Skip to content
2000
image of Protective Effect of Aloe-emodin on Cognitive Function in Copper-loaded Rats Based on The Inhibition of Hippocampal Neuron Ferroptosis

Abstract

Background

Aloe-emodin (AE), a monomer derived from traditional Chinese medicine, has demonstrated remarkable efficacy in the clinical management of cognitive disorders. Ferroptosis (FPT), a specialized form of programmed cell death, plays a critical role in the pathological progression of various cognitive diseases.

Methods

This study explored the therapeutic potential of AE in a rat model of Wilson's disease cognitive impairments (WDCI) and examined whether these effects are mediated through the silencing information regulator 1 (SIRT1)-regulated FPT signaling pathway. Employing techniques, such as the Morris water maze (MWM), Hematoxylin & eosin (H&E) staining, Transmission electron microscopy (TEM), Immunofluorescence (IF), assessments of oxidative stress markers, and measurements of FPT-related protein levels, we evaluated the extent of SIRT1-mediated FPT and the therapeutic efficacy of AE.

Results

The findings from the WD copper-loaded rat model experiments revealed that MWM, H&E, TEM, and IF outcomes indicated AE's potential to promote the restoration of learning and memory functions, ameliorate hippocampal neuronal morphological damage, and preserve cell membrane integrity. Results from western blot (WB) and ELISA analyses demonstrated that AE markedly upregulated the expression of SIRT1, nuclear factor erythroid-2-related factor 2 (Nrf2), solute carrier family 7 member 11 (SCL7A11), and glutathione peroxidase 4 (GPX4) proteins while simultaneously reversing the expression of oxidative stress markers such as malondialdehyde (MDA), glutathione (GSH), and superoxide dismutase (SOD), and reactive oxygen species (ROS). Consequently, we posit that AE may attenuate WD copper-loaded rat model hippocampal neuronal FPT by activating the SIRT1-mediated signaling pathway.

Conclusion

These findings suggested that AE mitigates WD copper-loaded rat model hippocampal neuronal damage through the activation of SIRT1-mediated FPT, thereby presenting a valuable candidate Chinese herbal monomer for the clinical treatment of WDCI.

Loading

Article metrics loading...

/content/journals/cnr/10.2174/0115672026348862241003042336
2024-10-15
2025-01-23
Loading full text...

Full text loading...

