Resveratrol-loaded cumin seed oil nanoemulsion ameliorates neurodegeneration in mice by inhibiting apoptosis, inflammation, and oxidative DNA damage

Document Type : Research Paper

Authors

1 Department of Zoology, Faculty of Science, Cairo University, Giza 12613, Egypt

2 Nanotechnology and Advanced Materials Central Lab, Agriculture Research Center, Egypt

10.22038/nmj.2024.75726.1841

Abstract

Objective(s): Neurodegenerative diseases affect over 50 million people worldwide. Unfortunately, there are no cures for these diseases, so finding effective treatments to improve human health is crucial. Resveratrol (Res) has neuroprotective effects due to its antioxidant and anti-inflammatory properties. However, Res is limited by poor water solubility and bioavailability. Therefore, the current study aimed to overcome Res’s limitations using recent nanotechnology.
Materials and Methods: Resveratrol was loaded onto a nanoemulsion of cumin seed oil (CSONEs). The CSONEs and Res-CSONEs were characterized. Additionally, we investigated the neuroprotective effects of Res-loaded CSONEs in mice with Trimethyltin (TMT)-induced neurodegeneration. Thirty mice were divided into control, vehicle, TMT, TMT-CSONEs, TMT-Res, and TMT-Res-CSONEs. Each group received intraperitoneal treatment six times per week for two weeks. oxidative stress biomarkers, DNA damage extent, and histopathological evaluations were assessed in brain and liver tissues. In addition, the mRNA expression of apoptotic and inflammatory genes (Bax/Bcl2 and il-1β) and immunohistochemical staining of tau protein were evaluated in the brain tissues. 
Results: The Res-CSONEs improved cellular homeostasis by increasing GSH, and SOD, and decreasing MDA levels while decreasing the DNA damage parameters. They also decreased the expression of apoptotic and inflammatory genes and reduced the aggregation of tau protein. Histopathological examination of the studied tissues showed improvement in Res and Res-CSONEs compared to TMT. 
Conclusion: Loading Res on CSONEs resulted in promising neuroprotective effects due to its solubility and bioavailability enhancement. Combining the antioxidant and anti-inflammatory properties of both Res and CSONEs resulted in perfect neuroprotective effects on the brain tissues of mice.

