Review on role of nrf2 pathway activation in neurological disorder

  • K. Manisha B Pharm final year student, Saastra College of Pharmaceutical Education and Research, Nellore.
  • K. Loganadhan B Pharm final year student, Saastra College of Pharmaceutical Education and Research, Nellore.
  • M. Aswini B Pharm final year student, Saastra College of Pharmaceutical Education and Research, Nellore.
  • M. Rajesh Kumar B Pharm final year student, Saastra College of Pharmaceutical Education and Research, Nellore.
  • R. Gautham Chakra Assistant Professor, Dept.of Pharmacy practice, Saastra College of Pharmaceutical Education and Research, Nellore
  • K. Swathi Krishna Principal, Saastra College of Pharmaceutical Education and Research, Nellore.

Abstract

With protein build-up and mitochondrial damage leading to brain problems, oxidative stress is a key factor in the onset of many neurodegenerative illnesses. Several defence systems, including nuclear erythroid factor2 (Nrf2)-Kelch-like ECH-associated protein1, protect nerve cells by producing antioxidants to reduce oxidative stress (Keap1) In a number of neurological illnesses, signalling pathway activation has been shown to be a promising therapeutic for reducing oxidative stress and neuroinflammation and protecting neurons. In this review, we specifically highlight Nrf2's beneficial effects on Alzheimer's and Parkinson's disorders. By releasing over 250 cytoprotective genes intended to combat oxidative stress and neuroinflammation, Nrf2 has demonstrated that it is a master regulator of antioxidants. It has been demonstrated in animal experiments that Nrf2 activation enhances autophagy, mitochondrial biogenesis, and the suppression of inflammatory cytokinin which protects neuronal cells and inhibit progressive neurodegeneration.

Keywords: Oxidative stress, Neurodegeneration, Nrf2, Parkinson’s disease, Antioxidant, Keap1

Downloads

Download data is not yet available.

References

1. Emerit J, Edeas, M, and Bricaire, F. Neurodegenerative diseases and oxidative stress. Biomed Pharmacother 2004; 58(1): 39–46.
2. Coppedè F and Migliore, L. DNA damage in neurodegenera- tive diseases. Mut Res/Fundament Mol Mech Mutag 2015; 776: 84–97.
3. Hetz C. The unfolded protein response: controlling cell fate decisions under ER stress and beyond. Nat Rev Mol Cell Biol 2012; 13(2): 89–102.
4. Kanduc D, Mittelman, A, and Serpico, R, et al. Cell death: Apoptosis versus necrosis (Review). Int J Oncol 2002; 21(1):165–70.
5. Cole, GM, Lim, GP, and Yang, F, et al. Prevention of Alzheimer’s disease: Omega-3 fatty acid and phenolic anti- oxidant interventions. Neurobiol Aging 2005; 26(1): 133–136.
6. Campbell, A. Inflammation, neurodegenerative diseases, and environmental exposures. Ann NY Acad Sci 2004; 1035(1): 117–132.
7. Uppugalla S, Male U, Srinivasan P. Design and synthesis of heteroatoms doped carbon/polyaniline hybrid material for high performance electrode in supercapacitor application. ElectrochimicaActa. 2014 Nov 10;146:242-8.
8. Kraft, AD. Nuclear factor E2-related factor 2-dependent anti- oxidant response element activation by tert-butylhydroquinone and sulforaphane occurring preferentially in astrocytes condi- tions neurons against oxidative insult. J Neurosci 2004; 24(5): 1101–1112.
9. Chan K, Lu, R, and Chang, JC, et al. NRF2, a member of the NFE2 family of transcription factors, is not essential for murine erythropoiesis, growth, and development. Proc Natl Acad Sci 1996; 93(24): 13943–13948.
10. Male U, Uppugalla S, Srinivasan P. Effect of reduced graphene oxide–silica composite in polyaniline: electrode material for high-performance supercapacitor. Journal of Solid State Electrochemistry. 2015 Nov;19(11):3381-8.
11. Moi P, Chan, K, and Asunis, I, et al. Isolation of NF-E2-related factor 2 (Nrf2), a NF-E2-like basic leucine zipper transcrip- tional activator that binds to the tandem NF-E2/AP1 repeat of the beta-globin locus control region. Proc Natl Acad Sci 1994; 91(21): 9926–9930.
