Attenuation of Oxidative Stress and Anti-Alzheimer Effect of Ursolic Acid

Download Article

DOI: 10.21522/TIJPH.2013.13.01.Art087

Authors : Parameswari Royapuram Parthasarathy, A. Padmanaban, Taarika, G., Royapuram Veeraragavan Geetha

Abstract:

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and neurodegeneration, with oxidative stress playing a pivotal role in its pathophysiology. Ursolic acid (UA), a triterpenoid found in various medicinal plants, exhibits antioxidant and neuroprotective properties that may counteract oxidative damage associated with AD. This study aimed to evaluate the antioxidant, neuroprotective, and anti-Alzheimer effects of Ursolic acid using in vitro assays. The antioxidant potential was assessed via the DPPH free radical scavenging assay. The neuroprotective effects were evaluated through acetylcholinesterase inhibition assays, while UA's anti-Alzheimer potential was examined using amyloid-beta aggregation and beta-secretase inhibition assays. Ursolic acid demonstrated significant (p<0.001) antioxidant activity, effectively scavenging DPPH radicals in a concentration-dependent manner. In the acetylcholinesterase inhibition assay, UA exhibited a notable (p<0.05) reduction in enzyme activity from 10 mM to the maximum concentration of 80mM, suggesting its potential to enhance cholinergic neurotransmission. Furthermore, UA significantly inhibited amyloid-beta aggregation and reduced beta-secretase activity between concentrations of 10 mM – 80 mM, indicating its promising role in mitigating key pathological features of Alzheimer’s disease. The findings suggest that Ursolic acid possesses potent antioxidant and neuroprotective effects, along with the ability to inhibit amyloid-beta aggregation and beta-secretase activity. These results highlight the therapeutic potential of Ursolic acid as a candidate for the prevention and treatment of Alzheimer’s disease, warranting further investigation in vivo models to validate its efficacy and mechanisms of action.


References:

[1].   Breijyeh, Z., & Karaman, R., 2020, Comprehensive review on Alzheimer’s disease: Causes and treatment. Molecules, 25(24), 5789. doi: 10.3390/molecules25245789.

[2].   Serrano-Pozo, A., Frosch, M. P., Masliah, E., & Hyman, B. T., 2011, Neuropathological alterations in Alzheimer disease. Cold Spring Harbor Perspectives in Medicine, 1(1), a006189. doi: 10.1101/cshperspect.a006189.

[3].   Spires-Jones, T. L., & Hyman, B. T., 2014, The intersection of amyloid beta and tau at synapses in Alzheimer’s disease. Neuron, 82(4), 756-771. doi: 10.1016/j.neuron.2014.05.004.

[4].   Guo, T., Zhang, D., Zeng, Y., Huang, T. Y., Xu, H., & Zhao, Y., 2020, Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease. Molecular neurodegeneration, 15, 1-37. doi: 10.1186/s13024-020-00391-7.

[5].   Parameswari, R.P., Ramesh, G., Chidambaram, S. B., & Thangavelu, L., 2022, Oxidative stress mediated neuroinflammation induced by chronic sleep restriction as triggers for Alzheimer’s disease. Alzheimer's & Dementia, 18, e059016. DOI:10.1002/alz.059016

[6].   Singh, B., Day, C. M., Abdella, S., & Garg, S., 2024, Alzheimer's disease current therapies, novel drug delivery systems and future directions for better disease management. Journal of Controlled Release, 367, 402-424. doi: 10.1016/j.jconrel.2024.01.047.

[7].   Cetin, S., Knez, D., Gobec, S., Kos, J., & Pišlar, A., 2022, Cell models for Alzheimer’s and Parkinson’s disease: At the interface of biology and drug discovery. Biomedicine & Pharmacotherapy, 149, 112924. doi: 10.1016/j.biopha.2022.112924.

[8].   Jager, S., Trojan, H., Kopp, T., Laszczyk, M. N., & Scheffler, A., 2009, Pentacyclic triterpene distribution in various plants–rich sources for a new group of multi-potent plant extracts. Molecules, 14(6), 2016-2031. https://doi.org/10.3390/molecules14062016

[9].   Kadasah, S. F., & Radwan, M. O., 2023, Overview of ursolic acid potential for the treatment of metabolic disorders, autoimmune diseases, and cancers via nuclear receptor pathways. Biomedicines, 11(10), 2845. doi: 10.3390/biomedicines11102845.

[10].  Liu, J., 1995, Pharmacology of oleanolic acid and ursolic acid. Journal of Ethnopharmacology, 49(2), 57-68. doi: 10.1016/0378-8741(95)90032-2.

[11].  Seo, D. Y., Lee, S. R., Heo, J. W., No, M. H., Rhee, B. D., Ko, K. S., Kwak, H.B., Han, J., 2018, Ursolic acid in health and disease. The Korean Journal of Physiology & Pharmacology: Official Journal of the Korean Physiological Society and the Korean Society of Pharmacology, 22(3), 235. doi: 10.4196/kjpp.2018.22.3.235.

