Acta Medica Iranica 2015. 53(2):89-96.

Chronic lithium treatment increased intracellular S100ß levels in rat primary neuronal culture.
Masoumeh Emamghoreishi, Mojtaba Keshavarz, Ali Akbar Nekooeian


S100ß a neurotrophic factor mainly released by astrocytes, has been implicated in the pathogenesis of bipolar disorder. Thus, lithium may exert its neuroprotective effects to some extent through S100ß. Furthermore, the possible effects of lithium on astrocytes as well as on interactions between neurons and astrocytes as a part of its mechanisms of actions are unknown. This study was undertaken to determine the effect of lithium on S100β in neurons, astrocytes and a mixture of neurons and astrocytes. Rat primary astrocyte, neuronal and mixed neuro-astroglia cultures were prepared from cortices of 18-day's embryos. Cell cultures were exposed to lithium (1mM) or vehicle for 1day (acute) or 7 days (chronic). RT-PCR and ELISA determined S100β mRNA and intra- and extracellular protein levels. Chronic lithium treatment significantly increased intracellular S100β in neuronal and neuro-astroglia cultures in comparison to control cultures (P<0.05). Acute and chronic lithium treatments exerted no significant effects on intracellular S100β protein levels in astrocytes, and extracellular S100β protein levels in three studied cultures as compared to control cultures. Acute and chronic lithium treatments did not significantly alter S100β mRNA levels in three studied cultures, compared to control cultures. Chronic lithium treatment increased intracellular S100ß protein levels in a cell-type specific manner which may favor its neuroprotective action. The findings of this study suggest that lithium may exert its neuroprotective action, at least partly, by increasing neuronal S100ß level, with no effect on astrocytes or interaction between neurons and astrocytes.


Lithium; S100β; Astrocytes; Neurons; Primary cell culture

Full Text:



Rajkowska G. Cell pathology in bipolar disorder. Bipolar Disord 2002;4(2):105-16.

Machado-Vieira R, Manji HK, Zarate CA, Jr. The role of lithium in the treatment of bipolar disorder: convergent evidence for neurotrophic effects as a unifying hypothesis. Bipolar Disord 2009;11(Suppl 2):92-109.

Donato R, Sorci G, Riuzzi F, et al. S100B's double life: Intracellular regulator and extracellular signal. Biochim Biophys Acta 2009;1793(6):1008-22.

Donato R, Cannon BR, Sorci G, et al. Functions of S100 proteins. Curr Mol Med 2013;13(1):24-57.

Gerlai R, Roder J. Abnormal exploratory behavior in transgenic mice carrying multiple copies of the human gene for S100 beta. J J Psychiatry Neurosci 1995;20(2):105-12.

Machado-Vieira R, Schmidt AP, Ávila TT, et al. Increased cerebrospinal fluid levels of S100B protein in the rat model of mania induced by ouabain. Life Sci 2004;76(7):805-11.

Andreazza AC, Cassini C, Rosa AR, et al. Serum S100B and antioxidant enzymes in bipolar patients. J Psychiatr Res 2007;41(6):523-9.

Machado-Vieira R, Lara DR, Portela LVC, et al. Elevated serum S100B protein in drug-free bipolar patients during first manic episode: a pilot study. Eur Neuropsychopharmacol 2002;12(3):269-72.

Schroeter ML, Abdul-Khaliq H, Diefenbacher A, et al. S100B is increased in mood disorders and may be reduced by antidepressive treatment. Neuroreport 2002;13(13):1675-8.

Dean B, Gray L, Scarr E. Regionally specific changes in levels of cortical S100ß in bipolar 1 disorder but not schizophrenia. Aust N Z J Psychiatry 2006;40(3):217-24.

Roche S, Cassidy F, Zhao C, et al. Candidate gene analysis of 21q22: Support for S100B as a susceptibility gene for bipolar affective disorder with psychosis. Am J Med Genet B Neuropsychiatr Genet 2007;144B(8):1094-6.

McQuillin A, Bass NJ, Kalsi G, et al. Fine mapping of a susceptibility locus for bipolar and genetically related unipolar affective disorders, to a region containing the C21ORF29 and TRPM2 genes on chromosome 21q22.3. Mol Psychiatry 2005;11(2):134-42.

