DNPH OF ISOSTEVIOL VIA SIRT 1/ NRF2 SIGNALING PATHWAY ABROGATES NEURONAL SYNAPSE & MEMORY DEFICITS IN AGING MOUSE MODEL
Main Article Content
Keywords
DNPH, Isosteviol, SIRT1/NRF2/HO, NFKB, D-Gal
Abstract
Aging is a natural process which can’t be stopped and reversed. The physiological changes of aging are inevitable and complex. There are a variety of causatives which speed up this process. The aim of the present study was to find the rational process of aging and to slow down or reverse the molecular intervention in ageing. The current study investigated the neurotherapeutic potential of Dinitrophenyl hydrazine (DNPH) of Isosteviol against D galactose (D-Gal) induced oxidative stress-mediated cognitive deficits in adult albino mice. DNPH of Isosteviol is naturally occurring compound with biological anti-aging properties in adult male albino mice. For a period of eight weeks, intraperitoneal (IP) administration of D-Gal at a dose of 100 mg/kg followed by the administration of DNPH of Isosteviol at a dose of 10 mg/kg on alternating days for the last four weeks. The results have shown that DNPH of Isosteviol significantly restored the cognitive deficits in mice that is assessed with Morris’s water maze and Y-maze test. Similarly this DNPH of Isosteviol markedly decreased the oxidative stress induced by D-Gal is determined through various antioxidant assay such as catalase, POD, SOD, glutathione and LPO. Moreover, DNPH of Isosteviol reduced the amyloidogenic pathway of Amyloid beta (Aβ) to diminish neuroinflammation by decreasing NF-kB and its downstream signaling such as TNF-α. Interestingly, this DNPH of Isosteviol rescued male adult albino mice by stimulating SIRT1 protein to reduce the Aβ production through SIRT1/NRF2/HO-1 signaling pathway.
Taken together, our results suggest that DNPH of Isosteviol is a novel neurotherapeutic agent that can be proved to be a safe, effective in reducing cognitive deficits and other complication associated with aging. A more in detail work is warranted to check the mechanism behind the DNPH of Isosteviol in aging mice.
References
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3. Winklhofer, K. F., & Haass, C. (2010). Mitochondrial dysfunction in Parkinson's disease. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease, 1802(1), 29-44.
4. Arthur, C. R., Morton, S. L., Dunham, L. D., Keeney, P. M., & Bennett, J. P. (2009). Parkinson's disease brain mitochondria have impaired respirasome assembly, age-related increases in distribution of oxidative damage to mtDNA and no differences in heteroplasmic mtDNA mutation abundance. Molecular neurodegeneration, 4(1), 1-13.
5. Carvalho, C., Correia, S. C., Santos, R. X., Cardoso, S., Moreira, P. I., Clark, T. A., ... & Perry, G. (2009). Role of mitochondrial-mediated signaling pathways in Alzheimer disease and hypoxia. Journal of bioenergetics and biomembranes, 41, 433-440.
6. DeKosky, S. T., & Scheff, S. W. (1990). Synapse loss in frontal cortex biopsies in Alzheimer's disease: Correlation with cognitive severity. Annals of Neurology, 27(5), 457-464.
7. Harada, C. N., Natelson Love, M. C., & Triebel, K. L. (2013). Normal cognitive aging. Clinics in Geriatric Medicine, 29(4), 737-752
8. Zhao FF, Zhou YZ, Gao L, Qin XM, Du GH. (2017). [Advances in the study of the rat model of aging induced by D-galactose]. Yao Xue Xue Bao, 52(3), 347-54. Chinese. PMID: 29979551.
9. Chen, L., Deng, H., Cui, H., Fang, J., Zuo, Z., Deng, J., ... & Yang, M. (2020). Inflammatory responses and inflammation-associated diseases in organs. Oncotarget, 9(6), 7204.
10. Ren, Z., He, H., Zuo, Z., et al. (2019). The role of different SIRT1-mediated signaling pathways in toxic injury. Cell Mol Biol Lett, 24, 36. https://doi.org/10.1186/s11658-019-0158-9
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13. Chen C, Zhou M, Ge Y, Wang X. (2020). SIRT1 and aging related signaling pathways. Mech Ageing Dev, 187, 111215. https://doi.org/10.1016/j.mad.2020.111215
14. Park, S. A., Kim, M. MY., & Kim, Y. S. (2021). The neuroprotective effects of Iso Steviol in primary cultures of rat cortical cells via the ROS-activated Erk1/2 and PI3K/Akt signaling pathways. Food and Chemical Toxicology, 146, 111867.