[12].  Liang, W., Zhao, X., Feng, J., Song, F., & Pan, Y., 2016, Ursolic acid attenuates beta-amyloid-induced memory impairment in mice. Arquivos de neuro-psiquiatria, 74(6), 482-488. doi: 10.1590/0004-282X20160065.

[13].  Koleva, I. I., Van Beek, T. A., Linssen, J. P., Groot, A. D., & Evstatieva, L. N., 2002, Screening of plant extracts for antioxidant activity: a comparative study on three testing methods. Phytochemical Analysis: An International Journal of Plant Chemical and Biochemical Techniques, 13(1), 8-17. doi: 10.1002/pca.611.

[14].  Ellman, G. L., Courtney, K. D., Andres Jr, V., & Featherstone, R. M., 1961, A new and rapid colorimetric determination of acetylcholinesterase activity. Biochemical Pharmacology, 7(2), 88-95. doi: 10.1016/0006-2952(61)90145-9.

[15].  Katayama, S., Sugiyama, H., Kushimoto, S., Uchiyama, Y., Hirano, M., & Nakamura, S., 2016, Effects of sesaminol feeding on brain Aβ accumulation in a senescence-accelerated mouse-prone 8. Journal of Agricultural and Food Chemistry, 64(24), 4908-4913. doi: 10.1021/acs.jafc.6b01237.

[16].  Miyazaki, H., Okamoto, Y., Motoi, A., Watanabe, T., Katayama, S., Kawahara, S. I., Makabe, H., Fujii, H., Yonekura, S., 2019, Adzuki bean (Vigna angularis) extract reduces amyloid-β aggregation and delays cognitive impairment in Drosophila models of Alzheimer's disease. Nutr. Res. Pract, 13, 64-69. doi: 10.4162/nrp.2019.13.1.64.

[17].  Panyatip, P., Tadtong, S., Sousa, E., & Puthongking, P., 2020, BACE1 inhibitor, neuroprotective, and neuritogenic activities of melatonin derivatives. Scientia Pharmaceutica, 88(4), 58. doi.org/10.3390/scipharm88040058

[18].  Zhao, M., Wu, F., Tang, Z., Yang, X., Liu, Y., Wang, F., & Chen, B., 2023, Anti-inflammatory and antioxidant activity of ursolic acid: A systematic review and meta-analysis. Frontiers in Pharmacology, 14, 1256946. doi.org/10.3389/fphar.2023.1256946

[19].  Pritam, P., Deka, R., Bhardwaj, A., Srivastava, R., Kumar, D., Jha, A. K., Jha, N. K., Villa, C., Jha, S. K., 2022, Antioxidants in Alzheimer’s disease: Current therapeutic significance and future prospects. Biology, 11(2), 212.  doi: 10.3390/biology11020212

[20].  Mirza, F. J., & Zahid, S., 2022, Ursolic acid and rosmarinic acid ameliorate alterations in hippocampal neurogenesis and social memory induced by amyloid beta in mouse model of Alzheimer’s disease. Frontiers in Pharmacology, 13, 1058358. doi.org/10.3389/fphar.2022.1058358.

[21].  Peitzika, S. C., & Pontiki, E., 2023, A review on recent approaches on molecular docking studies of novel compounds targeting acetylcholinesterase in Alzheimer disease. Molecules, 28(3), 1084. doi: 10.3390/molecules28031084.

[22].  García-Ayllón, M. S., Small, D. H., Avila, J., & Sáez-Valero, J., 2011, Revisiting the role of acetylcholinesterase in Alzheimer’s disease: cross-talk with P-tau and β-amyloid. Frontiers in molecular neuroscience, 4, 22. doi.org/10.3389/fnmol.2011.00022.

[23].  Mlala, S., Oyedeji, A. O., Gondwe, M., & Oyedeji, O. O., 2019, Ursolic acid and its derivatives as bioactive agents. Molecules, 24(15), 2751. doi: 10.3390/molecules24152751.

[24].  Piccialli, I., Tedeschi, V., Caputo, L., D’Errico, S., Ciccone, R., De Feo, V., Secondo, A., Pannaccione, A., 2022, Exploring the therapeutic potential of phytochemicals in Alzheimer’s disease: Focus on polyphenols and monoterpenes. Frontiers in Pharmacology, 13, 876614.

[25].  Mugundhan, V., Arthanari, A., & Parthasarathy, P. R., 2024, Protective Effect of Ferulic Acid on Acetylcholinesterase and Amyloid Beta Peptide Plaque Formation in Alzheimer’s Disease: An In Vitro Study. Cureus, 16(2). doi: 10.7759/cureus.54103.

[26].  Das, B., & Yan, R., 2019, A close look at BACE1 inhibitors for Alzheimer’s disease treatment. CNS Drugs, 33(3), 251-263. doi: 10.1007/s40263-019-00613-7.