Abstract
Lithium has been the treatment of choice for patients with bipolar disorder. However, lithium overdose happens more frequently since it has a very narrow therapeutic range in blood, necessitating investigation of its adverse effects on blood cells. The possible changes that lithium exposure may have on functional and morphological characteristics of human red blood cells (RBCs) have been studied ex vivo using single-cell Raman spectroscopy, optical trapping, and membrane fluorescent probe. The Raman spectroscopy was performed with excitation at 532 nm light, which also results in simultaneous photoreduction of intracellular hemoglobin (Hb). The level of photoreduction of lithium-exposed RBCs was observed to decline with lithium concentration, indicating irreversible oxygenation of intracellular Hb from lithium exposure. The lithium exposure may also have an effect on RBC membrane, which was investigated via optical stretching in a laser trap and the results suggest lower membrane fluidity for the lithium-exposed RBCs. The membrane fluidity of RBCs was further studied using the Prodan generalized polarization method and the results verify the reduction of membrane fluidity upon lithium exposure.
Similar content being viewed by others
Data availability
The experimental data generated and analyzed during the present study are available from the corresponding author on reasonable request.
References
Ahlawat S, Kumar N, Dasgupta R et al (2013) Raman spectroscopic investigations on optical trap induced deoxygenation of red blood cells. Appl Phys Lett 103:183704
Asghari-Khiavi M, Mechler A, Bambery KR et al (2009) A resonance Raman spectroscopic investigation into the effects of fixation and dehydration on heme environment of hemoglobin. J Raman Spectrosc 40:1668–1674
Basselin M, Kim H-W, Chen M et al (2010) Lithium modifies brain arachidonic and docosahexaenoic metabolism in rat lipopolysaccharide model of neuroinflammation. J Lipid Res 51:1049–1056
Brunner H, Mayer A, Sussner H (1972) Resonance Raman scattering on the haem group of oxy- and deoxyhaemoglobin. J Mol Biol 70:153–156
Calkin CV, Gardner DM, Ransom T, Alda M (2013) The relationship between bipolar disorder and type 2 diabetes: More than just co-morbid disorders. Ann Med 45:171–181
Chan JW (2013) Recent advances in laser tweezers Raman spectroscopy (LTRS) for label-free analysis of single cells. J Biophotonics 6:36–48
Dasgupta R, Ahlawat S, Verma RS et al (2010) Hemoglobin degradation in human erythrocytes with long-duration near-infrared laser exposure in Raman optical tweezers. J Biomed Opt 15:055009
Dasgupta R, Verma RS, Ahlawat S et al (2011) Studies on erythrocytes in malaria infected blood sample with Raman optical tweezers. J Biomed Opt 16:077009
De LAC, Rusciano G, Ciancia R et al (2008) Spectroscopical and mechanical characterization of normal and thalassemic red blood cells by Raman Tweezers. Opt Express 16:7943–7957
Evrard JL, Baumann P, Bally RP, Peters Haefeli L (1978) Lithium concentrations in saliva, plasma and red blood cells of patients given lithium acetate. Acta Psychiatr Scand 58:67–79
Fong TM, McNamee MG (1986) Correlation between acetylcholine receptor function and structural properties of membranes. Biochemistry 25:830–840
Fukai T, Ushio-Fukai M (2011) Superoxide dismutases: role in redox signaling, vascular function, and diseases. Antioxid Redox Signal 15:1583–1606
Glenn Tisman; Show-Jen G. Wu (1980) Haematological Side-Effects of Lithium. In: F.N. Johnson (ed). MTP Press Limited
Grizelj M, Crnković D, Kostanjšak L et al (2017) Comparison of lithium concentration in serum, plasma and erythrocytes. Alcohol Psychiatry Res J Psychiatr Res Addict 53:99–114
Hajek T, Calkin C, Blagdon R et al (2014) Insulin resistance, diabetes mellitus, and brain structure in bipolar disorders. Neuropsychopharmacology 39:2910–2918
Hajek T, Calkin C, Blagdon R et al (2015) Type 2 diabetes mellitus: a potentially modifiable risk factor for neurochemical brain changes in bipolar disorders. Biol Psychiatry 77:295–303
Holstein-Rathlou NH (1990) Lithium transport across biological membranes. Kidney Int Suppl 28:S4-9
Imandt L, Tijhuis D, Wessels H, Haanen C (1981) Lithium inhibits adenylate cyclase of human platelets. Thromb Haemost 45:142–145
Jain SK (1989) Hyperglycemia can cause membrane lipid peroxidation and osmotic fragility in human red blood cells. J Biol Chem 264:21340–21345
Ji H-L, Bishop LR, Anderson SJ et al (2004) The role of pre-H2 domains of α- and δ-epithelial Na+ channels in ion permeation, conductance, and amiloride sensitivity*. J Biol Chem 279:8428–8440
Khan H, JanHashmatullah SU et al (2010) Effect of lithium metal on the chemical status of glutathione (GSH) present in whole blood (especially in plasma and cytosolic fraction in human blood). Pak J Pharm Sci 23:188–193
Krasnowska EK, Gratton E, Parasassi T (1998) Prodan as a membrane surface fluorescence probe: partitioning between water and phospholipid phases. Biophys J 74:1984–1993
