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LITHIUM HAS NEUROPROTECTIVE EFFECT ON NEUROBLASTOMA CELL LINE IN LOW DOSAGES

Year 2023, , 17 - 24, 31.03.2023
https://doi.org/10.7197/cmj.1172075

Abstract

Lithium (Li) was presented as a protective agent in neuron degeneration which is an important process in neurodegenerative diseases. The aim of this study was to determine the effect of certain amounts of Li on neuroblastoma cells by considering several specific genes which act on neuroprotection. Li solutions were prepared as 1 μM, 15 μM (low dosage), 30 μM and 45 µM (high dosage) concentrations then applied to neuroblastoma cell line. XTT and trypan blue assays were performed to determine the cell proliferation and viability, respectively. mRNA expression levels of NES, BDNF, GRIN2A, LRRK2, PRKN, and SNCA were detected by quantitative real time polymerase chain reaction (qRT-PCR). Cell viability detected as significantly increased in cells treated with low dosage Li however, it was significantly decreased in high dosage applied cells compared to untreated control. In addition, cell proliferation ratios were significantly decreased in high dosage applied cells compared to control. It was demonstrated that mRNA expression levels of several genes (NES, LRRK2, PRKN) were significantly upregulated. Regarding to BDNF, expression of the gene was significantly upregulated in the cells only treated with very low amount of Li. However, no significant data could be obtained for GRIN2A. Furthermore, mRNA expression level of SNCA was determined as significantly downregulated compared to control. Statistically significant expression of NES, LRRK2, PRKN, BDNF and SNCA genes due to the variable Li concentrations applied to cells suggests that Li acts on transcriptional regulation of certain genes associated with neuronal survival. These findings support that dose dependent Li treatment might have a protective effect for neurodegenerative diseases.

