprotection by lithium and valproate varies between cell types and cellular stresses. Eur J Pharmacol 539:18–26
Laursen UH, Pihakaski-Maunsbach K, Kwon TH, Østergaard Jensen E, Nielsen S, Maunsbach AB (2004) Changes of rat kidney AQP2 and Na,K-ATPase mRNA expression in lithium-induced nephrogenic diabetes insipidus. Nephron Exp Nephrol 97: e1–16
Lazzara CA, Kim YH (2015) Potential application of lithium in Parkinson's and other neurodegenerative diseases. Front Neurosci 9:403
Le-Niculescu H, Kurian SM, Yehyawi N, Dike C, Patel SD, Edenberg HJ, Tsuang MT, Salomon DR, Nurnberger JI, Niculescu AB (2009) Identifying blood biomarkers for mood disorders using convergent functional genomics. Mol Psychiatry 14:156–174
Le-Niculescu H, Levey DF, Ayalew M, Palmer L, Gavrin LM, Jain N, Winiger E, Bhosrekar S, Shankar G, Radel M, Bellanger E, Duckworth H, Olesek K, Vergo J, Schweitzer R, Yard M, Ballew A, Shekhar A, Sandusky GE, Schork NJ, Kurian SM, Salomon DR, Niculescu AB 3rd (2013) Discovery and validation of blood biomarkers for suicidality. Mol Psychiatry 18:1249–1264
Li R, El-Mallakh RS (2004) Differential response of bipolar and normal control lymphoblastoid cell sodium pump to ethacrynic acid. J Affect Disord 80:11–17
Lin YC, Boone M, Meuris L, Lemmens I, Van Roy N, Soete A, Reumers J, Moisse M, Plaisance S, Drmanac R, Chen J, Speleman F, Lambrechts D, Van de Peer Y, Tavernier J, Callewaert N (2014) Genome dynamics of the human embryonic kidney 293 lineage in response to cell biology manipulations. Nat Commun 5:4767
Logan JG (1980) In vitro effects of lithium chloride on ATPases of rabbit cerebral synaptic membranes. Biochem Pharmacol 29:887–889
Looney SW, el-Mallakh RS (1997) Meta-analysis of erythrocyte Na,K-ATPase activity in bipolar illness. Depress Anxiety 5:53–65
Lopez-Corcuera B, Gimenez C, Aragon C (1988) Change of synaptic membrane lipid composition and fluidity by chronic administration of lithium. Biochim Biophys Acta 939:467–475
Machado-Vieira R, Andreazza AC, Viale CI, Zanatto V, Cereser V, da Silva VR, Kapczinski F, Portela LV, Souza DO, Salvador M, Gentil V (2007) Oxidative stress parameters in unmedicated and treated bipolar subjects during initial manic episode: a possible role for lithium antioxidant effects. Neurosci Lett 421:33–36
Malhi GS, Tanious M, Das P, Coulston CM, Berk M (2013) Potential mechanisms of action of lithium in bipolar disorder. Current understanding. CNS Drugs 27:135–153
McKnight RF, Adida M, Budge K, Stockton S, Goodwin GM, Geddes JR (2012) Lithium toxicity profile: a systematic review and meta-analysis. Lancet 379:721–728
Mezni A, Khazri A, Khazri O, Limam F, Cosette P, Aouani E (2017) Neuroprotective activity of grape seed and skin extract against lithium exposure using proteomic research. Mol Neurobiol 54:2720–2730
Morel P, Tallineau C, Pontcharraud R, Piriou A, Huguet F (1998) Effects of 4-hydroxynonenal, a lipid peroxidation product, on dopamine transport and Na+/K+ ATPase in rat striatal synaptosomes. Neurochem Int 33:531–540
Muller CP, Reichel M, Muhle C, Rhein C, Gulbins E, Kornhuber J (2015) Brain membrane lipids in major depression and anxiety disorders. Biochim Biophys Acta 1851:1052–1065
Naylor GJ, Smith AH, Dick EG, Dick DA, McHarg AM, Chambers CA (1980) Erythrocyte membrane cation carrier in manic-depressive psychosis. Psychol Med 10:521–525
Nciri R, Desmoulin F, Allagui MS, Murat JC, Feki AE, Vincent C, Croute F (2013) Neuroprotective effects of chronic exposure of SH-SY5Y to low lithium concentration involve glycolysis stimulation, extracellular pyruvate accumulation and resistance to oxidative stress. Int J Neuropsychopharmacol 16:365–376
