Oxycinnamic acids as NOX4 inhibitors in Alzheimer's disease therapy. An experimental study

Cover Page

Cite item

Full Text

Open Access Open Access
Restricted Access Access granted
Restricted Access Subscription or Fee Access

Abstract

Relevance. Alzheimer's disease is a terminal form of dementia with a complex pathogenesis in which NOX-dependent oxidative stress plays an extremely important role.

Aim of the study. To evaluate the influence of oxycinnamic acids on the alteration of NOX4 activity in brain tissue of animals with experimental Alzheimer's disease.

Material and methods. Alzheimer's disease was modeled in Wistar rats by injection of β-amyloid aggregates with amino acid sequence 1-42 into hippocampal tissue (CA1 segment). Oxycinnamic acids: caffeic acid, coumaric acid, ferulic acid and synapic acid were administered at a dose of 100 mg/kg, orally for 60 days after the Alzheimer's disease model. Ethylmethylhydroxypyridine succinate was used as a reference drug in a similar dosage and dosing mode. Changes in the concentration of active NOX4 isophrome, hydrogen peroxide as well as β-amyloid in brain tissue of rats were assessed after the indicated time period.

Results. This study showed that the analyzed oxycinnamic acids were comparable with each other and the referent. Thus, a statistically significant (p<0.05) decrease of NOX4, hydrogen peroxide and β-amyloid concentrations was observed against the background of the studied substances application relative to the untreated animals. Correlation analysis showed that there was a strong correlation (r= 0.96968) between changes in β-amyloid and NOX4 content. Also a strong correlation relationship is observed in the case of analysis of changes in β-amyloid and hydrogen peroxide concentration (r=0,97060).

Conclusion. On the basis of the obtained data, it may be assumed that the use of oxycinnamic acids decrease the activity of NOX4, resulting in reduced formation of peroxides and, as a consequence, oxidative stress. At the same time, reduction of oxidative processes intensity leads to decrease of β-amyloid content in brain tissue.

Full Text

Restricted Access

About the authors

D. I. Pozdnyakov

Pyatigorsk Medical and Pharmaceutical Institute

Author for correspondence.
Email: pozdniackow.dmitry@yandex.ru

Ph.D. (Pharm.), Head of Living System Laboratory, Associate Professor, Department of Pharmacology with Clinical Pharmacology Course

Russian Federation, Pyatigorsk

References

  1. Khan S., Barve K.H., Kumar M.S. Recent Advancements in Pathogenesis, Diagnostics and Treatment of Alzheimer's Disease. Curr Neuropharmacol. 2020; 18(11): 1106–1125.
  2. Scheltens P., De Strooper B., Kivipelto M., Holstege H., Chételat G., Teunissen C.E., Cummings J., van der Flier W.M. Alzheimer's disease. Lancet. 2021; 397(10284): 1577–1590.
  3. Oren O., Taube R., Papo N. Amyloid β structural polymorphism, associated toxicity and therapeutic strategies. Cell Mol Life Sci. 2021; 78(23): 7185–7198.
  4. Cheignon C., Tomas M., Bonnefont-Rousselot D., Faller P., Hureau C., Collin F. Oxidative stress and the amyloid beta peptide in Alzheimer's disease. Redox Biol. 2018; 14: 450–464.
  5. Tarafdar A., Pula G. The Role of NADPH Oxidases and Oxidative Stress in Neurodegenerative Disorders. Int J Mol Sci. 2018; 19(12): 3824.
  6. Wang K., Shi J., Zhou Y., He Y., Mi J., Yang J., Liu S., Tang X., Liu W., Tan Z., Sang Z. Design, synthesis and evaluation of cinnamic acid hybrids as multi-target-directed agents for the treatment of Alzheimer's disease. Bioorg Chem. 2021; 112: 104879.
  7. Manczak M., Reddy P.H. Abnormal interaction between the mitochondrial fission protein Drp1 and hyperphosphorylated tau in Alzheimer's disease neurons: implications for mitochondrial dysfunction and neuronal damage. Hum Mol Genet. 2012; 21(11): 2538–2547.
  8. Voronkov A.V., Pozdnjakov D.I., Adzhiahmetova S.L., Chervonnaja N.M., Rukovicina V.M., Oganesjan Je.T. Vlijanie nekotoryh proizvodnyh korichnoj kisloty na izmenenie aktivnosti fermentov cikla trikarbonovyh kislot u krys v uslovijah ishemii golovnogo mozga. Medicinskij akademicheskij zhurnal. 2020; 20(2): 27–32 (in Russ)
  9. Summers F.A., Zhao B., Ganini D., Mason R.P. Photooxidation of Amplex Red to resorufin: implications of exposing the Amplex Red assay to light. Methods Enzymol. 2013; 526: 1–17.
  10. Butterfield D.A. The 2013 SFRBM discovery award: selected discoveries from the butterfield laboratory of oxidative stress and its sequela in brain in cognitive disorders exemplified by Alzheimer disease and chemotherapy induced cognitive impairment. Free Radic Biol Med. 2014; 74: 157–74.
  11. Wang X., Wang W., Li L., Perry G., Lee H.G., Zhu X. Oxidative stress and mitochondrial dysfunction in Alzheimer's disease. Biochim Biophys Acta. 2014; 1842(8): 1240–1247.
  12. Luengo E., Trigo-Alonso P., Fernández-Mendívil C., Nuñez Á., Campo M.D., Porrero C., García-Magro N., Negredo P., Senar S., Sánchez-Ramos C., Bernal J.A., Rábano A., Hoozemans J., Casas A.I., Schmidt H.H.H.W., López M.G. Implication of type 4 NADPH oxidase (NOX4) in tauopathy. Redox Biol. 2022; 49: 102210.

Supplementary files

Supplementary Files
Action
1. JATS XML
Download
2. Fig. 1. Effect of the studied compounds and the reference drug on the change in NOX4 concentration in the brain tissue of animals with experimental Alzheimer's disease: LO, sham-operated animals; NC - group of negative control animals; EGMPS, a group of rats treated with ethylmethylhydroxypyridine succinate; # - significant in comparison with the LO group (p<0.05 Tukey's test); * - significant in comparison with the NK group (p<0.05 Tukey test)

Download (120KB)
Indexing metadata
3. Fig. 2. Influence of the studied compounds and the reference drug on the change in the concentration of hydrogen peroxide in the brain tissue in animals with experimental Alzheimer's disease: LO - sham-operated animals; NC - group of negative control animals; EGMPS, a group of rats treated with ethylmethylhydroxypyridine succinate; # - significant in comparison with the LO group (p<0.05 Tukey's test); * - significant in comparison with the NK group (p<0.05 Tukey test)

Download (54KB)
Indexing metadata
4. Fig. 3. The effect of the studied compounds and the reference drug on the change in the concentration of β-amyloid in the brain tissue of animals with experimental Alzheimer's disease: LO - sham-operated animals; NC - group of negative control animals; EGMPS, a group of rats treated with ethylmethylhydroxypyridine succinate; # - significant in comparison with the LO group (p<0.05 Tukey's test); * - significant in comparison with the NK group (p<0.05 Tukey test)

Download (132KB)
Indexing metadata

Copyright (c) 2023 Russkiy Vrach Publishing House