15. Ullah, A., Munir, S., Mabkhot, Y., & Badshah, S. L. (2019). Bioactivity profile of the diterpene isosteviol and its derivatives. Molecules, 24(4), 678.
16. Vorhees, C., Williams, M. Morris water maze: procedures for assessing spatial and related forms of learning and memory. Nat Protoc 1, 848–858 (2006). https://doi.org/10.1038/nprot.2006.116
17. Kraeuter AK, Guest PC, Sarnyai Z. The Y-Maze for Assessment of Spatial Working and Reference Memory in Mice. Methods Mol Biol. 2019;1916:105-111. doi: 10.1007/978-1-4939-8994-2_10. PMID: 30535688.
18. Zhang J, Chen R, Yu Z, Xue L. Superoxide Dismutase (SOD) and Catalase (CAT) Activity Assay Protocols for Caenorhabditis elegans. Bio Protoc. 2017 Aug 20;7(16):e2505. doi: 10.21769/BioProtoc.2505. PMID: 34541169; PMCID: PMC8413628.
19. Owen JB, Butterfield DA. Measurement of oxidized/reduced glutathione ratio. Methods Mol Biol. 2010;648:269-77. doi: 10.1007/978-1-60761-756-3_18. PMID: 20700719.
20. Aguilar Diaz De Leon J, Borges CR. Evaluation of Oxidative Stress in Biological Samples Using the Thiobarbituric Acid Reactive Substances Assay. J Vis Exp. 2020 May 12;(159):10.3791/61122. doi: 10.3791/61122. PMID: 32478759; PMCID: PMC9617585.
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22. McCord, J. M., & Fridovich, I. (1969). Superoxide dismutase: an enzymic function for erythrocuprein (hemocuprein). Journal of Biological chemistry, 244(22), 6049-6055. McCord, J. M., & Fridovich, I. (1969). Superoxide dismutase: an enzymic function for erythrocuprein (hemocuprein). Journal of Biological chemistry, 244(22), 6049-6055.
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24. Rana RM, Rampogu S, Abid NB, Zeb A, et al., (2020) In silico study identified methotrexate analog as potential inhibitor of drug resistant human dihydrofolate reductase for cancer therapeutics. Molecules 25 (15), 3510
25. Irfanullah, Amir Zeb, et al., (2018) Molecular and in silico analyses validates pathogenicity of homozygous mutations in the NPR2 gene underlying variable phenotypes of Acromesomelic dysplasia, type Maroteaux. The International Journal of Biochemistry & Cell Biology 102, 76-86
26. Kumar, A., & Singh, A. (2015). A review on Alzheimer's disease pathophysiology and its management: an update. Pharmacological reports, 67(2), 195-203.
27. Parameshwaran K, Irwin MH, Steliou K, Pinkert CA. D-galactose effectiveness in modeling aging and therapeutic antioxidant treatment in mice. Rejuvenation Res. 2010 Dec;13(6):729-35. doi: 10.1089/rej.2010.1020. Epub 2011 Jan 4. PMID: 21204654; PMCID: PMC3034100.
28. Hammad, M., Raftari, M., Cesário, R., Salma, R., Godoy, P., Emami, S. N., & Haghdoost, S. (2023). Roles of oxidative stress and Nrf2 signaling in pathogenic and non-pathogenic cells: A possible general mechanism of resistance to therapy. Antioxidants, 12(7), 1371.
29. Shwe, T., Pratchayasakul, W., Chattipakorn, N., & Chattipakorn, S. C. (2018). Role of D-galactose-induced brain aging and its potential used for therapeutic interventions. Experimental gerontology, 101, 13-36.
30. Ahmad, S., Khan, A., Ali, W., Jo, M. H., Park, J., Ikram, M., & Kim, M. O. (2021). Fisetin rescues the mice brains against D-galactose-induced oxidative stress, neuroinflammation and memory impairment. Frontiers in pharmacology, 12, 612078.
31. Dai H, Case AW, Riera TV et al. Crystallographic structure of a small molecule SIRT1 activator-enzyme complex. Nat. Comm. 6 (2015), 7645
32. Cao D, Wang M, Qiu X et al. Structural basis for allosteric, substrate-dependent stimulation of SIRT1 activity by resveratrol. Gene & Development. 29 (2015), 1316-1325
33. Azminah A, Erlina L, Radji M et al. In silico and in vitro identification of candidate SIRT1 activators from Indonesian medicinal plants compounds database. 83 (2019), 107096.
