Role of 6-amino flavone in attenuating cisplatin induced neurotoxicity via inhibition of p-JNK signaling pathway in post-natal day-7 mice
Article Sidebar
Main Article Content
Abstract
OBJECTIVE: To investigate the protective role of 6-amino flavone (6-AF) in cisplatin-induced neuro-inflammation in the developing brains of post-natal day-7 (PND-7) mice.
METHODS: This experimental study, conducted at the Neuro Molecular Medicines Research Center in Peshawar, Pakistan, included 20 PND-7 mice from January to March 2023. PND-7 mice were randomly distributed into four groups, a control group, a cisplatin group, a cisplatin + 6-AF group, and a 6-AF group. Cisplatin was administered intraperitoneally at a dose of 20 mg/kg to the cisplatin group. 6-AF was injected at a dose of 30 mg/kg after cisplatin administration to cisplatin+6-AF group and 6-AF group mice. After 4 hours of the drug treatment, all the PND-7 mice were sacrificed for Western blot analysis. ImageJ software was used for the densitometry of the blots. One-way ANOVA and post-hoc Tukey tests through Prism Graph-5 were applied for statistical analysis.
RESULTS: Significant differences in p-JNK levels along with TNF-α, NF-κB, and IL-1β proteins were observed in the brain homogenates of PND-7 mice in various groups. A post-hoc Tukey test revealed a significant increase (p<0.001) in the p-JNK, COX-2, NF-κB, and IL-1β levels in the cisplatin group as compared to control group mice. However, a significant decrease (p<0.001) was observed in p-JNK, COX-2, NF-κB, and IL-1β expression levels in the cisplatin + 6-AF group as compared to the cisplatin group.
CONCLUSION: Administration of 6-AF effectively reduced cisplatin-induced neurotoxicity in PND-7 mice, demonstrating a neuroprotective effect by suppressing p-JNK and its downstream TNF-α, NF-κB, and IL-1β proteins.
Article Details
This work is licensed under a Creative Commons Attribution 4.0 International License.
Work published in KMUJ is licensed under a
Creative Commons Attribution 4.0 License
Authors are permitted and encouraged to post their work online
(e.g., in institutional repositories or on their website) prior to and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work.
References
Yan D, An G, Kuo MT. C-Jun N-terminal kinase signalling pathway in response to cisplatin. J Cell Mol Med 2016;20(11):2013-19. https://doi.org/10.1111/jcmm.12908
Lu RM, Hwang YC, Liu IJ, Lee CC, Tsai HZ, Li HJ, et al. Development of therapeutic antibodies for the treatment of diseases. J Biomed Sci 2020;27(1):1-30. https://doi.org/10.1186/s12929-019-0592-z
Aldossary SA. Review on pharmacology of cisplatin: Clinical use, toxicity and mechanism of resistance of cisplatin. Biomed Pharmacol J 2019;12(1):7-15. https://dx.doi.org/10.13005/bpj/1608
Feliu J, Heredia-Soto V, Gironés R, Jiménez-Munarriz B, Saldaña J, Guillén-Ponce C, et al. Management of the toxicity of chemotherapy and targeted therapies in elderly cancer patients. Clin Transl Oncol 2020;22:457-67. https://doi.org/10.1007/s12094-019-02167-y
Gwathmey KG. Sensory neuronopathies. Muscle Nerve 2016;53(1):8-19. https://doi.org/10.1002/mus.24943
Cankara FN, Günaydın C, Çelik ZB, Şahin Y, Pekgöz Ş, Erzurumlu Y, et al. Agomelatine confers neuroprotection against cisplatin-induced hippocampal neurotoxicity. Metab Brain Dis 2021;36(2):339-49. https://doi.org/10.1007/s11011-020-00634-y
Rottenberg S, Disler C, Perego P. The rediscovery of platinum-based cancer therapy. Nat Rev Cancer 2021;21(1):37-50. https://doi.org/10.1038/s41568-020-00308-y