12. Cuadrado A, Rojo AI, and Wells, G, et al. Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases. Nat Rev Drug Disc 2019; 18(4): 295–317. https://www.nature.com/ articles/s41573-018-0008-x
13. Song M-Y, Lee D-Y, Chun, K-S, et al. The role of NRF2/ KEAP1 signaling pathway in cancer metabolism. Int J Mol Sci 2021; 22(9): 4376.
14. Singh, A., 2022. Hyperlipidemia in cardiovascular health and digestion. In Nutrition and Functional Foods in Boosting Digestion, Metabolism and Immune Health (pp. 141-150). Academic Press.
15. Namani A, Li Y, and Wang, XJ, et al. Modulation of NRF2 signaling pathway by nuclear receptors: implications for can- cer. Biochimica et Biophysica Acta (BBA) – Mol Cell Res 2014; 1843(9): 1875–1885.
16. Plafker, KS, Nguyen, L, and Barneche, M, et al. The ubiqui- tin-conjugating enzyme UbcM2 can regulate the stability and activity of the antioxidant transcription factor Nrf2. J Biol Chem 2010; 285(30): 23064–23074.
17. Tong KI, Katoh Y, and Kusunoki, H, et al. Keap1 recruits Neh2 through binding to ETGE and DLG motifs: characterization of the two-site molecular recognition model. Mol Cell Biol 2006; 26(8): 2887–900.
18. Hayes JD and Dinkova-Kostova AT. The Nrf2 regulatory net- work provides an interface between redox and intermediary metabolism. Trends Biochem Sci 2014; 9(4): 199–218. https:// pubmed.ncbi.nlm.nih.gov/24647116/
19. Nioi P, Nguyen T, and Sherratt PJ, et al. The carboxy-terminal Neh3 domain of Nrf2 is required for transcriptional activation. Mol Cell Biol 2005; 25(24): 10895–10906. https://www.ncbi. nlm.nih.gov/pmc/articles/PMC1316965
20. Uppugalla S, Srinivasan P. High-performance supercapacitor coin cell: polyaniline and nitrogen, sulfur-doped activated carbon electrodes in aqueous electrolyte. Journal of Solid State Electrochemistry. 2019 Jan;23(1):295-306.
21. Kim S, Indu Viswanath AN, Park, J-H, et al. Nrf2 activator via interference of Nrf2-Keap1 interaction has antioxidant and anti- inflammatory properties in Parkinson’s disease animal model. Neuropharmacology 2020; 167: 107989.
22. Ma Q. Role of Nrf2 in oxidative stress and toxicity. Ann Rev Pharmacol Toxicol 2013; 53: 401–426. https://www.ncbi.nlm. nih.gov/pmc/articles/PMC4680839/
23. Uppugalla S, Srinivasan P. Polyaniline nanofibers and porous Ni [OH] 2 sheets coated carbon fabric for high performance super capacitor. Journal of Applied Polymer Science. 2019 Nov 5;136(41):48042.
24. Stępkowski TM and Kruszewski MK. Molecular cross-talk between the NRF2/KEAP1 signaling pathway, autophagy, and apoptosis. Free Radic Biol Med 2011;50(9):1186–95. doi: 10.1016/j.freeradbiomed.2011.01.033
25. Singh, A., 2022. Role of microbial metabolites in cardiovascular and human health. In Microbiome, Immunity, Digestive Health and Nutrition (pp. 137-148). Academic Press.
26. Roh, J., Hill, J.A., Singh, A.,Valero-Muñoz, M. and Sam, F., 2022. Heart failure with preserved ejection fraction: heterogeneous syndrome, diverse preclinical models. Circulation Research, 130(12), pp.1906-1925.
27. Baird, L, Llères, D, and Swift, S, et al. Regulatory flexibility in the Nrf2-mediated stress response is conferred by conforma- tional cycling of the Keap1-Nrf2 protein complex. Proc Natl Acad Sci 2013; 110(38): 15259–15264. https://www.pnas.org/ content/110/38/15259.short
28. Wakabayashi, N, Itoh, K, and Wakabayashi, J, et al. Keap1-null mutation leads to postnatal lethality due to constitutive Nrf2 activation. Nat Genet 2003; 5(3): 238–245. https://www.nature. com/articles/ng1248/briefing/signup/?origin=Nature&originRe ferralPoint=EmailBanner
29. Devling, TWP, Lindsay, CD, and McLellan, LI, et al. Utility of siRNA against Keap1 as a strategy to stimulate a cancer che- mopreventive phenotype. Proc Natl Acad Sci 2005; 102(20): 7280–7285.
