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İnterlökin - 1 Reseptör Antagonisti Ve RNA Polimeraz İnhibitörünün Hipokampal Hücre Hattında Nörodejenerasyon Üzerine Etkilerinin İncelenmesi

Year 2024, , 136 - 142, 29.06.2024
https://doi.org/10.7197/cmj.1482552

Abstract

Amaç: Bu çalışmada bir RNA polimeraz inhibitörü; favipravirin ve İnterlökin-1 reseptörü antagonisti anakinranın, hipokampal hücrelerde glutamatla oluşturulacak sitotoksisite üzerine anti-nörodejeneratif etkilerinin araştırılması amaçlandı. Glutamata olan aşırı duyarlılığı nedeniyle HT22 hücre hattı kullanıldı. Yöntem: Kontrol, glutamat (10 mM), anakinra (1,10,25,50,100 μg), favipravir (1,10,25,50,100 μg) ve anakinra+favipravir hücre grupları oluşturuldu Kontrol grubuna herhangi bir tedavi uygulanmadı. Glutamat ile indüklenen grubun hücrelerine 24 saat boyunca 10 mM glutamat verildi. Anakinra grubundaki hücrelere 24 saat boyunca çeşitli konsantrasyonlarda (1,10, 25, 50, 100 μg) anakinra verildi. Favipravir grubundaki hücrelere 24 saat boyunca çeşitli konsantrasyonlarda (1,10,25,50,100 μg) favipravir verildi. Anakinra+glutamat grubundaki hücreler, 1 saat boyunca farklı konsantrasyonlarda (1,10,25,50,100 μg) anakinra ile ön işleme tabi tutuldu ve ardından 24 saat boyunca 10 mM glutamat uygulandı. Favipiravir+glutamat grubundaki hücreler, 1 saat boyunca farklı konsantrasyonlarda (1, 10, 25, 50,100 μg) favipiravir ile ön işleme tabi tutuldu ve ardından 24 saat boyunca 10 mM glutamat uygulandı. Ardından etkili dozlar belirlenerek anakinra+favipiavir+glutamattan oluşan kombinasyonları uygulandı. Bulgular: Yalnızca favipravirin farklı dozlarının uygulanmasınında viabilite üzerinde herhangi bir etkisi gözlenmedi (p< 0.01 kontrole göre). 100 μg anakinra uygulanan grupta hücre canlılığının diğer gruplara göre daha fazla olduğu gözlendi (p<0.01 glutamata göre). Anakinranın farklı dozlarının uygulanmasınında viabilite üzerinde herhangi bir etkisi gözlenmedi (p< 0.01 kontrole göre). Sitotoksisitenin anakinra 100 μg uygulamasıyla önlendiği gözlendi. Anakinranın bu dozda nörodejenerasyon üzerine koruyucu etkisi izlendi. Anakinra+favipravir+glutamat kombine uygulanan grupta ise anakinranın glutamat toksisitesine karşı koruyucu fakat anakinra+favipravir kombinasyonu bu etkiyi değiştirmediği gözlendi. Sonuç: Ancak bu etkinin klinik açıdan önemi için daha detaylı hayvan ve insan çalışmalarına gereksinim vardır.