Dagdan E, Morris DW, Campbell M, et al. Functional assessment of a promoter polymorphism in S100B, a putative risk variant for bipolar disorder. Am J Med Genet B Neuropsychiatr Genet 2011;156(6):691-9.

Keshavarz M, Emamghoreishi M, Nekooeian AA, et al. Increased bcl-2 Protein Levels in Rat Primary Astrocyte Culture Following Chronic Lithium Treatment. Iran J Med Sci 2013;38(3):255-62.

Hashimoto R, Takei N, Shimazu K, et al. Lithium induces brain-derived neurotrophic factor and activates TrkB in rodent cortical neurons: an essential step for neuroprotection against glutamate excitotoxicity. Neuropharmacology 2002;43(7):1173-9.

Nishino S, Ohtomo K, Numata Y, et al. Divergent effects of lithium and sodium valproate on brain-derived neurotrophic factor (BDNF) production in human astrocytoma cells at therapeutic concentrations. Prog Neuropsychopharmacol Biol Psychiatry 2012;39(1):17-22.

Yasuda S, Liang MH, Marinova Z, et al. The mood stabilizers lithium and valproate selectively activate the promoter IV of brain-derived neurotrophic factor in neurons. Mol Psychiatry 2009;14(1):51-9.

Chomczynski P, Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenolchloroform extraction. Anal Biochem 1987;162(1):156-9.

Pfaffl MW, Horgan GW, Dempfle L. Relative expression software tool (REST©) for group-wise comparison and statistical analysis of relative expression results in realtime PCR. Nucleic Acids Res 2002;30(9):e36.

Kruger NJ. The Bradford Method for Protein Quantitation. In: Walker JM, editors. The Protein Protocols Handbook. 2nd ed. Totowa, NJ: Humana Press; 2002: p. 15-21.

Hertz L, Schousboe I, Hertz L, et al. Receptor expression in primary cultures of neurons or astrocytes. Prog Neuropsychopharmacol Biol Psychiatry 1984;8(4-6):521-7.

Ahlemeyer B, Beier H, Semkova I, et al. S-100β protects cultured neurons against glutamate- and staurosporineinduced damage and is involved in the antiapoptotic action of the 5 HT1A-receptor agonist, Bay x 3702. Brain Res2000;858(1):121-8.

Tardy M, Costa MF, Fages C, et al. Uptake and binding of serotonin by primary cultures of mouse astrocytes. Dev Neurosci 1982;5(1):19-26.

Goodwin GM, Souza RJ, Wood AJ, et al. The enhancement by lithium of the 5-HT1A mediated serotonin syndrome produced by 8-OH-DPAT in the rat: evidence for a post-synaptic mechanism. Psychopharmacology (Berl) 1986;90(4):488-93.

Gonçalves C-A, Concli Leite M, Nardin P. Biological and methodological features of the measurement of S100B, a putative marker of brain injury. Clin Biochem 2008;41(10-11):755-63.

Zimmer DB, Chessher J, Wilson GL, et al. S100A1 and S100B Expression and Target Proteins in Type I Diabetes. Endocrinology 1997;138(12):5176-83.

Van Eldik LJ, Zimmer DB. Secretion of S-100 from rat C6 glioma cells. Brain Res 1987;436(2):367-70.

Ellis EF, Willoughby KA, Sparks SA, et al. S100B protein is released from rat neonatal neurons, astrocytes, and microglia by in vitro trauma and anti-S100 increases ntrauma-induced delayed neuronal injury and negates the protective effect of exogenous S100B on neurons. J Neurochem 2007;101(6):1463-70.

Jacobsen JPR, Mørk A. The effect of escitalopram, desipramine, electroconvulsive seizures and lithium on brain-derived neurotrophic factor mRNA and protein expression in the rat brain and the correlation to 5-HT and5-HIAA levels. Brain Res 2004;1024(1-2):183-92.

Angelucci F, Aloe L, Jiménez-Vasquez P, et al. Lithium treatment alters brain concentrations of nerve growth factor, brain-derived neurotrophic factor and glial cell linederived neurotrophic factor in a rat model of depression. Intl J Neuropsychopharmacol 2003;6(3):225-31.

