Abstract
Lithium (Li) represents a first choice mood stabilizer for bipolar disorder (BD). Despite extensive clinical use, questions regarding its mechanism of action and pathological mechanism of renal function impairment by Li remain open. The present study aimed to improve our knowledge in this area paying special attention to the relationship between the length of Li action, lipid peroxidation (LP), and Na+/K+-ATPase properties. The effects of therapeutic Li doses, administered daily to male Wistar rats for 1 (acute), 7 (short term) and 28 days (chronic), were studied. For this purpose, Na+/K+-ATPase activity measurements, [3H]ouabain binding and immunoblot analysis of α-Na+/K+-ATPase were performed. Li-induced LP was evaluated by determining the malondialdehyde concentration by HPLC. Sleep deprivation (SD) was used as an experimental approach to model the manic phase of BD. Results obtained from the kidney were compared to those obtained from erythrocytes and different brain regions in the same tested animals. Whereas treatment with therapeutic Li concentration did not bring any LP damage nor significant changes of Na+/K+-ATPase expression and [3H]ouabain binding in the kidney, it conferred strong protection against this type of damage in the forebrain cortex. Importantly, the observed changes in erythrocytes indicated changes in forebrain cortices. Thus, different resistance to SD-induced changes of LP and Na+/K+-ATPase was detected in the kidney, erythrocytes and the brain of Li-treated rats. Our study revealed the tissue-specific protective properties of Li against LP and Na+/K+-ATPase regulation.
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References
Alda M (2015) Lithium in the treatment of bipolar disorder: pharmacology and pharmacogenetics. Mol Psychiatry 20:661–670. https://doi.org/10.1038/mp.2015.4
Alsady M, Baumgarten R, Deen PM, de Groot T (2016) Lithium in the kidney: friend and foe? J Am Soc Nephrol 27:1587–1595. https://doi.org/10.1681/asn.2015080907
Andrabi M et al (2019) Lithium acts to modulate abnormalities at behavioral, cellular, and molecular levels in sleep deprivation-induced mania-like behavior. Bipolar Disord. https://doi.org/10.1111/bdi.12838
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. https://doi.org/10.1155/2014/360438
Azab AN, Shnaider A, Osher Y, Wang D, Bersudsky Y, Belmaker RH (2015) Lithium nephrotoxicity. Int J Bipolar Disord 3:28. https://doi.org/10.1186/s40345-015-0028-y
Baldessarini RJ, Tondo L, Vazquez GH (2019) Pharmacological treatment of adult bipolar disorder. Mol Psychiatry 24:198–217. https://doi.org/10.1038/s41380-018-0044-2
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. https://doi.org/10.1016/j.pnpbp.2011.12.006
Behl T, Kotwani A, Kaur I, Goel H (2015) Mechanisms of prolonged lithium therapy-induced nephrogenic diabetes insipidus. Eur J Pharmacol 755:27–33. https://doi.org/10.1016/j.ejphar.2015.02.040
Can A, Schulze TG, Gould TD (2014) Molecular actions and clinical pharmacogenetics of lithium therapy. Pharmacol Biochem Behav 123:3–16. https://doi.org/10.1016/j.pbb.2014.02.004
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. https://doi.org/10.1016/j.chemphyslip.2008.09.004
Catala A (2014) Lipid peroxidation modifies the assembly of biological membranes “The Lipid Whisker Model”. Front Physiol 5:520. https://doi.org/10.3389/fphys.2014.00520
Choi J, Yin T, Shinozaki K, Lampe JW, Stevens JF, Becker LB, Kim J (2018) Comprehensive analysis of phospholipids in the brain, heart, kidney, and liver: brain phospholipids are least enriched with polyunsaturated fatty acids. Mol Cell Biochem 442:187–201. https://doi.org/10.1007/s11010-017-3203-x