30. Taniguchi, K, Yamachika, S, and He, F, et al. p62/SQSTM1-Dr. Jekyll and Mr. Hyde that prevents oxidative stress but promotes liver cancer. FEBS Lett 2016; 590(15): 2375–2397.
31. Uppugalla S, Boddula R, Srinivasan P. Methyl triphenylphosphonium permanganate as a novel oxidant for aniline to polyaniline-manganese (II, IV) oxide: material for high performance pseudocapacitor. Journal of Solid State Electrochemistry. 2018 Feb;22(2):407-15.
32. Umemura, A, He, F, and Taniguchi, K, et al. p62, Upregulated during preneoplasia, induces hepatocellular carcinogenesis by maintaining survival of stressed HCC-initiating cells. Cancer Cell 2016; 29(6): 935–948.
33. Hast, BE, Goldfarb, D, and Mulvaney, KM, et al. Proteomic analysis of ubiquitin ligase KEAP1 reveals associated proteins that inhibit NRF2 ubiquitination. Canc Res 2013; 73(7): 2199– 2210.
34. Parajuli D, Uppugalla S, Murali N, Ramakrishna A, Suryanarayana B, Samatha K. Synthesis and Characterization MXene-Ferrite Nanocomposites and its application for Dying and Shielding. Inorganic Chemistry Communications. 2022 Dec 16:110319.
35. Lau, A, Wang, X-J, and Zhao, F, et al. A noncanonical mecha- nism of Nrf2 activation by autophagy deficiency: direct inter- action between Keap1 and p62. Mol Cell Biol 2010; 0(13): 3275–3285.
36. Camp, ND, James, RG, and Dawson, DW, et al. Wilms tumor gene on X chromosome (WTX) inhibits degradation of NRF2 protein through competitive binding to KEAP1 protein. J Biol Chem 2012; 287(9): 6539–6550.
37. Singh, A., Kumar, A. and Kalaiselvi, P., 2018. Aegeline, targets LOX1, the receptor for oxidized LDL to mitigate hypercholesterolemia: a new perspective in its anti-atherosclerotic action. Free Radical Biology and Medicine, 128, p.S41.
38. Botsa SM, Seetharam P, Raju IM, Suresh P, Satyanarayana G, Sambasivam S, Susmitha U, Tejeswararao D. Nanohybrid material of Co–TiO2 and optical performance on methylene blue dye under visible light illumination. Hybrid Advances. 2022 Dec 8:100008.
39. Gorrini, C, Baniasadi, PS, and Harris, IS, et al. BRCA1 interacts with Nrf2 to regulate antioxidant signaling and cell survival. J Exp Med 2013; 210(8): 1529–1544.
40. Ganner, A, Pfeiffer, Z-C, and Wingendorf, L, et al. The acet- yltransferase p300 regulates NRF2 stability and localization. Biochem Biophys Res Commun 2020; 524(4): 895–902.
41. Akmal A, Javaid A, and Hussain R, et al. Screening of phy- tochemicals against Keap1- NRF2 interaction to reactivate NRF2 Functioning: Pharmacoinformatics based approach. Pak J Pharm Sci 2019 ;32(6(Supplementary)):2823–2828.
42. Lee, J-M, Calkins, MJ, and Chan, K, et al. Identification of the NF-E2-related factor-2-dependent genes conferring protection against oxidative stress in primary cortical astrocytes using oli- gonucleotide microarray analysis. J Biol Chem 2003; 278(14): 12029–12038.
43. Uppugalla S, Rajesh K, Surendra AV, Kumar K, Gayasuddin M. Effect Of Pisonia Alba Root Extract On Cafeteria Diet-Induced Obesity In Rats. Journal of Pharmaceutical Negative Results. 2022 Dec 1:3732-9.