Romani AMP. Cisplatin in cancer treatment. Biochem Pharmacol 2022;206:115323. https://doi.org/10.1016/j.bcp.2022.115323
Guven H, Arici A, Simsek O. Flavonoids in our foods: A short review. J Basic Clin Health Sci 2019;3(2):96-106. https://doi.org/10.30621/jbachs.2019.555
Patel DK. Pharmacological activities and therapeutic potential of kaempferitrin in medicine for the treatment of human disorders: A review of medicinal importance and health benefits. Cardiovasc Haematol Disord Drug Targets 2021;21(2):104-14. https://doi.org/10.2174/1871529X21666210812111931
Souiei S, Bouajila J, Saidi I, Znati M, Jannet HB, El Garah F. Synthesis, in vitro and in silico evaluation of new flavonoids-trifluoroacetylated amino acid conjugates as anti-acetylcholinesterase and anti-proliferative agents. J Mol Struct 2023;1292:136180. https://doi.org/10.1016/j.molstruc.2023.136180
Shah SA, Khan M, Jo MH, Jo MG, Amin FU, Kim MO. Melatonin Stimulates the SIRT 1/Nrf2 signaling pathway counteracting lipopolysaccharide (LPS)-induced oxidative stress to rescue postnatal rat brain. CNS Neurosci Ther 2017;23(1):33-44. https://doi.org/10.1111/cns.12588
Volarevic V, Djokovic B, Jankovic MG, Harrell CR, Fellabaum C, Djonov V, et al. Molecular mechanisms of cisplatin-induced nephrotoxicity: A balance on the knife edge between renoprotection and tumor toxicity. J Biomed Sci 2019;26(1):1-14. https://doi.org/10.1186/s12929-019-0518-9
Jayaram, S, Krishnamurthy PT. Role of microgliosis, oxidative stress and associated neuroinflammation in the pathogenesis of parkinson’s disease: The therapeutic role of Nrf2 activators. Neurochem Int 2021;145:105014. https://doi.org/10.1016/j.neuint.2021.105014
Qi L, Luo Q, Zhang Y, Jia F, Zhao Y, Wang F. Advances in toxicological research of the anticancer drug cisplatin. Chem Res Toxicol 2019;32(8):1469-86. https://doi.org/10.1021/acs.chemrestox.9b00204
Cao M, Liu F, Ji F, Liang J, Liu L, Wu Q, et al. Effect of C-Jun N-terminal kinase (JNK)/P38 mitogen-activated protein kinase (P38 MAPK) in morphine-induced tau protein hyperphosphorylation. Behav Brain Res 2013;237:249-55. https://doi.org/10.1016/j.bbr.2012.09.040
Xie X, Kaoud TS, Edupuganti R, Zhang T, Kogawa T, Zhao Y, et al. C-Jun N-terminal kinase promotes stem cell phenotype in triple-negative breast cancer through upregulation of notch1 via activation of C-Jun. Oncogene 2017;36(18):2599-608. https://doi.org/10.1038/onc.2016.417
Nailwal NP, Doshi GM. Role of intracellular signaling pathways and their inhibitors in the treatment of inflammation. Inflammopharmacology 2021;29(3):617-40. https://doi.org/10.1007/s10787-021-00813-y
Sharma VK, Singh TG, Singh S, Garg N, Dhiman S. Apoptotic pathways and alzheimer’s disease: Probing therapeutic potential. Neurochem Res 2021;46:3103-22. https://doi.org/10.1007/s11064-021-03418-7
Wang T, He C. Pro-inflammatory cytokines: The link between obesity and osteoarthritis. Cytokine Growth Factor Rev 2018;44:38-50. https://doi.org/10.1016/j.cytogfr.2018.10.002
Chen L, Deng H, Cui H, Fang J, Zuo Z, Deng J, et al. Inflammatory responses and inflammation-associated diseases in organs. Oncotarget 2018;9(6):7204-18. https://doi.org/10.18632/oncotarget.23208
Sun W, Zhang N, Liu B, Yang J, Loers G, Siebert HC, et al. HDAC3 inhibitor RGFP966 ameliorated neuroinflammation in the cuprizone-induced demyelinating mouse model and LPS-stimulated BV2 cells by downregulating the P2X7R/STAT3/NF-κB65/NLRP3 activation. ACS Chem Neurosci 2022;13(17):2579-98. https://doi.org/10.1021/acschemneuro.1c00826