References

  1. Lucena-Valera A. Ruz-Zafra P. Ampuero J. Wilson’s disease: Overview. Med. Clin. (Barc.) 2023 160 6 261 267 10.1016/j.medcli.2022.12.016 36697289
    [Google Scholar]
  2. Roberts E.A. Update on the Diagnosis and Management of Wilson Disease. Curr. Gastroenterol. Rep. 2018 20 12 56 10.1007/s11894‑018‑0660‑7 30397835
    [Google Scholar]
  3. Dev S. Kruse R.L. Hamilton J.P. Lutsenko S. Wilson Disease: Update on Pathophysiology and Treatment. Front. Cell Dev. Biol. 2022 10 871877 10.3389/fcell.2022.871877 35586338
    [Google Scholar]
  4. Alkhouri N. Gonzalez-Peralta R.P. Medici V. Wilson disease: a summary of the updated AASLD Practice Guidance. Hepatol. Commun. 2023 7 6 e0150 10.1097/HC9.0000000000000150 37184530
    [Google Scholar]
  5. Huang Q. Lu G. Shen H.M. Chung M.C.M. Ong C.N. Anti‐cancer properties of anthraquinones from rhubarb. Med. Res. Rev. 2007 27 5 609 630 10.1002/med.20094 17022020
    [Google Scholar]
  6. Hamman J.H. Composition and applications of Aloe vera leaf gel. Molecules 2008 13 8 1599 1616 10.3390/molecules13081599 18794775
    [Google Scholar]
  7. Yi T. Leung K.S.Y. Lu G.H. Zhang H. Chan K. Identification and determination of the major constituents in traditional Chinese medicinal plant Polygonum multiflorum thunb by HPLC coupled with PAD and ESI/MS. Phytochem. Anal. 2007 18 3 181 187 10.1002/pca.963 17500359
    [Google Scholar]
  8. Dong X. Zeng Y. Liu Y. You L. Yin X. Fu J. Ni J. Aloe‐emodin: A review of its pharmacology, toxicity, and pharmacokinetics. Phytother. Res. 2020 34 2 270 281 10.1002/ptr.6532 31680350
    [Google Scholar]
  9. Hu B. Zhang H. Meng X. Wang F. Wang P. Aloe-emodin from rhubarb (Rheum rhabarbarum) inhibits lipopolysaccharide-induced inflammatory responses in RAW264.7 macrophages. J. Ethnopharmacol. 2014 153 3 846 853 10.1016/j.jep.2014.03.059 24685589
    [Google Scholar]
  10. Li S.W. Yang T.C. Lai C.C. Huang S.H. Liao J.M. Wan L. Lin Y.J. Lin C.W. Antiviral activity of aloe-emodin against influenza A virus via galectin-3 up-regulation. Eur. J. Pharmacol. 2014 738 125 132 10.1016/j.ejphar.2014.05.028 24877694
    [Google Scholar]
  11. Woo S.W. Nan J.X. Lee S.H. Park E.J. Zhao Y.Z. Sohn D.H. Aloe emodin suppresses myofibroblastic differentiation of rat hepatic stellate cells in primary culture. Pharmacol. Toxicol. 2002 90 4 193 198 10.1034/j.1600‑0773.2002.900404.x 12076313
    [Google Scholar]
  12. Tao L. Xie J. Wang Y. Wang S. Wu S. Wang Q. Ding H. Protective effects of aloe-emodin on scopolamine-induced memory impairment in mice and H2O2-induced cytotoxicity in PC12 cells. Bioorg. Med. Chem. Lett. 2014 24 23 5385 5389 10.1016/j.bmcl.2014.10.049 25453793
    [Google Scholar]
  13. Dixon S.J. Lemberg K.M. Lamprecht M.R. Skouta R. Zaitsev E.M. Gleason C.E. Patel D.N. Bauer A.J. Cantley A.M. Yang W.S. Morrison B. III Stockwell B.R. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 2012 149 5 1060 1072 10.1016/j.cell.2012.03.042 22632970
    [Google Scholar]
  14. Litwin T. Dusek P. Szafrański T. Dzieżyc K. Członkowska A. Rybakowski J.K. Psychiatric manifestations in Wilson’s disease: possibilities and difficulties for treatment. Ther. Adv. Psychopharmacol. 2018 8 7 199 211 10.1177/2045125318759461 29977520
    [Google Scholar]
  15. Wang X. Shao N. Zhang X. Chen H. Chang Z. Xie D. Zhang J. Ferulic Acid Activates SIRT1-Mediated Ferroptosis Signaling Pathway to Improve Cognition Dysfunction in Wilson’s Disease. Neuropsychiatr. Dis. Treat. 2023 19 2681 2696 10.2147/NDT.S443278 38077239
    [Google Scholar]