44. Mitsuishi, Y, Taguchi, K, and Kawatani, Y, et al. Nrf2 redirects glucose and glutamine into anabolic pathways in metabolic reprogramming. Canc Cell 2012; 22(1): 66–79.
45. Barbeau, A, Dallaire, L, and Buu, NT, et al. Comparative behavioral, biochemical and pigmentary effects of MPTP, MPP+ and paraquat in rana pipiens. Life Sci 1985; 7(16): 1529–1538.
46. Yun, J and Finkel, T. Mitohormesis. Cell Metab 2014; 19(5): 757–766.
47. Hayashi, Y, Regnier, T, and Nishiguchi, S, et al. ChemInform abstract: Efficient total synthesis of (+)-Negamycin, a poten- tial chemotherapeutic agent for genetic diseases. ChemInform 2008; 9(38): 2379–81. doi: 10.1039/b801498a
48. Mahajan, A, and Ahuja, A. Authors’ reply to Tandon et al., Kudva et al., and Krishnan et al. Canc Res Stat Treat 2020; (2): 412.
49. Sriram N, Uppugalla S, Rajesh K. Cognitive Enhancing And Antioxidant Activity Of Ethyl Acetate Soluble Fraction Of The Methanol Extract Of Pisonia Alba Leaves In Scopolamine-Induced Amnesia. Journal of Pharmaceutical Negative Results. 2022 Dec 1:3740-9.
50. Monach, PA. Global versus organ-specific outcome measures in systemic lupus erythematosus: comment on the articles by Furie et al, Nikpour et al, Wallace et al, Burgos et al, and Ramos-Casals et al. Arthrit Care Res 2010; 62(4): 580–581.
51. Wang S, Wang Z, and Gao, H, et al. Highly regioselective palladium-catalyzed domino reaction for post-functionalization of BODIPY. Chem Commun (Camb) 2021;57(14):1758–1761. doi: 10.1039/d0cc08163a
52. Singh, A., Srinivasan, A.K., Chakrapani, L.N. and Kalaiselvi, P., 2019. LOX-1, the common therapeutic target in hypercholesterolemia: a new perspective of antiatherosclerotic action of aegeline. Oxidative medicine and cellular longevity, 2019.
53. Ammal Kaidery, N, Ahuja, M and Thomas, B. Crosstalk between Nrf2 signaling and mitochondrial function in Parkinson’s dis- ease. Mol Cell Neurosci 2019; 101: 103413.
54. Bing, RG, Sulis, DB, and Wang, JP, et al. Thermophilic micro- bial deconstruction and conversion of natural and transgenic lignocellulose. Environ Microbiol Rep 2021; 13(3): 272–293.
55. Osama A, Zhang J, and Yao, J, et al. Nrf2: A dark horse in Alzheimer’s disease treatment. Ageing Res Rev 2020;64:101206. doi: 10.1016/j.arr.2020.101206
56. Shiv Chandra Singh, A., Yu, A., Chang, B., Li, H., Rosenzweig, A. and Roh, J.D., 2021. Exercise Training Attenuates Activin Type II Receptor Signaling in the Aged Heart. Circulation, 144(Suppl_1), pp.A14259-A14259.
57. Dickenson, et al. v. Ramsey et al. Nov. 20, 1913 [79 S. E. 1025]. The Virginia Law Register 1914; 19(11): 845.
58. Conrad, B. In Response to Murphy et al., Löwer et al., and Lan et al. Cell 1998; 95(1): 16.
59. Zhang Z, Li G, and Szeto, SSW, et al. Examining the neuropro- tective effects of protocatechuic acid and chrysin on in vitro and in vivo models of Parkinson disease. Free Rad Biol Med 2015; 84: 331–343.
60. Tanji K, Odagiri S, and Miki, Y, et al. p62 Deficiency enhances α-synuclein pathology in mice. Brain Pathol 2014; 25(5): 552–564.
61. Oddo, S, Caccamo, A, and Shepherd, JD, et al. Triple-transgenic model of Alzheimer’s disease with plaques and tangles: intra- cellular Abeta and synaptic dysfunction. Neuron 2003; 9(3): 409–421. https://www.ncbi.nlm.nih.gov/pubmed/12895417
62. Singh, A., Gowtham, S., Chakrapani, L.N., Ashokkumar, S., Kumar, S.K., Prema, V., Bhavani, R.D., Mohan, T. and Sathyamoorthy, Y.K., 2018. Aegeline vs Statin in the treatment of Hypercholesterolemia: A comprehensive study in rat model of liver steatosis. Functional Foods in Health and Disease, 8(1), pp.1-16.