Supporting Institution

TC GENELKURMAY BAŞKANLIĞI GÜLHANE ASKERİ TIP AKADEMİSİ KOMUTANLIĞI

Project Number

AR-2015/22

Thanks

-

References

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  • 3. Grimes CA, Jope RS. The multifaceted roles of glycogen synthase kinase 3beta in cellular signaling. Prog Neurobiol. 2001;65(4):391-426.
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  • 6. Chuang DM, Chen RW, Chalecka- Franaszek E, et al. Neuroprotective effects of lithium in cultured cells and animal models of diseases. Bipolar Disord. 2002 4(2):129-136.
  • 7. Hashimoto R, Senatorov V, Kanai H, Leeds P, Chuang DM. Lithium stimulates progenitor proliferation in cultured brain neurons. Neuroscience 2003; 117(1):55-61
  • 8. Bott CJ, Johnson CG, Yap CC, et al. Nestin in immature embryonic neurons affects axon growth cone morphology and Semaphorin3a sensitivity. Molecular Biology of the Cell. 2019,30(10):1214-1229.
  • 9. Shastry P, Basu A, Rajadhyaksha MS. Neuroblastoma cell lines--a versatile in vitro model in neurobiology. Int J Neurosci. 2001;108(1-2):109-126.
  • 10. Ribeiro D, Petrigna L, Pereira FC, Muscella A, Bianco A, Tavares P. The Impact of Physical Exercise on the Circulating Levels of BDNF and NT 4/5: A Review. Int J Mol Sci. 2021;22(16):8814.
  • 11. Endele S, Rosenberger G, Geider K, et al. Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes. Nat Genet. 2010;42(11):1021-1026.
  • 12. Michalczyk K, Ziman M. Nestin structure and predicted function in cellular cytoskeletal organization. Histol. Histopathol. 2005;20 (2) 665–671.
  • 13. Magdalena M, Facundo MJ, Belén ZM, Pedro B. Brain-Derived Neurotrophic Factor: A Key Molecule for Memory in the Healthy and the Pathological Brain. Front Cell Neurosci. 2019;7(13):363.
  • 14. Hamza TH, Chen H, Hill-Burns EM, et al. Genome-wide gene-environment study identifies glutamate receptor gene GRIN2A as a Parkinson's disease modifier gene via interaction with coffee. PLOS Genetics 2011;7(8): e1002237.
  • 15. Park IH, Arora N, Huo H, et al. Disease-specific induced pluripotent stem cells. Cell 2008;134:877–886.
  • 16. Erkekoğlu P, Baydar T. Current In Vitro Cytotoxicity Tests. Hacettepe University Journal of the Faculty of Pharmacy 41(1); 45-63: 2021.
  • 17. Marshall NJ, Goodwin CJ, Holt SJ. A critical assessment of the use of microculture tetrazolium assays to measure cell growth and function. Growth Regul. 1995;5(2): 69-84.
  • 18. Coco-Martin JM, Oberink JW, van der Velden-de Groot TA, Beuvery EC. Viability measurements of hybridoma cells in suspension cultures. Cytotechnology 1992;8(1): 57-64.
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  • 20. Dugger BN, Dickson DW. Pathology of Neurodegenerative Diseases. Cold Spring Harb Perspect Biol. 2017;9(7):a028035.
  • 21. Wada A , Yokoo H, Yanagita T, Kobayashi H. Lithium: potential therapeutics against acute brain injuries and chronic neurodegenerative diseases. J Pharmacol Sci 2005; 99(4):307-321.
  • 22. Kotlyarova, A., Bgatova, N., Popova, T., Letyagin, A., Tolstikova, T., & Pedder, V. Cognitive Outcome and Neuroprotective Effect of Lithium on Sub chronic Alcohol-induced Brain Damage in Mice. 2019 International Multi-Conference on Engineering, Computer and Information Sciences (SIBIRCON).
  • 23. Rispin A, Farrar D, Margosches E, et al. Alternative methods for the median lethal dose (LD (50)) test: the up-and-down procedure for acute oral toxicity. ILAR J. 2002; 43(4): 233-243.
  • 24. Paul P, Iyer S, Nadella RK, et al. Lithium response in bipolar disorder correlates with improved cell viability of patient derived cell lines. Sci Rep. 2020;10(1):7428.
  • 25. Hashimoto R, Senatorov V, Kanai H, Leeds P, Chuang DM. Lithium stimulates progenitor proliferation in cultured brain neurons. Neuroscience 2003;117(1):55-61.
  • 26. Michalczyk K, Ziman M. Nestin structure and predicted function in cellular cytoskeletal organization. Histol. Histopathol. 2005;20 (2):665–671.
  • 27. Zimprich A, Biskup S, Leitner P, et al. Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron. 2004;44(4):601–607.
  • 28. Sepulveda B, Mesias R, Li X, Yue Z, Benson DL. Short- and Long-Term Effects of LRRK2 on Axon and Dendrite Growth. PLoS ONE. 2013;8(4): e61986.
  • 29. Wallings RL, Tansey MG. LRRK2 regulation of immune-pathways and inflammatory disease. Biochem Soc Trans. 2019;47(6):1581-1595.
  • 30. Zhang C, Lin M, Wu R, et a. Parkin, a p53 target gene, mediates the role of p53 in glucose metabolism and the Warburg effect. Proceedings of the National Academy of Sciences of the United States of America. 2011;108 (39):16259–16264.
  • 31. Dawson TM, Dawson VL. The role of parkin in familial and sporadic Parkinson's disease. Movement Disorders. 2014; 25(Suppl 1):S32-39.
  • 32. Acheson A, Conover JC, Fandl JP, et al. A BDNF autocrine loop in adult sensory neurons prevents cell death. Nature. 1995;374 (6521):450–453.
  • 33. Binder DK, Scharfman HE. Brain-derived neurotrophic factor. Growth Factors. 2004; 22 (3):123–131.
  • 34. Chandra S, Chen X, Rizo J, Jahn R, Südhof TC. A broken alpha -helix in folded alpha -Synuclein. The Journal of Biological Chemistry 2003;278 (17):15313–15318.
  • 35. Uéda K, Fukushima H, Masliah E, et al. Molecular cloning of cDNA encoding an unrecognized component of amyloid in Alzheimer disease. Proceedings of the National Academy of Sciences of the United States of America. 1993;90 (23):11282–11286.
  • 36. Zeng H, Liu N, Yang Y, Xing H, Liu X, Li F, La G, Huang M and Zhou M. Lentivirus-mediated downregulation of α-synuclein reduces neuroinflammation and promotes functional recovery in rats with spinal cord injury. Journal of Neuroinflammation. 2019; 16:283.
  • 37. Zhao Q, Liu H, Cheng J, et al. Neuroprotective effects of lithium on a chronic MPTP mouse model of Parkinson's disease via regulation of α synuclein methylation. Mol Med Rep. 2019;19(6):4989-4997.
Year 2023, , 17 - 24, 31.03.2023
https://doi.org/10.7197/cmj.1172075