Jha AK, Gairola S, Kundu S, Doye P, Syed AM, Ram C, et al. Toll-like receptor 4: An attractive therapeutic target for acute kidney injury. Life Sci 2021;271:119155. https://doi.org/10.1016/j.lfs.2021.119155
Fang C, Lou D, Zhou L, Wang J, Yang B, He Q, et al. Natural products: Potential treatments for cisplatin-induced nephrotoxicity. Acta Pharmacol Sin 2021;42(12):1951-69. https://doi.org/10.1038/s41401-021-00620-9
Suzdaltseva Y, Goryunov K, Silina E, Manturova N, Stupin V, Kiselev SL. Equilibrium among inflammatory factors determines human MSC-mediated immunosuppressive effect. Cells 2022;11(7):1210. https://doi.org/10.3390/cells11071210
Saral S, Topçu A, Alkanat M, Mercantepe T, Akyıldız K, Yıldız L, et al. Apelin-13 activates the hippocampal BDNF/TrkB signaling pathway and suppresses neuroinflammation in male rats with cisplatin-induced cognitive dysfunction. Behav Brain Res 2021;408:113290. https://doi.org/10.1016/j.bbr.2021.113290
Wen L, Tao S, Guo F, Li L, Yang H, Liang Y, et al. Selective EZH2 inhibitor Zld1039 alleviates inflammation in cisplatin-induced acute kidney injury partially by enhancing RKIP and suppressing NF-κB P65 pathway. Acta Pharmacol Sin 2022;43(8):2067-80. https://doi.org/10.1038/s41401-021-00837-8
Afshari AR, Sanati M, Mollazadeh H, Kesharwani P, Johnston TP, Sahebkar A. Nanoparticle-based drug delivery systems in cancer: A focus on inflammatory pathways. Semin Cancer Biol 2022;86:860-72. https://doi.org/10.1016/j.semcancer.2022.01.008
Qin X, Meghana K, Sowjanya NL, Sushma KR, Krishna CG, Manasa J, et al. Embelin attenuates cisplatin-induced nephrotoxicity: Involving inhibition of oxidative stress and inflammation in addition with activation of Nrf-2/Ho-1 pathway. Biofactors 2019;45(3):471-8. https://doi.org/10.1002/biof.1502
Wang T, He C. Pro-inflammatory cytokines: The link between obesity and osteoarthritis. Cytokine Growth Factor Rev 2018;44:38-50. https://doi.org/10.1016/j.cytogfr.2018.10.002
Lei CQ, Wu X, Zhong X, Jiang L, Zhong B, Shu HB. USP19 inhibits TNF-α–and IL-1β–triggered NF-κB activation by deubiquitinating TAK1. J Immunol 2019;203(1):259-68. https://doi.org/10.4049/jimmunol.1900083
Liu Y, Yang Y, Zhang C, Huang F, Wang F, Yuan J, et al. Clinical and biochemical indexes from 2019-nCoV infected patients linked to viral loads and lung injury. Sci China Life Sci 2020;63(3):364-74. https://doi.org/10.1007/s11427-020-1643-8
Lu L, Liu W, Li S, Bai M, Zhou Y, Jiang Z, et al. Flavonoid derivative DMXAA attenuates cisplatin-induced acute kidney injury independent of STING signaling. Clin Sci (Lond) 2023;137(6):435-52. https://doi.org/10.1042/CS20220728
Altindağ F. Silymarin ameliorates cisplatin-induced nephrotoxicity by downregulating TNF-α and NF-kB and by upregulating IL-10. J Exp Clin Med 2022;39(1):216-20. https://doi.org/10.52142/omujecm.39.1.42
Alsayari A, Muhsinah AB, Hassan MZ, Ahsan MJ, Alshehri JA, Begum N. Aurone: A biologically attractive scaffold as anticancer agent. Eur J Med Chem 2019;166:417-31. https://doi.org/10.1016/j.ejmech.2019.01.078
Naeimi AF, Alizadeh M. Antioxidant properties of the flavonoid fisetin: An updated review of in vivo and in vitro studies. Trends Food Sci Technol 2017;70:34-44. https://doi.org/10.1016/j.tifs.2017.10.003
Li AL, Li GH, Li YR, Wu XY, Ren DM, Lou HX, et al. Lignan and flavonoid support the prevention of cinnamon against oxidative stress related diseases. Phytomedicine 2019;53:143-53. https://doi.org/10.1016/j.phymed.2018.09.022