  16. Mishra P. Mittal A.K. Kalonia H. Madan S. Ghosh S. Sinha J.K. Rajput S.K. SIRT1 Promotes Neuronal Fortification in Neurodegenerative Diseases through Attenuation of Pathological Hallmarks and Enhancement of Cellular Lifespan. Curr. Neuropharmacol. 2021 19 7 1019 1037 10.2174/18756190MTA44NjIg1 32727328
    [Google Scholar]
  17. Qiongyue Z. Xin Y. Meng P. Sulin M. Yanlin W. Xinyi L. Xuemin S. Post-treatment with irisin attenuates acute kidney injury in sepsis mice through anti-ferroptosis via the SIRT1/Nrf2 Pathway. Front. Pharmacol. 2022 13 857067 10.3389/fphar.2022.857067 35370723
    [Google Scholar]
  18. Li D. Liu X. Pi W. Zhang Y. Yu L. Xu C. Sun Z. Jiang J. Fisetin attenuates doxorubicin-induced cardiomyopathy in vivo and in vitro by inhibiting ferroptosis through SIRT1/Nrf2 signaling pathway activation. Front. Pharmacol. 2022 12 808480 10.3389/fphar.2021.808480 35273493
    [Google Scholar]
  19. Tonelli C. Chio I.I.C. Tuveson D.A. Transcriptional Regulation by Nrf2. Antioxid. Redox Signal. 2018 29 17 1727 1745 10.1089/ars.2017.7342 28899199
    [Google Scholar]
  20. Kerins M.J. Ooi A. The Roles of NRF2 in Modulating Cellular Iron Homeostasis. Antioxid. Redox Signal. 2018 29 17 1756 1773 10.1089/ars.2017.7176 28793787
    [Google Scholar]
  21. Torrente L. DeNicola G.M. Targeting NRF2 and Its Downstream Processes: Opportunities and Challenges. Annu. Rev. Pharmacol. Toxicol. 2022 62 1 279 300 10.1146/annurev‑pharmtox‑052220‑104025 34499527
    [Google Scholar]
  22. Xu J. Jiang H. Li J. Cheng K.K. Dong J. Chen Z. 1H NMR-based metabolomics investigation of copper-laden rat: a model of Wilson’s disease. PLoS One 2015 10 4 e0119654 10.1371/journal.pone.0119654 25849323
    [Google Scholar]
  23. Zhang X. Wang X. Ye T. Shao N. Wang J. Cai B. Xie D. Network pharmacology-based approach to understand the effect and mechanism of chrysophanol against cognitive impairment in Wilson disease. Metab. Brain Dis. 2023 39 1 89 99 10.1007/s11011‑023‑01321‑4 37999884
    [Google Scholar]
  24. Zhang G. Li Q. Gao W. Liu S. Wu R. Shen Z. Liu W. Chen Y. Copper chloride dose-dependently alters spatial learning and memory, and glutamate levels, in the hippocampus of rats. Mol. Med. Rep. 2018 17 3 4074 4082 29257305
    [Google Scholar]
  25. Zhang Y. Zhou Q. Lu L. Su Y. Shi W. Zhang H. Liu R. Pu Y. Yin L. Copper Induces Cognitive Impairment in Mice via Modulation of Cuproptosis and CREB Signaling. Nutrients 2023 15 4 972 10.3390/nu15040972 36839332
    [Google Scholar]
  26. Palmieri G.R. De Michele G. Matarazzo M. Di Dato F. Perillo S. Dello Iacovo D.C.P. Cuomo N. Pane C. Russo C.V. Iorio R. De Michele G. De Rosa A. Prevalence and features of non-motor symptoms in Wilson’s disease. Parkinsonism Relat. Disord. 2022 95 103 106 10.1016/j.parkreldis.2022.01.016 35093711
    [Google Scholar]
  27. Kirk F.T. Munk D.E. Laursen T.L. Vilstrup H. Ott P. Grønbæk H. Lauridsen M.M. Sandahl T.D. Cognitive impairment in stable Wilson disease across phenotype. Metab. Brain Dis. 2021 36 7 2173 2177 10.1007/s11011‑021‑00804‑6 34342812
    [Google Scholar]
  28. Kalita J. Kumar V. Misra U.K. Bora H.K. Memory and Learning Dysfunction Following Copper Toxicity: Biochemical and Immunohistochemical Basis. Mol. Neurobiol. 2018 55 5 3800 3811 28536976
    [Google Scholar]
  29. Philbert S.A. Schönberger S.J. Xu J. Church S.J. Unwin R.D. Cooper G.J.S. Elevated hippocampal copper in cases of type 2 diabetes. EBioMedicine 2022 86 104317 10.1016/j.ebiom.2022.104317 36335667
    [Google Scholar]