Keywords


1. International AsD. World Alzheimer Report 2021: Journey through the diagnosis of dementia. London Alzheimers Dis Int. 2021. 
2. Organization WH. The top 10 causes of death. 9 December 2020. World Health Organization(20182020 https://www who int/news-room/fact-sheets/detail/the-top-10-causes of- death. 2021. 
3. Dorsey E, Sherer T, Okun MS, Bloem BR. The emerging evidence of the Parkinson pandemic. J Parkinsons Dis. 2018;8(s1):S3-S8.
4. Yang W, Hamilton JL, Kopil C, Beck JC, Tanner CM, Albin RL, et al. Current and projected future economic burden of Parkinson’s disease in the US. NPJ Parkinsons Dis. 2020;6(1):15. 
5. Berman AY, Motechin RA, Wiesenfeld MY, Holz MK. The therapeutic potential of resveratrol: a review of clinical trials. NPJ Precis Oncol. 2017;1(1):35. 
6. Rauf A, Imran M, Suleria HAR, Ahmad B, Peters DG, Mubarak MS. A comprehensive review of the health perspectives of resveratrol. Food Funct. 2017;8(12):4284-4305. 
7. Rauf A, Imran M, Butt MS, Nadeem M, Peters DG, Mubarak MS. Resveratrol as an anti-cancer agent: A review. Crit Rev Food Sci Nutr. 2018;58(9):1428-1447. 
8. Tellone E, Galtieri A, Russo A, Giardina B, Ficarra S. Resveratrol: a focus on several neurodegenerative diseases. Oxid Med Cell Longev. 2015;2015(1):392169.
9. Wang H, Jiang T, Li W, Gao N, Zhang T. Resveratrol attenuates oxidative damage through activating mitophagy in an in vitro model of Alzheimer’s disease. Toxicol Lett. 2018;282:100-108.
10. Truong VL, Jun M, Jeong WS. Role of resveratrol in regulation of cellular defense systems against oxidative stress. Biofactors. 2018;44(1):36-49.
11. Wang Q, Liu Y, Zhou J. Neuroinflammation in Parkinson’s disease and its potential as therapeutic target. Transl Neurodegener. 2015;4:1-9. 
12. Francioso A, Mastromarino P, Masci A, d’Erme M, Mosca L. Chemistry, stability and bioavailability of resveratrol. Med Chem. 2014;10(3):237-245. 
13. Wang S, Wang Z, Yang S, Yin T, Zhang Y, Qin Y, et al. Tissue distribution of trans‐resveratrol and its metabolites after oral administration in human eyes. J Ophthalmol.         2017;2017(1):4052094.
14. Nirale P, Paul A, Yadav KS. Nanoemulsions for targeting the neurodegenerative diseases: Alzheimer’s, Parkinson’s and Prion’s. Life Sci. 2020;245:117394.
15. Suyal J, Kumar B, Jakhmola V. Novel approach self-nanoemulsifying drug delivery system: a review. Advances in Pharmacology and Pharmacy. 2023;11(2):131-139.
16. Patel RP, Joshi JR. An overview on nanoemulsion: a novel approach. Int J Pharm Sci Res.2012;3(12):4640. 
17. Sutradhar KB, Amin ML. Nanoemulsions: increasing possibilities in drug delivery. Eur J Nanomed. 2013;5(2):97 110.
18. Jaiswal M, Dudhe R, Sharma P. Nanoemulsion: an advanced mode of drug delivery system. 3 Biotech. 2015;5:123-127. 
19. Patel D, Sawant KK. Self micro-emulsifying drug delivery system: formulation development and biopharmaceutical evaluation of lipophilic drugs. Curr Drug Deliv. 2009;6(4):419-424. 
20. Singh Y, Meher JG, Raval K, Khan FA, Chaurasia M, Jain NK, et al. Nanoemulsion: Concepts, development and applications in drug delivery. J Control Release. 2017;252:28-49.
21. Locatelli FM, Kawano T, Iwata H, Aoyama B, Eguchi S, Nishigaki A, et al. Resveratrol-loaded nanoemulsion prevents cognitive decline after abdominal surgery in aged rats. J Pharmacol Sci. 2018;137(4):395-402.
22. Nirmala MJ, Durai L, Rao KA, Nagarajan R. Ultrasonic nanoemulsification of Cuminum cyminum essential oil and its applications in medicine. Int J Nanomedicine. 2020;795-807. 
23. Fernandes SS, Egea MB, Salas-Mellado MdlM, Segura-Campos MR. Chia Oil and Mucilage Nanoemulsion: Potential Strategy to Protect a Functional Ingredient. Int J Mol Sci. 2023;24(8):7384.
24. Atli O, Can Karaca A, Ozcelik B. Encapsulation of Cumin (Cuminum cyminum L.) seed essential oil in the Chickpea Protein–Maltodextrin matrix. ACS Omega. 2023;8(4): 4156-4164.
25. Li R, Jiang ZT. Chemical composition of the essential oil of Cuminum cyminum L. from China. Flavour Fragr J. 2004;19(4):311-313. 
