Neurology, Neuropsychiatry, Psychosomatics

Advanced search

Targeted proteins involved in the neuroprotective effects of lithium citrate

Full Text:


Preparations based on organic lithium salts are promising neuroprotective agents that are effective just in the micromolar concentration range and, at the same time, have high safety (Toxicity Class V).

Objective: to elucidate more detailed mechanisms responsible for the biological and pharmacological effects of lithium citrate, by analyzing the possible interactions of lithium ion with human proteome proteins that are also represented in the rat proteome.

Material and methods. The targets of lithium are two proteins, such as glycogen synthase-3β (GSK-3β) and inositol monophosphatase 1 (IMPA1), were experimentally validated using lithium citrate.

Results. The cycle use of oral lithium citrate was shown to decrease the activity of these proteins in the rat brain hydrolysates. The effects of lithium were analyzed in the human and rat proteomes. 47 proteins were ascertained to be present in the human and rat proteomes, the activity of which depended on lithium ions. There were 4 groups of lithium-dependent proteins: 1) the proteins regulated by GSK3β kinase; 2) those modulating the level of inositol phosphates; 3) those modulating the metabolism of neurotransmitters; 4) those working via other mechanisms.

About the Authors

I. Yu. Torshin
Moscow Institute of Physics and Technology
Russian Federation
9, Institutsky Lane, Dolgoprudnyi, Moscow Region 141700

O. A. Gromova
Ivanovo State Medical Academy, Ministry of Health of Russia
Russian Federation
8, Sheremetevsky Passage, Ivanovo 153300

L. A. Mayorova
Ivanovo State University of Chemistry and Technology
Russian Federation

7, Sheremetevsky Passage, Ivanovo 153460

A. Yu. Volkov
Russian State Agrarian University, K.A. Timiryazev Moscow Agricultural Academy
Russian Federation
49, Timiryazevskaya St., Moscow 127550


1. Torshin IYu. Sensing the change from molecular genetics to personalized medicine. New York: Nova Biomedical Books; 2009.

2. Громова ОА, Торшин ИЮ, Гришина ТР и др. Систематический анализ молекулярно- физиологических эффектов миоинозитола: данные молекулярной биологии, экспериментальной и клинической медицины. Эффективная фармакотерапия. 2013; (28):4-12. [Gromova OA, Torshin IYu, Grishina TR, et al. A systematic analysis of the molecular physiological effects of myo-Inositol: evidence from molecular biology, experimental and clinical medicine. Effektivnaya farmakoterapiya. 2013;(28):4-12. (In Russ.)].

3. Громова ОА, Торшин ИЮ, Гришина ТР, Лисица АВ. Перспективы использования препаратов на основе органических солей кальция. Молекулярные механизмы кальция. Лечащий врач. 2013;(4):42–4. [Gromova OA, Torshin IYu, Grishina TR, Lisitsa AV. Prospects of use of preparations based on organic calcium salts. Molekulyarnye mekhanizmy kal'tsiya. Lechashchii vrach. 2013;(4):42–4. (In Russ.)].

4. Багметов МН. Церебропротективное действие композиций фенибута и фенотропила и их солей в условиях экспериментальной ишемии головного мозга. Дисс. докт. мед. наук. Волгоград; 2006. [Bagmetov MN. Cerebroprotective effect of the compositions of Phenotropil and phenibut and their salts in experimental cerebral ischemia. Diss. doct. med. sci. Volgograd; 2006.]

5. /2/mak307bul.pdf

6. Jho Eh, Lomvardas S, Costantini F. A GSK3beta phosphorylation site in axin modulates interaction with beta-catenin and Tcf-mediated gene expression. Biochem Biophys Res Commun. 1999 Dec 9;266(1):28-35.

7. Jope RS, Johnson GV. The glamour and gloom of glycogen synthase kinase-3. Trends Biochem Sci. 2004 Feb;29(2):95-102.

8. Ali A, Hoeflich KP, Woodgett JR. Glycogen synthase kinase-3: properties, functions, and regulation. Chem Rev. 2001 Aug;101(8):2527-40.

9. Zheng J, Liu Z, Li W, et al. Lithium posttreatment confers neuroprotection through glycogen synthase kinase-3beta inhibition in intracerebral hemorrhage rats. J Neurosurg. 2016 Oct 14:1-9. [Epub ahead of print].

10. Foltz DR, Santiago MC, Berechid BE, Nye JS. Glycogen synthase kinase-3beta modulates notch signaling and stability. Curr Biol. 2002 Jun 25;12(12):1006-11.