Project Number

T – 984

References

  • Mark LP, Prost RW, Ulmer JL, Smith MM, Daniels DL, Strottmann JM, et al. Pictorial Review of Glutamate Excitotoxicity: Fundamental Concepts for Neuroimaging. Vol. 22, AJNR Am J Neuroradiol.
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  • Lau A, Tymianski M. Glutamate receptors, neurotoxicity and neurodegeneration. Vol. 460, Pflugers Archiv European Journal of Physiology. 2010. p. 525–42.
  • Danbolt NC. Glutamate uptake [Internet]. Vol. 65, Progress in Neurobiology. 2001. Available from: www.elsevier.com/locate/pneurobio
  • Tilleux S, Hermans E. Neuroinflammation and regulation of glial glutamate uptake in neurological disorders. Vol. 85, Journal of Neuroscience Research. 2007. p. 2059–70.
  • ÖZ A. Experimental cell culture models for investigating neurodegenerative diseases. J Cell Neurosci Oxidative Stress [Internet]. 2019 Jun 23 [cited 2020 Dec 9];11(2):835–51. Available from: https://dergipark.org.tr/tr/doi/10.37212 /jcnos.683400
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  • Park JS, Park JH, Kim KY. Neuroprotective effects of myristargenol A against glutamate-induced apoptotic HT22 cell death. RSC Adv. 2019;9(54):31247–54.
  • Ergül M, Taşkıran AŞ. Thiamine Protects Glioblastoma Cells against Glutamate Toxicity by Suppressing Oxidative/Endoplasmic Reticulum Stress. Vol. 832, Chem. Pharm. Bull. 2021.
  • Taskiran AS, Ergul M. The effect of salmon calcitonin against glutamate-induced cytotoxicity in the C6 cell line and the roles the inflammatory and nitric oxide pathways play. Metab Brain Dis. 2021 Oct 1;36(7):1985–93.
  • Maher P. The potential of flavonoids for the treatment of neurodegenerative diseases. Int J Mol Sci. 2019;20(12).
  • Cariccio VL, Samà A, Bramanti P, Mazzon E. Mercury Involvement in Neuronal Damage and in Neurodegenerative Diseases. Biol Trace Elem Res. 2019;187(2):341–56.
  • Gitler AD, Dhillon P, Shorter J. Neurodegenerative disease: Models, mechanisms, and a new hope. DMM Dis Model Mech. 2017;10(5):499–502.
  • Gentile A, Fresegna D, Musella A, Sepman H, Bullitta S, De Vito F, et al. Interaction between interleukin-1β and type-1 cannabinoid receptor is involved in anxiety-like behavior in experimental autoimmune encephalomyelitis. J Neuroinflammation [Internet]. 2016;13(1):1–14. Available from: http://dx.doi.org/10.1186/s12974-016-0682-8
  • Block ML, Zecca L, Hong JS. Microglia-mediated neurotoxicity: Uncovering the molecular mechanisms. Nat Rev Neurosci. 2007;8(1):57–69.
  • Strome EM, Doudet DJ. Animal models of neurodegenerative disease: Insights from in vivo imaging studies. Mol Imaging Biol. 2007;9(4):186–95.
  • Albanese S, Greco A, Auletta L, Mancini M. Mouse models of neurodegenerative disease: preclinical imaging and neurovascular component. Brain Imaging Behav. 2018;12(4):1160–96.
  • Woerman AL. The importance of developing strain-specific models of neurodegenerative disease. Acta Neuropathol. 2017;134(5):809–12.
  • Jay TR, Von Saucken VE, Landreth GE. TREM2 in Neurodegenerative Diseases. Vol. 12, Molecular Neurodegeneration. Molecular Neurodegeneration; 2017. 1–33 p.
  • Ben Menachem-Zidon O, Menahem Y Ben, Hur T Ben, Yirmiya R. Intra-hippocampal transplantation of neural precursor cells with transgenic over-expression of IL-1 receptor antagonist rescues memory and neurogenesis impairments in an alzheimer’s disease model. Neuropsychopharmacology [Internet]. 2014;39(2):401–14. Available from: http://dx.doi.org/10.1038/npp.2013.208
  • Cavalli G, Dinarello CA. Anakinra therapy for non-cancer inflammatory diseases. Front Pharmacol. 2018 Nov 6;9(NOV).
  • Cliteur M, van der Kolk A, Hannink G, Hofmeijer J, Jolink W, Klijn C, et al. Anakinra in cerebral haemorrhage to target secondary injury resulting from neuroinflammation (ACTION): Study protocol of a phase II randomised clinical trial. Eur Stroke J. 2023 Sep 15;
  • Soy M, Keser G, Atagündüz P, Tabak F, Atagündüz I, Kayhan S. Cytokine storm in COVID-19: pathogenesis and overview of anti-inflammatory agents used in treatment. Clin Rheumatol. 2020;39(7):2085–94.
  • Gonçalves NP, Vieira P, Saraiva MJ. Interleukin-1 signaling pathway as a therapeutic target in transthyretin amyloidosis. Amyloid. 2014;21(3):175–84.
  • Juźwik CA, S. Drake S, Zhang Y, Paradis-Isler N, Sylvester A, Amar-Zifkin A, et al. microRNA dysregulation in neurodegenerative diseases: A systematic review. Prog Neurobiol [Internet]. 2019;182(July):101664. Available from: https://doi.org/10.1016/j.pneurobio.2019.101664
  • Petkau TL, Leavitt BR. Progranulin in neurodegenerative disease. Trends Neurosci [Internet]. 2014;37(7):388–98. Available from: http://dx.doi.org/10.1016/j.tins.2014.04.003
  • Qi Y, Klyubin I, Claudio Cuello A, Rowan MJ. NLRP3-dependent synaptic plasticity deficit in an Alzheimer’s disease amyloidosis model in vivo. Neurobiol Dis [Internet]. 2018;114(October 2017):24–30. Available from: https://doi.org/10.1016/j.nbd.2018.02.016
  • Gonçalves NP, Teixeira-Coelho M, Saraiva MJ. Protective role of anakinra against transthyretin-mediated axonal loss and cell death in a mouse model of familial amyloidotic polyneuropathy. J Neuropathol Exp Neurol. 2015;74(3):203–17.
  • Ejlerskov P, Ashkenazi A, Rubinsztein DC. Genetic enhancement of macroautophagy in vertebrate models of neurodegenerative diseases. Neurobiol Dis [Internet]. 2019;122(December 2017):3–8. Available from: https://doi.org/10.1016/j.nbd.2018.04.001
  • Djajadikerta A, Keshri S, Pavel M, Prestil R, Ryan L, Rubinsztein DC. Autophagy Induction as a Therapeutic Strategy for Neurodegenerative Diseases. J Mol Biol [Internet]. 2020;432(8):2799–821. Available from: https://doi.org/10.1016/j.jmb.2019.12.035
  • Bender A, Klopstock T. Creatine for neuroprotection in neurodegenerative disease: end of story? Amino Acids. 2016;48(8):1929–40.
  • Osaki T, Shin Y, Sivathanu V, Campisi M, Kamm RD. In Vitro Microfluidic Models for Neurodegenerative Disorders. Adv Healthc Mater. 2018;7(2):1–29.
  • Zhao L, Zhong W. Mechanism of action of favipiravir against SARS-CoV-2: Mutagenesis or chain termination? Vol. 2, Innovation. Cell Press; 2021.