Abstract

Project Number

AR-2015/22

References

  • REFERENCES 1. Rubinsztein DC. The roles of intracellular protein-degradation pathways in neurodegeneration. Nature 2006; 443(7113):780–786.
  • 2. Bredesen DE, Rao RV, Mehlen P. Cell death in the nervous system. Nature 2006;443 (7113): 796–802.
  • 3. Grimes CA, Jope RS. The multifaceted roles of glycogen synthase kinase 3beta in cellular signaling. Prog Neurobiol. 2001;65(4):391-426.
  • 4. Manji HK, Moore GJ, Chen G. Lithium at 50: have the neuroprotective effects of this unique cation been overlooked? Biol Psychiatry. 1999;46(7):929-940.
  • 5. Hashimoto R, Fujimaki K, Jeong MR, Senatorov VV, Christ L, Leeds P, Chuang DM, Takeda M. Neuroprotective actions of lithium. Seishin Shinkeigaku Zasshi 2003; 105(1):81-86.
  • 6. Chuang DM, Chen RW, Chalecka- Franaszek E, et al. Neuroprotective effects of lithium in cultured cells and animal models of diseases. Bipolar Disord. 2002 4(2):129-136.
  • 7. Hashimoto R, Senatorov V, Kanai H, Leeds P, Chuang DM. Lithium stimulates progenitor proliferation in cultured brain neurons. Neuroscience 2003; 117(1):55-61
  • 8. Bott CJ, Johnson CG, Yap CC, et al. Nestin in immature embryonic neurons affects axon growth cone morphology and Semaphorin3a sensitivity. Molecular Biology of the Cell. 2019,30(10):1214-1229.
  • 9. Shastry P, Basu A, Rajadhyaksha MS. Neuroblastoma cell lines--a versatile in vitro model in neurobiology. Int J Neurosci. 2001;108(1-2):109-126.
  • 10. Ribeiro D, Petrigna L, Pereira FC, Muscella A, Bianco A, Tavares P. The Impact of Physical Exercise on the Circulating Levels of BDNF and NT 4/5: A Review. Int J Mol Sci. 2021;22(16):8814.
  • 11. Endele S, Rosenberger G, Geider K, et al. Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes. Nat Genet. 2010;42(11):1021-1026.
  • 12. Michalczyk K, Ziman M. Nestin structure and predicted function in cellular cytoskeletal organization. Histol. Histopathol. 2005;20 (2) 665–671.
  • 13. Magdalena M, Facundo MJ, Belén ZM, Pedro B. Brain-Derived Neurotrophic Factor: A Key Molecule for Memory in the Healthy and the Pathological Brain. Front Cell Neurosci. 2019;7(13):363.
  • 14. Hamza TH, Chen H, Hill-Burns EM, et al. Genome-wide gene-environment study identifies glutamate receptor gene GRIN2A as a Parkinson's disease modifier gene via interaction with coffee. PLOS Genetics 2011;7(8): e1002237.
  • 15. Park IH, Arora N, Huo H, et al. Disease-specific induced pluripotent stem cells. Cell 2008;134:877–886.
  • 16. Erkekoğlu P, Baydar T. Current In Vitro Cytotoxicity Tests. Hacettepe University Journal of the Faculty of Pharmacy 41(1); 45-63: 2021.
  • 17. Marshall NJ, Goodwin CJ, Holt SJ. A critical assessment of the use of microculture tetrazolium assays to measure cell growth and function. Growth Regul. 1995;5(2): 69-84.
  • 18. Coco-Martin JM, Oberink JW, van der Velden-de Groot TA, Beuvery EC. Viability measurements of hybridoma cells in suspension cultures. Cytotechnology 1992;8(1): 57-64.
  • 19. Moini J, Piran P. Histophysiology. Functional and Clinical Neuroanatomy, Academic Press, 2020.
  • 20. Dugger BN, Dickson DW. Pathology of Neurodegenerative Diseases. Cold Spring Harb Perspect Biol. 2017;9(7):a028035.
  • 21. Wada A , Yokoo H, Yanagita T, Kobayashi H. Lithium: potential therapeutics against acute brain injuries and chronic neurodegenerative diseases. J Pharmacol Sci 2005; 99(4):307-321.