34. Samad, N., Hafeez, F., & Imran, I. (2022). D-galactose induced dysfunction in mice hippocampus and the possible antioxidant and neuromodulatory effects of selenium. Environmental Science and Pollution Research, 29(4), 5718-5735.
35. Rusu, M. E., Mocan, A., Ferreira, I. C., & Popa, D. S. (2019). Health benefits of nut consumption in middle-aged and elderly population. Antioxidants, 8(8), 302.
36. Latimer, C. S., Brewer, L. D., Searcy, J. L., Chen, K. C., Popović, J., Kraner, S. D., ... & Porter, N. M. (2014). Vitamin D prevents cognitive decline and enhances hippocampal synaptic function in aging rats. Proceedings of the National Academy of Sciences, 111(41), E4359-E4366.
37. Niedzielska, E., Smaga, I., Gawlik, M. et al. Oxidative Stress in Neurodegenerative Diseases. Mol Neurobiol 53, 4094–4125 (2016). https://doi.org/10.1007/s12035-015-9337-5
38. Ikram, M., Muhammad, T., Rehman, S. U., Khan, A., Jo, M. G., Ali, T., et al. (2019a). Hesperetin confers neuroprotection by regulating nrf2/TLR4/NFkappaB signaling in an abeta mouse model. Mol. Neurobiol. 56(9), 6293–6309. doi:10.1007/s12035-019-1512-7
39. Khan, A., Ikram, M., Muhammad, T., Park, J., and Kim, M. O. (2019a). Caffeine modulates cadmium-induced oxidative stress, neuroinflammation, and cognitive impairments by regulating nrf-2/HO-1 in vivo and in vitro. J. Clin. Med. 8(5), 680. doi:10.3390/jcm8050680
40. Badshah, H., Ikram, M., Ali, W., Ahmad, S., Hahm, J. R., and Kim, M. O. (2019). Caffeine may abrogate LPS-induced oxidative stress and neuroinflammation by regulating nrf2/TLR4 in adult mouse brains. Biomolecules 9(11), 719. doi:10.3390/biom9110719
41. Chang, L., Liu, X., Liu, J., Li, H., Yang, Y., Liu, J., et al. (2014). D-galactose induces a mitochondrial complex I deficiency in mouse skeletal muscle: potential benefits of nutrient combination in ameliorating muscle impairment. J. Med. Food 17, 357–364. doi:10.1089/jmf.2013.2830
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Jun 07, 2024
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How to Cite
Saif Ullah, Muhammad Zahid, Rahmat ali, Muhammad Shimran Khan Afridi, Dr. Muhammad Ismail Khan, Shahid Ali Shah, Amir Zeb, & Asad Ullah. (2024). DNPH OF ISOSTEVIOL VIA SIRT 1/ NRF2 SIGNALING PATHWAY ABROGATES NEURONAL SYNAPSE & MEMORY DEFICITS IN AGING MOUSE MODEL. Journal of Population Therapeutics and Clinical Pharmacology, 31(6), 572-590. https://doi.org/10.53555/jptcp.v31i6.6535
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Author Biographies
Saif Ullah
Department of Zoology, Islamia College University, Peshawar
Muhammad Zahid
Department of Zoology, Islamia College University, Peshawar
Rahmat ali
Department of Zoology, Islamia College University, Peshawar
Muhammad Shimran Khan Afridi
Department of Zoology, Islamia College University, Peshawar
Dr. Muhammad Ismail Khan
Department of Zoology, Islamia College University, Peshawar
Shahid Ali Shah
Department of Biology, Haripur University, Peshawar
Amir Zeb
Department of Natural and Basic Science, University of Turbat
Asad Ullah
Department of Chemistry, Islamia College University, Peshawar
How to Cite
Saif Ullah, Muhammad Zahid, Rahmat ali, Muhammad Shimran Khan Afridi, Dr. Muhammad Ismail Khan, Shahid Ali Shah, Amir Zeb, & Asad Ullah. (2024). DNPH OF ISOSTEVIOL VIA SIRT 1/ NRF2 SIGNALING PATHWAY ABROGATES NEURONAL SYNAPSE & MEMORY DEFICITS IN AGING MOUSE MODEL. Journal of Population Therapeutics and Clinical Pharmacology, 31(6), 572-590. https://doi.org/10.53555/jptcp.v31i6.6535