Analysing of The Effects of an Interleukin – 1 Receptor Antagonist and a RNA Polymerase Inhibitor on Neurodegeneration in the Hippocampal Cell Line

Year 2024, , 136 - 142, 29.06.2024
https://doi.org/10.7197/cmj.1482552

Abstract

Objective: The aim of the present study is to investigate the anti-neurodegenerative effects of favipiravir, a RNA polymerase inhibitor, and anakinra, an interleukin-1 receptor antagonist, on glutamate-induced cytotoxicity. Due to their heightened sensitivity to glutamate, the hippocampal HT22 cell line were used. Methods: Five groups of cells were established to examine the effects of anakinra and favipiravir on glutamate-induced cytotoxicity. The control group received no treatment. The group induced with glutamate received 10 mM of glutamate for 24 hours. The anakinra group was exposed to different concentrations (1,10,25,50,100 μg) of anakinra for 24 hours. The favipiravir group was exposed to different concentrations (1,10,25,50,100 μg) of favipiravir for 24 hours. The anakinra+glutamate group was pre-treated with anakinra at various concentrations (1,10,25,50,100 μg) for 1 hour and then exposed to 10 mM of glutamate for 24 hours. The favipiravir+glutamate group was pre-treated with favipiravir at various concentrations (1,10,25,50,100 μg) for 1 hour and then exposed to 10 mM of glutamate for 24 hours. Effective doses were subsequently determined, and combinations of anakinra+favipiravir+glutamate were applied. Results: Viability was not affected by the application of different doses of favipiravir alone (p < 0.01 compared to the control group). It was observed that the group treated with 100 μg anakinra showed higher viability compared to other groups (p < 0.01 compared to glutamate). Viability was not affected by the application of different doses of anakinra alone (p< 0.01 compared to the control group). However, anakinra was observed to prevent the cytotoxicity induced by glutamate when applied at 100 μg, exhibiting a protective effect against neurodegeneration at this dose. In the group where anakinra and favipiravir were combined and applied with glutamate, anakinra showed a protective effect against glutamate toxicity, but the combination of anakinra and favipiravir did not alter this effect. Conclusion: More extensive animal and human studies are required to determine the clinical implications of these findings.

Ethical Statement

etik onay no2022-04/66

Supporting Institution

CUBAP

Project Number

T – 984

Thanks

CUBAP a teşekkür ederiz.