de Vasconcellos AP et al (2006) Chronic lithium treatment has antioxidant properties but does not prevent oxidative damage induced by chronic variate stress. Neurochem Res 31:1141–1151. https://doi.org/10.1007/s11064-006-9139-2
Easley JR (1982) The effect of lithium chloride on renal structure and sodium-potassium-adenosine triphosphatase activity in dogs. Vet Pathol 19:38–45. https://doi.org/10.1177/030098588201900107
el-Mallakh RS, Wyatt RJ (1995) The Na,K-ATPase hypothesis for bipolar illness. Biol Psychiatry 37:235–244. https://doi.org/10.1016/0006-3223(94)00201-D
Frey BN et al (2006) Effects of lithium and valproate on amphetamine-induced oxidative stress generation in an animal model of mania. J Psychiatry Neurosci 31:326–332
Fukumoto T, Morinobu S, Okamoto Y, Kagaya A, Yamawaki S (2001) Chronic lithium treatment increases the expression of brain-derived neurotrophic factor in the rat brain. Psychopharmacology 158:100–106. https://doi.org/10.1007/s002130100871
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. https://doi.org/10.1017/neu.2015.47
Gawlik-Kotelnicka O, Mielicki W, Rabe-Jabłońska J, Strzelecki D (2015) Impact of lithium alone or in combination with haloperidol on selected oxidative stress parameters in human plasma in vitro. Redox Rep. https://doi.org/10.1179/1351000215y.0000000030
Gong R, Wang P, Dworkin L (2016) What we need to know about the effect of lithium on the kidney. Am J Physiol Ren Physiol 311:F1168–F1171. https://doi.org/10.1152/ajprenal.00145.2016
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
Kassak P, Sikurova L, Kvasnicka P, Bryszewska M (2006) The response of Na+/K+ -ATPase of human erythrocytes to green laser light treatment. Physiol Res 55:189–194
Khairova R et al (2012) Effects of lithium on oxidative stress parameters in healthy subjects. Mol Med Rep 5:680–682. https://doi.org/10.3892/mmr.2011.732
Kielczykowska M, Pasternak K, Musik I, Wroniska J (2004) The effect of lithium administration in a diet on the chosen parameters of the antioxidant barrier in rats. Ann Univ Mariae Curie Sklodowska Med 59:140–145
Kielczykowska M, Pasternak K, Musik J, Wronska-Tyra J, Hordyjewska A (2006) The influence of different doses of lithium administred in drinking water on lipid peroxidation and the activity of antioxidant enzymes in rats. Pol J Environ Stud 15:747–751
Kishore BK, Ecelbarger CM (2013) Lithium: a versatile tool for understanding renal physiology. Am J Physiol Ren Physiol 304:F1139–F1149. https://doi.org/10.1152/ajprenal.00718.2012
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–e16. https://doi.org/10.1159/000077593
Le-Niculescu H et al (2009) Identifying blood biomarkers for mood disorders using convergent functional genomics. Mol Psychiatry 14:156–174. https://doi.org/10.1038/mp.2008.11
Le-Niculescu H et al (2013) Discovery and validation of blood biomarkers for suicidality. Mol Psychiatry 18:1249–1264. https://doi.org/10.1038/mp.2013.95
Logan RW, McClung CA (2016) Animal models of bipolar mania: The past, present and future. Neuroscience 321:163–188. https://doi.org/10.1016/j.neuroscience.2015.08.041
Machado-Vieira R et al (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. https://doi.org/10.1016/j.neulet.2007.05.016
Nciri R, Allagui MS, Bourogaa E, Saoudi M, Murat JC, Croute F, Elfeki A (2012) Lipid peroxidation, antioxidant activities and stress protein (HSP72/73, GRP94) expression in kidney and liver of rats under lithium treatment. J Physiol Biochem 68:11–18. https://doi.org/10.1007/s13105-011-0113-3
Nciri R, Allagui MS, Vincent C, Murat JC, Croute F, El Feki A (2010) Chronic lithium administration triggers an over-expression of GRP94 stress protein isoforms in mouse liver. Food Chem Toxicol 48:1638–1643. https://doi.org/10.1016/j.fct.2010.03.038
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. https://doi.org/10.1017/s1461145712000132