63. Tian, Y, Wang, W, and Xu, L, et al. Activation of Nrf2/ARE pathway alleviates the cognitive deficits in PS1V97L‐Tg mouse model of Alzheimer’s disease through modulation of oxidative stress. J Neurosci Res 2018; 97(4): 492–505.
64. Rojo, AI, Pajares, M, and García-Yagüe, AJ, et al. Deficiency in the transcription factor NRF2 worsens inflammatory parameters in a mouse model with combined tauopathy and amyloidopathy. Redox Biol 2018; 18: 173–180.
65. Zgorzynska E, Dziedzic B, and Walczewska A. An overview of the Nrf2/ARE pathway and its role in neurodegenera- tive diseases. Int J Mol Sci 2021;22(17):9592. doi: 10.3390/ ijms22179592
66. van Muiswinkel, FL, de Vos, RAI, and Bol, JGJM, et al. Expression of NAD(P)H:quinone oxidoreductase in the nor- mal and Parkinsonian substantia nigra. Neurobiol Aging 2004; 25(9): 1253–1262.
67. Lastres-Becker, I, Ulusoy, A, and Innamorato, NG, et al. α-Synuclein expression and Nrf2 deficiency cooperate to aggra- vate protein aggregation, neuronal death and inflammation in early-stage Parkinson’s disease. Human Mol Genet 2012; 21(14): 3173–3192.
68. Gan, L, Vargas, MR, and Johnson, DA, et al. Astrocyte- specific overexpression of Nrf2 delays motor pathology and synuclein aggregation throughout the CNS in the alpha-synu- clein mutant (A53T) mouse model. J Neurosci 2012; 2(49): 17775–17787.
69. Aguiar, AS, Duzzioni, M, and Remor, AP, et al. Moderate- intensity physical exercise protects against experimental 6-hydroxydopamine-induced hemiparkinsonism through Nrf2- antioxidant response element pathway. Neurochem Res 2015; 41(1–2): 64–72.
70. Boini, K.M., singh, A. and Koka, S.S., 2021. Gut Microbial Metabolite Trimethylamine N-oxide Enhances Endoplasmic Reticular Stress and Promotes Endothelial Dysfunction. Circulation, 144(Suppl_1), pp.A14071-A14071.
71. Wills, J, Jones, J, and Haggerty, T, et al. Elevated tauopathy and alpha-synuclein pathology in postmortem Parkinson’s disease brains with and without dementia. Exp Neurol 2010; 225(1): 210–218.
72. Zhang, C, Li, C, and Chen, S, et al. Berberine protects against 6-OHDA-induced neurotoxicity in PC12 cells and zebrafish through hormetic mechanisms involving PI3K/AKT/Bcl-2 and Nrf2/HO-1 pathways. Redox Biol 2017; 11: 1–11.
73. Bresciani A, Missineo A, and Gallo, M, et al. Nuclear factor (ery- throid-derived 2)-like 2 (NRF2) drug discovery: Biochemical toolbox to develop NRF2 activators by reversible binding of Kelch-like ECH-associated protein 1 (KEAP1). Arch Biochem Biophys 2017;631:31–41. doi: 10.1016/j.abb.2017.08.003
74. Wang L, Cai X, and Shi, M, et al. Identification and optimi- zation of piperine analogues as neuroprotective agents for the treatment of Parkinson’s disease via the activation of Nrf2/ keap1 pathway. Eur J Med Chem 2020; 199: 112385. https:// doi.org/10.1016/j.ejmech.2020.112385
Published
31/12/2022
Statistics
47 Views | 39 Downloads
Citatons
How to Cite
K, M., L. K, A. M, R. K. M, G. C. R, and S. K. K. “Review on Role of Nrf2 Pathway Activation in Neurological Disorder ”. International Journal of Health Care and Biological Sciences, Vol. 3, no. 4, Dec. 2022, pp. 99-108, doi:10.46795/ijhcbs.v3i4.402.
Section
Review Articles