Onyango AN, Baba N (2010) New hypotheses on the pathways of formation of malondialdehyde and isofurans. Free Radic Biol Med 49:1594–1600
Rapoport SI, Basselin M, Kim HW, Rao JS (2009) Bipolar disorder and mechanisms of action of mood stabilizers. Brain Res Rev 61:185–209
Riegel RE, Valvassori SS, Moretti M, Ferreira CL, Steckert AV, de Souza B, Dal-Pizzol F, Quevedo J (2010) Intracerebroventricular ouabain administration induces oxidative stress in the rat brain. Int J Dev Neurosci 28:233–237
Rose AM, Mellett BJ, Valdes R, Kleinman JE, Herman MM, Li R, el-Mallakh RS (1998) Alpha 2 isoform of the Na,K-adenosine triphosphatase is reduced in temporal cortex of bipolar individuals. Biol Psychiatry 44:892–897
Roubalova L, Vosahlikova M, Brejchova J, Sykora J, Rudajev V, Svoboda P (2015) High efficacy but low potency of delta-opioid receptor-G protein coupling in Brij-58-treated, low-density plasma membrane fragments. PLoS One 10:e0135664
Roy S, Dasgupta A, Banerjee U, Chowdhury P, Mukhopadhyay A, Saha G, Singh O (2016) Role of membrane cholesterol and lipid peroxidation in regulating the Na. Indian J Psychiatry 58:317–325
Schreiber G, Avissar S (2007) Regulators of G-protein-coupled receptor-G-protein coupling: antidepressants mechanism of action. Expert Rev Neurother 7:75–84
Shao L, Young LT, Wang JF (2005) Chronic treatment with mood stabilizers lithium and valproate prevents excitotoxicity by inhibiting oxidative stress in rat cerebral cortical cells. Biol Psychiatry 58:879–884
Shaw G, Morse S, Ararat M, Graham FL (2002) Preferential transformation of human neuronal cells by human adenoviruses and the origin of HEK 293 cells. FASEB J 16:869–871
Siems WG, Hapner SJ, van Kuijk FJ (1996) 4-hydroxynonenal inhibits Na(+)-K(+)-ATPase. Free Radic Biol Med 20:215–223
Singh MM (1970) A unifying hypothesis on the biochemical basis of affective disorder. Psychiatr Q 44:706–724
Skou JC, Esmann M (1992) The Na,K-ATPase. J Bioenerg Biomembr 24:249–261
Srikanthan K, Shapiro JI, Sodhi K (2016) The role of Na/K-ATPase signaling in oxidative stress related to obesity and cardiovascular disease. Molecules 21
Stout J, Hanak AS, Chevillard L, Djemaï B, Risède P, Giacomini E, Poupon J, Barrière DA, Bellivier F, Mégarbane B, Boumezbeur F (2017) Investigation of lithium distribution in the rat brain ex vivo using lithium-7 magnetic resonance spectroscopy and imaging at 17.2 T. NMR Biomed 30:e3770
Suwalsky M, Fierro P, Villena F, Sotomayor CP (2007) Effects of lithium on the human erythrocyte membrane and molecular models. Biophys Chem 129:36–42
Svoboda P, Amler E, Teisinger J (1988) Different sensitivity of ATP + mg + Na (I) and pi + mg (II) dependent types of ouabain binding to phospholipase A2. J Membr Biol 104:211–221
Thellier ME, Wissocq J-C, Ripoll C (1997) NCR and SIMS study of whether lithium ions have limited intracellular access. J Trace Microprobe Techn 15:93–99
Tsikas D (2017) Assessment of lipid peroxidation by measuring malondialdehyde (MDA) and relatives in biological samples: analytical and biological challenges. Anal Biochem 524:13–30
Tsikas D, Rothmann S, Schneider JY, Suchy MT, Trettin A, Modun D, Stuke N, Maassen N, Frölich JC (2016) Development, validation and biomedical applications of stable-isotope dilution GC-MS and GC-MS/MS techniques for circulating malondialdehyde (MDA) after pentafluorobenzyl bromide derivatization: MDA as a biomarker of oxidative stress and its relation to 15(S)-8-iso-prostaglandin F2α and nitric oxide (NO). J Chromatogr B Anal Technol Biomed Life Sci 1019:95–111