Oktem F, Ozguner F, Sulak O, Olgar S, Akturk O, Yilmaz HR, Altuntas I (2005) Lithium-induced renal toxicity in rats: protection by a novel antioxidant caffeic acid phenethyl ester. Mol Cell Biochem 277:109–115. https://doi.org/10.1007/s11010-005-5426-5
Ossani GP, Uceda AM, Acosta JM, Lago NR, Repetto MG, Martino DJ, Toblli JE (2019) Role of oxidative stress in lithium-induced nephropathy. Biol Trace Elem Res. https://doi.org/10.1007/s12011-018-1617-2
Riegel RE et al (2010) Intracerebroventricular ouabain administration induces oxidative stress in the rat brain. Int J Dev Neurosci 28:233–237. https://doi.org/10.1016/j.ijdevneu.2010.02.002
Seifert R, Schirmer B (2020) A simple mechanistic terminology of psychoactive drugs: a proposal. Naunyn Schmiedeberg's Arch Pharmacol 393:1331–1339. https://doi.org/10.1007/s00210-020-01918-x
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. https://doi.org/10.1016/j.biopsych.2005.04.052
Ujcikova H et al (2014) Opioid-Receptor (OR) Signaling cascades in rat cerebral cortex and model cell lines: the role of plasma membrane structure. Physiol Res 63:S165–S176
Vosahlikova M, Roubalova L, Ujcikova H, Hlouskova M, Musil S, Alda M, Svoboda P (2019) 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 Schmiedebergs. Arch Pharmacol 392:785–799. https://doi.org/10.1007/s00210-019-01631-4
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, 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. https://doi.org/10.1016/j.bbagen.2017.02.011
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. https://doi.org/10.1016/j.bcp.2018.06.004
Vosahlikova M et al. (2020) Na(+)/K(+)-ATPase and lipid peroxidation in forebrain cortex and hippocampus of sleep-deprived rats treated with therapeutic lithium concentration for different periods of time. Prog Neuropsychopharmacol Biol Psychiatry 109953 doi:https://doi.org/10.1016/j.pnpbp.2020.109953
Wu BJ, Else PL, Storlien LH, Hulbert AJ (2001) Molecular activity of Na(+)/K(+)-ATPase from different sources is related to the packing of membrane lipids. J Exp Biol 204:4271–4280
Yoshida Y, Umeno A, Shichiri M (2013) Lipid peroxidation biomarkers for evaluating oxidative stress and assessing antioxidant capacity in vivo. J Clin Biochem Nutr 52:9–16. https://doi.org/10.3164/jcbn.12-112
Young W (2009) Review of lithium effects on brain and blood. Cell Transplant 18:951–975. https://doi.org/10.3727/096368909X471251
Zhang XY, Yao JK (2013) Oxidative stress and therapeutic implications in psychiatric disorders. Prog Neuro-Psychopharmacol Biol Psychiatry 46:197–199. https://doi.org/10.1016/j.pnpbp.2013.03.003
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This work was supported by the Czech Science Foundation GA CR (GA17-07070S) and from the institutional project of the Institute of Physiology of the Czech Academy of Sciences (RVO:67985823).
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LR: experimental methodology, formal analysis, investigation, project administration. MV: conceptualization, experimental methodology, formal analysis, investigation, writing original draft, visualization, project administration. JS: experimental methodology, investigation. JK: formal analysis, investigation. MA: review and editing, supervision. PS: conceptualization, review and editing, supervision. All data were generated in-house and no paper mill was used.
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Roubalová, L., Vošahlíková, M., Slaninová, J. et al. Tissue-specific protective properties of lithium: comparison of rat kidney, erythrocytes and brain. Naunyn-Schmiedeberg's Arch Pharmacol 394, 955–965 (2021). https://doi.org/10.1007/s00210-020-02036-4
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DOI: https://doi.org/10.1007/s00210-020-02036-4