Huttunen HJ, Kuja-Panula J, Sorci G, et al. Coregulation of Neurite Outgrowth and Cell Survival by Amphoterin and S100 Proteins through Receptor for Advanced Glycation End Products (RAGE) Activation. J Biol Chem 2000;275(51):40096-105.

Schroeter ML, Sacher J, Steiner J, et al. Serum S100Brepresents a new biomarker for mood disorders. Current Drug Targets 2013;14(11):1237-48.

Schroeter ML, Abdul-Khaliq H, Sacher J, et al. Mood disorders are glial disorders: evidence from in vivo studies. Cardiovas Psychiatry Neurol 2010;2010:780645.

Emamghoreishi M, Keshavarz M, Nekooeian AA. Acuteand chronic effects of lithium on brain derived neurotrophic factor and glial cell line derived neurotrophic factor mRNA and protein levels in rat primary neuronal, astroglial and neuroastroglia cultures. Iran J Basic Med Sci [In Press].

Dean B, Gray L, Scarr E. Regionally specific changes in levels of cortical S100beta in bipolar 1 disorder but not schizophrenia. Aust N Z J Psychiatry 2006;40(3):217-24.

Luo KR, Hong CJ, Liou YJ, et al. Differential regulation of neurotrophin S100B and BDNF in two rat models of depression. Prog Neuropsychopharmacol Biol Psychiatry 2010;34(8):1433-9.

Rong H, Wang G, Liu T, et al. Chronic mild stress induces fluoxetine-reversible decreases in hippocampal and cerebrospinal fluid levels of the neurotrophic factor S100B and its specific receptor. Int J Mol Sci 2010;11(12):5310-22.

Emamghoreishi M, Schlichter L, Li PP, et al. High intracellular calcium concentrations in transformed blymphoblasts from subjects with bipolar I disorder. Am J nPsychiatr 1997;154(7):976-82.

Ahlemeyer B, Beier H, Semkova I, et al. S-100β protects cultured neurons against glutamate- and staurosporineinduced damage and is involved in the antiapoptotic action of the 5 HT1A-receptor agonist, Bay x 3702. Brain Res 2000;858(1):121-8.

Businaro R, Leone S, Fabrizi C, et al. S100B protects LAN-5 neuroblastoma cells against Aβ amyloid-induced neurotoxicity via RAGE engagement at low doses but increases Aβ amyloid neurotoxicity at high doses. J Neurosci Res 2006;83(5):897-906.

Chuang DM. The antiapoptotic actions of mood stabilizers: molecular mechanisms and therapeutic potentials. Ann N Y Acad Sci 2005;1053:195-204.

Chuang D-M, Chen R-W, Chalecka-Franaszek E, et al. Neuroprotective effects of lithium in cultured cells and animal models of diseases. Bipolar Disord 2002;4(2):129-36.

Wilson CC, Faber KM, Haring JH. Serotonin regulates synaptic connections in the dentate molecular layer of adult rats via 5-HT1a receptors: evidence for a glial mechanism. Brain Res 1998;782(1-2):235-9.

Azmitia EC, Dolan K, Whitaker-Azmitia PM. S-100B but not NGF, EGF, insulin or calmodulin is a CNS serotonergic growth factor. Brain Res 1990;516(2):354-6.

Price L, Charney D, Delgado P, et al. Lithium and serotonin function: implications for the serotonin hypothesis of depression. Psychopharmacology (Berl) 1990;100(1):3-12.

Wegener G, Bandpey Z, Heiberg IL, et al. Increased extracellular serotonin level in rat hippocampus induced by chronic citalopram is augmented by subchronic lithium: neurochemical and behavioural studies in the rat. Psychopharmacology (Berl) 2003;166(2):188-94.

Marmol F. Lithium: bipolar disorder and neurodegenerative diseases possible cellular mechanismsof the therapeutic effects of lithium. Prog Neuropsychopharmacol Biol Psychiatry. 2008;32(8):1761-71.


  • There are currently no refbacks.

Creative Commons Attribution-NonCommercial 3.0

This work is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License which allows users to read, copy, distribute and make derivative works for non-commercial purposes from the material, as long as the author of the original work is cited properly.