11. Espinosa L, Ingles-Esteve J, Aguilera C, Bigas A. Phosphorylation by glycogen synthase kinase-3 beta down-regulates Notch activity, a link for Notch and Wnt pathways. J Biol Chem. 2003 Aug 22;278(34): 32227-35. Epub 2003 Jun 6.

12. Bolos V, Grego-Bessa J, de la Pompa JL. Notch signaling in development and cancer. Endocr Rev. 2007 May;28(3):339-63. Epub 2007 Apr 4.

13. Welsh GI, Proud CG. Glycogen synthase kinase-3 is rapidly inactivated in response to insulin and phosphorylates eukaryotic initiation factor eIF-2B. Biochem J. 1993 Sep 15;294 ( Pt 3):625-9.

14. Shim M, Smart RC. Lithium stabilizes the CCAAT/enhancer-binding protein alpha (C/EBPalpha) through a glycogen synthase kinase 3 (GSK3)-independent pathway involving direct inhibition of proteasomal activity. J Biol Chem. 2003 May 30;278(22):19674-81. Epub 2003 Mar 30.

15. Haimovich A, Eliav U, Goldbourt A. 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. 2012 Mar 28;134(12):5647-51. doi: 10.1021/ja211794x. Epub 2012 Mar 15.

16. Ackermann KE, Gish BG, Honchar MP, Sherman WR. Evidence that inositol 1-phosphate in brain of lithium-treated rats results mainly from phosphatidylinositol metabolism. Biochem J. 1987 Mar 1;242(2):517-24.

17. Sherman WR, Gish BG, Honchar MP, Munsell LY. Effects of lithium on phosphoinositide metabolism in vivo. Fed Proc. 1986 Oct;45(11):2639-46.

18. Shtein L, Agam G, Belmaker RH, Bersudsky Y. Inositol-deficient food augments a behavioral effect of long-term lithium treatment mediated by inositol monophosphatase inhibition: an animal model with relevance for bipolar disorder. J Clin Psychopharmacol. 2015 Apr;35(2):175-7. doi: 10.1097/JCP.0000000000000284.

19. Damri O, Sade Y, Toker L, et al. Molecular effects of lithium are partially mimicked by inositolmonophosphatase (IMPA)1 knockout mice in a brain region-dependent manner. Eur Neuropsychopharmacol. 2015 Mar;25(3):425-34. doi: 10.1016/j.euroneuro.2014.06.012. Epub 2014 Aug 7.

20. Ryves WJ, Harwood AJ. Lithium inhibits glycogen synthase kinase-3 by competition for magnesium. Biochem Biophys Res Commun. 2001;280(3):720-725.

21. Shannon RD. Revised effective ionic radii and systematic studies of interatomic distances in halides and chalcogenides. Acta Cryst. 1976. A32, 751-67. doi: 10.1107/S0567739476001551

22. Dudev T, Lim C. Competition between Li+ and Mg2+ in metalloproteins. Implications for lithium therapy. J Am Chem Soc. 2011 Jun 22;133(24):9506-15. doi: 10.1021/ja201985s. Epub 2011 May 31.

23. McManus EJ, Sakamoto K, Armit LJ, et al. Role that phosphorylation of GSK3 plays in insulin and Wnt signalling defined by knockin analysis. EMBO J. 2005 Apr 20;24(8):1571-83. Epub 2005 Mar 24.

24. Fan M, Song C, Wang T, et al. Protective effects of lithium chloride treatment on repeated cerebral ischemia-reperfusion injury in mice. Neurol Sci. 2015 Feb;36(2):315-21. doi: 10.1007/s10072-014-1943-x. Epub 2014 Sep 7.

25. Pollack SJ, Atack JR, Knowles MR, et al. Mechanism of inositol monophosphatase, the putative target of lithium therapy. Proc Natl Acad Sci U S A. 1994 Jun 21;91(13):5766-70.

26. Greasley PJ, Gore MG. Bovine inositol monophosphatase. Studies on the binding interactions with magnesium, lithium and phosphate ions. FEBS Lett. 1993 Sep 27;331(1-2):114-8.

For citation:

Torshin I.Yu., Gromova O.A., Mayorova L.A., Volkov A.Yu. Targeted proteins involved in the neuroprotective effects of lithium citrate. Neurology, Neuropsychiatry, Psychosomatics. 2017;9(1):78-83. (In Russ.)

Views: 234

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.

ISSN 2074-2711 (Print)
ISSN 2310-1342 (Online)