References

  • Mark LP, Prost RW, Ulmer JL, Smith MM, Daniels DL, Strottmann JM, et al. Pictorial Review of Glutamate Excitotoxicity: Fundamental Concepts for Neuroimaging. Vol. 22, AJNR Am J Neuroradiol.
  • Sattler R, Tymianski M. Molecular mechanisms of calcium-dependent excitotoxicity. Vol. 78, Journal of Molecular Medicine. Springer Verlag; 2000. p. 3–13.
  • Dong XX, Wang Y, Qin ZH. Molecular mechanisms of excitotoxicity and their relevance to pathogenesis of neurodegenerative diseases. Vol. 30, Acta Pharmacologica Sinica. 2009. p. 379–87.
  • Lau A, Tymianski M. Glutamate receptors, neurotoxicity and neurodegeneration. Vol. 460, Pflugers Archiv European Journal of Physiology. 2010. p. 525–42.
  • Danbolt NC. Glutamate uptake [Internet]. Vol. 65, Progress in Neurobiology. 2001. Available from: www.elsevier.com/locate/pneurobio
  • Tilleux S, Hermans E. Neuroinflammation and regulation of glial glutamate uptake in neurological disorders. Vol. 85, Journal of Neuroscience Research. 2007. p. 2059–70.
  • ÖZ A. Experimental cell culture models for investigating neurodegenerative diseases. J Cell Neurosci Oxidative Stress [Internet]. 2019 Jun 23 [cited 2020 Dec 9];11(2):835–51. Available from: https://dergipark.org.tr/tr/doi/10.37212 /jcnos.683400
  • Wang C, Cai X, Hu W, Li Z, Kong F, Chen X, et al. Investigation of the neuroprotective effects of crocin via antioxidant activities in HT22 cells and in mice with Alzheimer’s disease. Int J Mol Med. 2019 Feb 1;43(2):956–66.
  • Park JS, Park JH, Kim KY. Neuroprotective effects of myristargenol A against glutamate-induced apoptotic HT22 cell death. RSC Adv. 2019;9(54):31247–54.
  • Ergül M, Taşkıran AŞ. Thiamine Protects Glioblastoma Cells against Glutamate Toxicity by Suppressing Oxidative/Endoplasmic Reticulum Stress. Vol. 832, Chem. Pharm. Bull. 2021.
  • Taskiran AS, Ergul M. The effect of salmon calcitonin against glutamate-induced cytotoxicity in the C6 cell line and the roles the inflammatory and nitric oxide pathways play. Metab Brain Dis. 2021 Oct 1;36(7):1985–93.
  • Maher P. The potential of flavonoids for the treatment of neurodegenerative diseases. Int J Mol Sci. 2019;20(12).
  • Cariccio VL, Samà A, Bramanti P, Mazzon E. Mercury Involvement in Neuronal Damage and in Neurodegenerative Diseases. Biol Trace Elem Res. 2019;187(2):341–56.
  • Gitler AD, Dhillon P, Shorter J. Neurodegenerative disease: Models, mechanisms, and a new hope. DMM Dis Model Mech. 2017;10(5):499–502.
  • Gentile A, Fresegna D, Musella A, Sepman H, Bullitta S, De Vito F, et al. Interaction between interleukin-1β and type-1 cannabinoid receptor is involved in anxiety-like behavior in experimental autoimmune encephalomyelitis. J Neuroinflammation [Internet]. 2016;13(1):1–14. Available from: http://dx.doi.org/10.1186/s12974-016-0682-8
  • Block ML, Zecca L, Hong JS. Microglia-mediated neurotoxicity: Uncovering the molecular mechanisms. Nat Rev Neurosci. 2007;8(1):57–69.
  • Strome EM, Doudet DJ. Animal models of neurodegenerative disease: Insights from in vivo imaging studies. Mol Imaging Biol. 2007;9(4):186–95.
  • Albanese S, Greco A, Auletta L, Mancini M. Mouse models of neurodegenerative disease: preclinical imaging and neurovascular component. Brain Imaging Behav. 2018;12(4):1160–96.
  • Woerman AL. The importance of developing strain-specific models of neurodegenerative disease. Acta Neuropathol. 2017;134(5):809–12.
  • Jay TR, Von Saucken VE, Landreth GE. TREM2 in Neurodegenerative Diseases. Vol. 12, Molecular Neurodegeneration. Molecular Neurodegeneration; 2017. 1–33 p.