Liu R, Zheng L, Matthews DL et al (2011) Power dependent oxygenation state transition of red blood cells in a single beam optical trap. Appl Phys Lett 99:5–8
Loehr TM, Loehr JS (1973) Determination of oxidation and spin states of heme iron. Resonance Raman spectroscopy of cytochrome c, microperoxidase, and horseradish per oxidase. Biochem Biophys Res Commun 55:218–223
Medić B, Stojanović M, Stimec BV et al (2020) Lithium - pharmacological and toxicological aspects: the current state of the art. Curr Med Chem 27:337–351
Mohanty SK, Uppal A, Gupta PK (2008) Optofluidic stretching of RBCs using single optical tweezers. J Biophotonics 1:522–525
Nagababu E, Chrest FJ, Rifkind JM (2003) Hydrogen-peroxide-induced heme degradation in red blood cells: the protective roles of catalase and glutathione peroxidase. Biochim Biophys Acta - Gen Subj 1620:211–217
Ong CW, Shen ZX, Ang KKH et al (1999) Resonance Raman microspectroscopy of normal erythrocytes and plasmodium berghei-infected erythrocytes. Appl Spectrosc 53:1097–1101
Parasassi T, De Stasio G, d’Ubaldo A, Gratton E (1990) Phase fluctuation in phospholipid membranes revealed by Laurdan fluorescence. Biophys J 57:1179–1186
Parasassi T, Krasnowska EK, Bagatolli L, Gratton E (1998) Laurdan and prodan as polarity-sensitive fluorescent membrane probes. J Fluoresc 8:365–373
Petrov DV (2007) Raman spectroscopy of optically trapped particles. J Opt A Pure Appl Opt 9:S139–S156
Pettegrew JW, Short JW, Woessner RD et al (1987) The effect of lithium on the membrane molecular dynamics of normal human erythrocytes. Biol Psychiatry 22:857–871
Pontremoli R, Zerbini G, Rivera A, Canessa M (1994) Insulin activation of red blood cell Na+/H+ exchange decreases the affinity of sodium sites. Kidney Int 46:365–375
Quig DW (1998) Cysteine metabolism and metal toxicity. Altern Med Rev 3(4):262–270
Quiroz JA, Gould TD, Manji HK (2004) Molecular effects of lithium. Mol Interv 4:259–272
Rao S, Bálint Š, Cossins B et al (2009) Raman study of mechanically induced oxygenation state transition of red blood cells using optical tweezers. Biophys J 96:209–216
Rottenberg H (1992) Probing the interactions of alcohols with biological membranes with the fluorescent probe prodan. Biochemistry 31:9473–9481
Rusciano G (2010) Experimental analysis of Hb oxy–deoxy transition in single optically stretched red blood cells. Phys Medica 26:233–239
Schatzberg AF, Nemeroff CB, The American Psychiatric Publishing Textbook of Psychopharmacology 4th edn. American Psychiatric Publishing (2009)
Silverstone PH, Wu RH, O’Donnell T et al (2002) Chronic treatment with both lithium and sodium valproate may normalize phosphoinositol cycle activity in bipolar patients. Hum Psychopharmacol Clin Exp 17:321–327
Singh Y, Chowdhury A, Mukherjee C et al (2019) Simultaneous photoreduction and Raman spectroscopy of red blood cells to investigate the effects of organophosphate exposure. J Biophotonics 12:e201800246
Swann AC, Berman N, Frazer A et al (1987) Lithium distribution in mania: Plasma and red blood cell lithium, clinical state, and monoamine metabolites during lithium treatment. Psychiatry Res 20:1–12
Timmer RT, Sands JM (1999) Lithium Intoxication. J Am Soc Nephrol 10:666–674
Viskupicova J, Blaskovic D, Galiniak S et al (2015) Effect of High Glucose Concentrations on Human Erythrocytes in Vitro 5:381–387
Ward ME, Musa MN, Bailey L (1994) Clinical Pharmacokinetics of Lithium. J Clin Pharmacol 34:280–285
Wilson-Ashworth HA, Bahm Q, Erickson J et al (2006) Differential detection of phospholipid fluidity, order, and spacing by fluorescence spectroscopy of bis-pyrene, prodan, nystatin, and merocyanine 540. Biophys J 91:4091–4101
Wood BR, Tait B, McNaughton D (2001) Micro-Raman characterisation of the R to T state transition of haemoglobin within a single living erythrocyte. Biochim Biophys Acta- Mol Cell Res 1539:58–70
Wood BR, Hammer L, Davis L, McNaughton D (2005) Raman microspectroscopy and imaging provides insights into heme aggregation and denaturation within human erythrocytes. J Biomed Opt 10:014005
Young W (2009) Review of lithium effects on brain and blood. Cell Transplant 18:951–975
Acknowledgements
Authors like to thank Dr. S. P. Jaiswal for providing the blood samples from Choithram Hospital and Research Centre, Indore. Yashveer Singh acknowledges the financial support by Raja Ramanna Centre for Advanced Technology (RRCAT), Department of Atomic Energy, Government of India and Homi Bhabha National Institute, Mumbai.
Author information
Authors and Affiliations
Corresponding author
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Singh, Y., Chowdhury, A., Dasgupta, R. et al. The effects of lithium on human red blood cells studied using optical spectroscopy and laser trap. Eur Biophys J 52, 91–100 (2023). https://doi.org/10.1007/s00249-023-01643-2
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00249-023-01643-2