26. Nostro A, Cellini L, Bartolomeo SD, Campli ED, Grande R, Cannatelli M, et al. Antibacterial effect of plant extracts against Helicobacter pylori. Phytother Res. 2005;19(3):198-202. 
27. Gachkar L, Yadegari D, Rezaei MB, Taghizadeh M, Astaneh SA, Rasooli I. Chemical and biological characteristics of Cuminum cyminum and Rosmarinus officinalis essential oils. Food Chem. 2007;102(3):898-904. 
28. Koppula S, Choi DK. Cuminum cyminum extract attenuates scopolamine-induced memory loss and stress-induced urinary biochemical changes in rats: a noninvasive biochemical approach. Pharm Biol. 2011;49(7):702-708. 
29. Misiti F, Orsini F, Clementi ME, Lattanzi W, Giardina B, Michetti F. Mitochondrial oxygen consumption inhibition importance for TMT-dependent cell death in undifferentiated PC12 cells. Neurochem Int. 2008;52(6):1092-1099.
30. Geloso MC, Corvino V, Michetti F. Trimethyltin-induced hippocampal degeneration as a tool to investigate neurodegenerative processes. Neurochem Int. 2011;58(7):729-738. 
31. Piacentini R, Gangitano C, Ceccariglia S, Fà AD, Azzena GB, Michetti F, et al. Dysregulation of intracellular calcium homeostasis is responsible for neuronal death in an experimental model of selective hippocampal degeneration induced by trimethyltin. J Neurochem. 2008;105(6):2109-2121.
32. Pompili E, Fabrizi C, Fumagalli L, Fornai F. Autophagy in trimethyltin-induced neurodegeneration. J Neural Transm. 2020;127:987-998.
33. Gong Q-H, Li F, Jin F, Shi J-S. Resveratrol attenuates neuroinflammation-mediated cognitive deficits in rats. J Health Sci. 2010;56(6):655-663. 
34. Sheweita SA, El-Hosseiny LS, Nashashibi MA. Protective effects of essential oils as natural antioxidants against hepatotoxicity induced by cyclophosphamide in mice. PloS one. 2016;11(11):e0165667.
35. Frozza RL, Bernardi A, Paese K, Hoppe JB, Silva Td, Battastini AM, et al. Characterization of trans-resveratrol-loaded lipid-core nanocapsules and tissue distribution studies in rats. J Biomed Nanotechnol. 2010;6(6):694-703. 
36. Sönmez Ü, Sönmez A, Erbil G, Tekmen I, Baykara B. Neuroprotective effects of resveratrol against traumatic brain injury in immature rats. Neurosci Lett. 2007;420(2):133-137.
37. Ohkawa H, Ohishi N, Yagi K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem. 1979;95(2):351-358. 
38. Beutler E, Duron O, Kelly BM. Improved method for the determination of blood glutathione. J Lab Clin Med. 1963;61:882-888.
39. Nishikimi M, Rao NA, Yagi K. The occurrence of superoxide anion in the reaction of reduced phenazine methosulfate and molecular oxygen. Biochem Biophys Res Commun. 1972;46(2):849-854. 
40. Tice RR, Agurell E, Anderson D, Burlinson B, Hartmann A, Kobayashi H, et al. Single cell gel/comet assay: guidelines for in vitro and in vivo genetic toxicology testing. Environ Mol Mutagen. 2000;35(3):206-221.
41. Nandhakumar S, Parasuraman S, Shanmugam M, Rao KR, Chand P, Bhat BV. Evaluation of DNA damage using single-cell gel electrophoresis (Comet Assay). J Pharmacol Pharmacother. 2011;2(2):107. 
42. Gad HA, Mansour M, Abbas H, Malatani RT, Khattab MA, Elmowafy E. “Plurol will not miss the boat”: A new manifesto of galantamine conveyance. J Drug Deliv Sci Technol. 2022;74:103516. 
43. Bancroft JD, Layton C, Suvarna SK. Bancroft’s theory and practice of histological techniques: Churchill Livingstone Elsevier. 2013.
44. Rocha‐González HI, Ambriz‐Tututi M, Granados‐Soto V. Resveratrol: a natural compound with pharmacological potential in neurodegenerative diseases. CNS Neurosci Ther. 2008;14(3):234-247. 
45. Andrade S, Ramalho MJ, Pereira MdC, Loureiro JA. Resveratrol brain delivery for neurological disorders prevention and treatment. Front pharmacol. 2018;9:1261. 
46. Amri A, Chaumeil J, Sfar S, Charrueau C. Administration of resveratrol: what formulation solutions to bioavailability limitations? J Control Release. 2012;158(2):182-193. 