  • 22. Kotlyarova, A., Bgatova, N., Popova, T., Letyagin, A., Tolstikova, T., & Pedder, V. Cognitive Outcome and Neuroprotective Effect of Lithium on Sub chronic Alcohol-induced Brain Damage in Mice. 2019 International Multi-Conference on Engineering, Computer and Information Sciences (SIBIRCON).
  • 23. Rispin A, Farrar D, Margosches E, et al. Alternative methods for the median lethal dose (LD (50)) test: the up-and-down procedure for acute oral toxicity. ILAR J. 2002; 43(4): 233-243.
  • 24. Paul P, Iyer S, Nadella RK, et al. Lithium response in bipolar disorder correlates with improved cell viability of patient derived cell lines. Sci Rep. 2020;10(1):7428.
  • 25. Hashimoto R, Senatorov V, Kanai H, Leeds P, Chuang DM. Lithium stimulates progenitor proliferation in cultured brain neurons. Neuroscience 2003;117(1):55-61.
  • 26. Michalczyk K, Ziman M. Nestin structure and predicted function in cellular cytoskeletal organization. Histol. Histopathol. 2005;20 (2):665–671.
  • 27. Zimprich A, Biskup S, Leitner P, et al. Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron. 2004;44(4):601–607.
  • 28. Sepulveda B, Mesias R, Li X, Yue Z, Benson DL. Short- and Long-Term Effects of LRRK2 on Axon and Dendrite Growth. PLoS ONE. 2013;8(4): e61986.
  • 29. Wallings RL, Tansey MG. LRRK2 regulation of immune-pathways and inflammatory disease. Biochem Soc Trans. 2019;47(6):1581-1595.
  • 30. Zhang C, Lin M, Wu R, et a. Parkin, a p53 target gene, mediates the role of p53 in glucose metabolism and the Warburg effect. Proceedings of the National Academy of Sciences of the United States of America. 2011;108 (39):16259–16264.
  • 31. Dawson TM, Dawson VL. The role of parkin in familial and sporadic Parkinson's disease. Movement Disorders. 2014; 25(Suppl 1):S32-39.
  • 32. Acheson A, Conover JC, Fandl JP, et al. A BDNF autocrine loop in adult sensory neurons prevents cell death. Nature. 1995;374 (6521):450–453.
  • 33. Binder DK, Scharfman HE. Brain-derived neurotrophic factor. Growth Factors. 2004; 22 (3):123–131.
  • 34. Chandra S, Chen X, Rizo J, Jahn R, Südhof TC. A broken alpha -helix in folded alpha -Synuclein. The Journal of Biological Chemistry 2003;278 (17):15313–15318.
  • 35. Uéda K, Fukushima H, Masliah E, et al. Molecular cloning of cDNA encoding an unrecognized component of amyloid in Alzheimer disease. Proceedings of the National Academy of Sciences of the United States of America. 1993;90 (23):11282–11286.
  • 36. Zeng H, Liu N, Yang Y, Xing H, Liu X, Li F, La G, Huang M and Zhou M. Lentivirus-mediated downregulation of α-synuclein reduces neuroinflammation and promotes functional recovery in rats with spinal cord injury. Journal of Neuroinflammation. 2019; 16:283.
  • 37. Zhao Q, Liu H, Cheng J, et al. Neuroprotective effects of lithium on a chronic MPTP mouse model of Parkinson's disease via regulation of α synuclein methylation. Mol Med Rep. 2019;19(6):4989-4997.
There are 37 citations in total.

Details

Primary Language English
Subjects Health Care Administration
Journal Section Basic Science Research Articles
Authors

Şefik Güran 0000-0002-1398-530X

Zehra Çoban 0000-0001-6397-9138

Hülya Gündeşli 0000-0002-1638-9087

Özgür Kılıçarslan 0000-0001-6106-708X

Project Number AR-2015/22
Publication Date March 31, 2023
Acceptance Date March 26, 2023
Published in Issue Year 2023

Cite

AMA Güran Ş, Çoban Z, Gündeşli H, Kılıçarslan Ö. LITHIUM HAS NEUROPROTECTIVE EFFECT ON NEUROBLASTOMA CELL LINE IN LOW DOSAGES. CMJ. March 2023;45(1):17-24. doi:10.7197/cmj.1172075