  • Ben Menachem-Zidon O, Menahem Y Ben, Hur T Ben, Yirmiya R. Intra-hippocampal transplantation of neural precursor cells with transgenic over-expression of IL-1 receptor antagonist rescues memory and neurogenesis impairments in an alzheimer’s disease model. Neuropsychopharmacology [Internet]. 2014;39(2):401–14. Available from: http://dx.doi.org/10.1038/npp.2013.208
  • Cavalli G, Dinarello CA. Anakinra therapy for non-cancer inflammatory diseases. Front Pharmacol. 2018 Nov 6;9(NOV).
  • Cliteur M, van der Kolk A, Hannink G, Hofmeijer J, Jolink W, Klijn C, et al. Anakinra in cerebral haemorrhage to target secondary injury resulting from neuroinflammation (ACTION): Study protocol of a phase II randomised clinical trial. Eur Stroke J. 2023 Sep 15;
  • Soy M, Keser G, Atagündüz P, Tabak F, Atagündüz I, Kayhan S. Cytokine storm in COVID-19: pathogenesis and overview of anti-inflammatory agents used in treatment. Clin Rheumatol. 2020;39(7):2085–94.
  • Gonçalves NP, Vieira P, Saraiva MJ. Interleukin-1 signaling pathway as a therapeutic target in transthyretin amyloidosis. Amyloid. 2014;21(3):175–84.
  • Juźwik CA, S. Drake S, Zhang Y, Paradis-Isler N, Sylvester A, Amar-Zifkin A, et al. microRNA dysregulation in neurodegenerative diseases: A systematic review. Prog Neurobiol [Internet]. 2019;182(July):101664. Available from: https://doi.org/10.1016/j.pneurobio.2019.101664
  • Petkau TL, Leavitt BR. Progranulin in neurodegenerative disease. Trends Neurosci [Internet]. 2014;37(7):388–98. Available from: http://dx.doi.org/10.1016/j.tins.2014.04.003
  • Qi Y, Klyubin I, Claudio Cuello A, Rowan MJ. NLRP3-dependent synaptic plasticity deficit in an Alzheimer’s disease amyloidosis model in vivo. Neurobiol Dis [Internet]. 2018;114(October 2017):24–30. Available from: https://doi.org/10.1016/j.nbd.2018.02.016
  • Gonçalves NP, Teixeira-Coelho M, Saraiva MJ. Protective role of anakinra against transthyretin-mediated axonal loss and cell death in a mouse model of familial amyloidotic polyneuropathy. J Neuropathol Exp Neurol. 2015;74(3):203–17.
  • Ejlerskov P, Ashkenazi A, Rubinsztein DC. Genetic enhancement of macroautophagy in vertebrate models of neurodegenerative diseases. Neurobiol Dis [Internet]. 2019;122(December 2017):3–8. Available from: https://doi.org/10.1016/j.nbd.2018.04.001
  • Djajadikerta A, Keshri S, Pavel M, Prestil R, Ryan L, Rubinsztein DC. Autophagy Induction as a Therapeutic Strategy for Neurodegenerative Diseases. J Mol Biol [Internet]. 2020;432(8):2799–821. Available from: https://doi.org/10.1016/j.jmb.2019.12.035
  • Bender A, Klopstock T. Creatine for neuroprotection in neurodegenerative disease: end of story? Amino Acids. 2016;48(8):1929–40.
  • Osaki T, Shin Y, Sivathanu V, Campisi M, Kamm RD. In Vitro Microfluidic Models for Neurodegenerative Disorders. Adv Healthc Mater. 2018;7(2):1–29.
  • Zhao L, Zhong W. Mechanism of action of favipiravir against SARS-CoV-2: Mutagenesis or chain termination? Vol. 2, Innovation. Cell Press; 2021.
There are 34 citations in total.

Details

Primary Language English
Subjects Health Services and Systems (Other)
Journal Section Research Article
Authors

Mehtap Şahin 0000-0003-4518-6489

Ahmet Kemal Filiz 0000-0001-9260-5549

Project Number T – 984
Publication Date June 29, 2024
Submission Date May 13, 2024
Acceptance Date June 23, 2024
Published in Issue Year 2024

Cite

AMA Şahin M, Filiz AK. Analysing of The Effects of an Interleukin – 1 Receptor Antagonist and a RNA Polymerase Inhibitor on Neurodegeneration in the Hippocampal Cell Line. CMJ. June 2024;46(2):136-142. doi:10.7197/cmj.1482552