47. ElZorkany HE, El-Shorbagy HM, Farroh KY, Youssef T, Sabet S, Salaheldin TA. Monitoring the  cellular uptake of silica-coated CdSe/ZnS quantum dots by time lapse confocal laser scanning  microscopy. J Appl Pharm Sci. 2018;8(3):001-008. 
48. Rehman S, Md S, Baboota S, Ali J. Analyzing nanotheraputics-based approaches for the management of psychotic disorders. J Pharmacol Sci. 2019;108(12):3757-3768.
49.Wei J, Zhang X, Bi Y, Miao R, Zhang Z, Su H. Anti‐inflammatory effects of cumin essential oil by blocking JNK, ERK, and NF‐κB signaling pathways in LPS‐stimulated RAW 264.7 cells. Evid Based Complement Alternat Med. 2015;2015(1):474509.
50. Platel K, Srinivasan K. Influence of dietary spices and their active principles on pancreatic digestive enzymes in albino rats. Food/Nahrung. 2000;44(1):42-46. 
51. Topal U, Sasaki M, Goto M, Otles S. Chemical compositions and antioxidant properties of essential oils from nine species of Turkish plants obtained by supercritical carbon dioxide extraction and steam distillation. Int J Food Sci Nutr. 2008;59(7-8):619-634. 
52. Ghofrani S, Joghataei M-T, Afshin-Majd S, Baluchnejadmojarad T, Roghani M. Crocin, a  bioactive constituent of Crocus sativus, alleviates trimethyltin-induced cognitive deficits through down-regulation of hippocampal apoptosis and oxidative stress. J basic clin pathophysiol.2022;10(1):38-44. 
53. Shin E-J, Suh S, Lim Y, Jhoo W-K, Hjelle O, Ottersen O,et al. Ascorbate attenuates trimethyltin-induced oxidative burden and neuronal degeneration in the rat hippocampus by maintaining glutathione homeostasis. Neuroscience. 2005;133(3):715-727. 
54. Wang X, Cai J, Zhang J, Wang C, Yu A, Chen Y, et al. Acute trimethyltin exposure induces oxidative stress response and neuronal apoptosis in Sebastiscus marmoratus. Aquat Toxicol. 2008;90(1):58-64. 
55. Farghaly AA, Abo-Zeid MA. Protective effect of vitamin C on trimethyltin induced DNA damage using comet assay and chromosomal aberrations. Cytologia. 2010;75(3):229-236.
56. Kang D-H. Oxidative stress, DNA damage, and breast cancer. AACN Adv Crit Care. 2002;13(4):540-549.  
57. Liu W, Tang Y, Feng J. Cross talk between activation of microglia and astrocytes in pathological conditions in the central nervous system. Life Sci. 2011;89(5-6):141-146. 
58. Gunasekar PG, Mickova V, Kotyzova D, Li L, Borowitz JL, Eybl V, et al. Role of astrocytes in trimethyltin neurotoxicity. J Biochem Mol Toxicol. 2001;15(5):256-262. 
59. Meng T, Xiao D, Muhammed A, Deng J, Chen L, He J. Anti-inflammatory action and mechanisms of resveratrol. Molecules. 2021;26(1):229.
60. Jeong E-S, Bajgai J, You I-S, Rahman M, Fadriquela A, Sharma S, et al. Therapeutic effects of hydrogen gas inhalation on trimethyltin-induced neurotoxicity and cognitive impairment in the C57BL/6 mice model. Int J Mol Sci. 2021;22(24):13313. 
61. Hou Y, Wang K, Wan W, Cheng Y, Pu X, Ye X. Resveratrol provides neuroprotection by regulating the JAK2/STAT3/PI3K/AKT/mTOR pathway after stroke in rats. Genes Dis. 2018;5(3):245-255.
62. Park SB, Kang JY, Kim JM, Park SK, Park SH, Kang JE, et al. Aruncus dioicus var. kamtschaticus extract suppresses mitochondrial apoptosis induced‐neurodegeneration in  trimethyltin‐injected ICR mice. J Food Biochem. 2018;42(6):e12667.
63. Pasinetti GM, Wang J, Ho L, Zhao W, Dubner L. Roles of resveratrol and other grape-derived polyphenols in Alzheimer’s disease prevention and treatment. Biochim Biophys Acta Mol Basis Dis. 2015;1852(6):1202-1208. 
64. Liu X-J, Wang Y-Q, Shang S-Q, Xu S, Guo M. TMT induces apoptosis and necroptosis in mouse kidneys through oxidative stress-induced activation of the NLRP3 inflammasome. Ecotoxicol Environ Saf. 2022;230:113167. 
65. Wang Y, Liu X, Jing H, Ren H, Xu S, Guo M. Trimethyltin induces apoptosis and necroptosis of mouse liver by oxidative stress through YAP phosphorylation. Ecotoxicol Environ Saf.       2022;248:114327. 
66. Chupradit S, Bokov D, Zamanian MY, Heidari M, Hakimizadeh E. Hepatoprotective and therapeutic effects of resveratrol: A focus on anti‐inflammatory and antioxidative activities. Fundam Clin Pharmacol. 2022;36(3):468-485.