Vereninov IA, Yurinskaya VE, Model MA, Vereninov AA (2016) Unidirectional flux balance of monovalent ions in cells with Na/Na and Li/Na exchange: experimental and computational studies on lymphoid U937 cells. PLoS One 11:e0153284
Viswanath B, Jose SP, Squassina A, Thirthalli J, Purushottam M, Mukherjee O, Vladimirov V, Patrinos GP, Del Zompo M, Jain S (2015) Cellular models to study bipolar disorder: a systematic review. J Affect Disord 184:36–50
Vosahlikova M, Svoboda P (2011) The influence of monovalent cations on trimeric G protein G(i)1 alpha activity in HEK293 cells stably expressing DOR-G(i)1 alpha (Cys(351)-Ile(351)) fusion protein. Physiol Res 60:541–547
Vosahlikova M, Svoboda P (2016) Lithium - therapeutic tool endowed with multiple beneficiary effects caused by multiple mechanisms. Acta Neurobiol Exp 76:1–19
Vosahlikova M, Jurkiewicz P, Roubalova L, Hof M, Svoboda P (2014) High- and low-affinity sites for sodium in delta-OR-G(i)1 alpha (Cys(351)-Ile(351)) fusion protein stably expressed in HEK293 cells; functional significance and correlation with biophysical state of plasma membrane. Naunyn Schmiedeberg's Arch Pharmacol 387:487–502
Vosahlikova M, Ujcikova H, Chernyayskiy O, Brejchova J, Roubalova L, Alda M, Svoboda P (2017) Effect of therapeutic concentration of lithium on live HEK293 cells; increase of Na+/K+-ATPase, change of overall protein composition and alteration of surface layer of plasma membrane. Biochim Biophys Acta-Gen Subj 1861:1099–1112
Vosahlikova M, Ujcikova H, Hlouskova M, Musil S, Roubalova L, Alda M, Svoboda P (2018) Induction of oxidative stress by long-term treatment of live HEK293 cells with therapeutic concentration of lithium is associated with down-regulation of δ-opioid receptor amount and function. Biochem Pharmacol 154:452–463
Wood AJ, Elphick M, Grahame-Smith DG (1989a) Effect of lithium and of other drugs used in the treatment of manic illness on the cation-transporting properties of Na+,K+-ATPase in mouse brain synaptosomes. J Neurochem 52:1042–1049
Wood AJ, Viswalingam A, Glue P, Aronson JK, Grahame-Smith DG (1989b) Measurement of cation transport in vivo in healthy volunteers after the oral administration of lithium carbonate. Clin Sci (Lond) 76:397–402
Young W (2009) Review of lithium effects on brain and blood. Cell Transplant 18:951–975
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This work was supported by the Czech Science Foundation GA CR (GA17-07070S), from the institutional project of the Institute of Physiology of the Czech Academy of Sciences (RVO:67985823) and from the institutional research plan of the Institute of Analytical Chemistry of the Czech Academy of Sciences (RVO:68081715).
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PS and MV conceived and designed research. MV, LR, HU, MH, and SM conducted experiments. MV, LR and PS analyzed data. MV, PS, and MA wrote the manuscript. All authors read and approved the manuscript.
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Vosahlikova, M., Roubalova, L., Ujcikova, H. et al. Na+/K+-ATPase level and products of lipid peroxidation in live cells treated with therapeutic lithium for different periods in time (1, 7, and 28 days); studies of Jurkat and HEK293 cells. Naunyn-Schmiedeberg's Arch Pharmacol 392, 785–799 (2019). https://doi.org/10.1007/s00210-019-01631-4
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DOI: https://doi.org/10.1007/s00210-019-01631-4