  30. Chen L.L. Fan Y.G. Zhao L.X. Zhang Q. Wang Z.Y. The metal ion hypothesis of Alzheimer’s disease and the anti-neuroinflammatory effect of metal chelators. Bioorg. Chem. 2023 131 106301 10.1016/j.bioorg.2022.106301 36455485
    [Google Scholar]
  31. Ren Q. Chen J. Wesseling S. Bouwmeester H. Rietjens I.M.C.M. Physiologically based kinetic modeling-facilitated quantitative in vitro to in vivo extrapolation to predict the effects of aloe-emodin in rats and humans. J. Agric. Food Chem. 2024 72 29 16163 16176 10.1021/acs.jafc.4c00969 38980703
    [Google Scholar]
  32. Liu H. Guo D. Wang J. Zhang W. Zhu Z. Zhu K. Bi S. Pan P. Liang G. Aloe-emodin from Sanhua Decoction inhibits neuroinflammation by regulating microglia polarization after subarachnoid hemorrhage. J. Ethnopharmacol. 2024 322 117583 10.1016/j.jep.2023.117583 38122912
    [Google Scholar]
  33. Xian M. Cai J. Zheng K. Liu Q. Liu Y. Lin H. Liang S. Wang S. Aloe-emodin prevents nerve injury and neuroinflammation caused by ischemic stroke via the PI3K/AKT/mTOR and NF-κB pathway. Food Funct. 2021 12 17 8056 8067 10.1039/D1FO01144H 34286782
    [Google Scholar]
  34. Litwin T. Dusek P. Antos A. Członkowska A. Bembenek J. Tackling the neurological manifestations in Wilson’s disease – currently available treatment options. Expert Rev. Neurother. 2023 23 12 1249 1259 10.1080/14737175.2023.2268841 37842984
    [Google Scholar]
  35. Lee E.J. Woo M.H. Moon J.S. Ko J.S. Efficacy and safety of D-penicillamine, trientine, and zinc in pediatric Wilson disease patients. Orphanet J. Rare Dis. 2024 19 1 261 10.1186/s13023‑024‑03271‑1 38982450
    [Google Scholar]
  36. Li Y. Du Y. Zhou Y. Chen Q. Luo Z. Ren Y. Chen X. Chen G. Iron and copper: critical executioners of ferroptosis, cuproptosis and other forms of cell death. Cell Commun. Signal. 2023 21 1 327 10.1186/s12964‑023‑01267‑1 37974196
    [Google Scholar]
  37. Teschke R. Eickhoff A. Wilson Disease: Copper-Mediated Cuproptosis, Iron-Related Ferroptosis, and Clinical Highlights, with Comprehensive and Critical Analysis Update. Int. J. Mol. Sci. 2024 25 9 4753 10.3390/ijms25094753 38731973
    [Google Scholar]
  38. Lane D.J.R. Metselaar B. Greenough M. Bush A.I. Ayton S.J. Ferroptosis and NRF2: an emerging battlefield in the neurodegeneration of Alzheimer’s disease. Essays Biochem. 2021 65 7 925 940 10.1042/EBC20210017 34623415
    [Google Scholar]
  39. Fu C. Wu Y. Liu S. Luo C. Lu Y. Liu M. Wang L. Zhang Y. Liu X. Rehmannioside A improves cognitive impairment and alleviates ferroptosis via activating PI3K/AKT/Nrf2 and SLC7A11/GPX4 signaling pathway after ischemia. J. Ethnopharmacol. 2022 289 115021 10.1016/j.jep.2022.115021 35091012
    [Google Scholar]
  40. Li Y. Zhang E. Yang H. Chen Y. Tao L. Xu Y. Chen T. Shen X. Gastrodin Ameliorates Cognitive Dysfunction in Vascular Dementia Rats by Suppressing Ferroptosis via the Regulation of the Nrf2/Keap1-GPx4 Signaling Pathway. Molecules 2022 27 19 6311 10.3390/molecules27196311
    [Google Scholar]
  41. Zhong Y. Liu L. Zhao Y. Feng Z. Liu Y. Elucidating the molecular mechanisms behind the therapeutic impact of median nerve stimulation on cognitive dysfunction post-traumatic brain injury. Exp. Gerontol. 2024 194 112500 10.1016/j.exger.2024.112500 38901771
    [Google Scholar]
  42. Shi Y.S. Chen J.C. Lin L. Cheng Y.Z. Zhao Y. Zhang Y. Pan X.D. Dendrobine rescues cognitive dysfunction in diabetic encephalopathy by inhibiting ferroptosis via activating Nrf2/GPX4 axis. Phytomedicine 2023 119 154993 10.1016/j.phymed.2023.154993 37567006
    [Google Scholar]
  43. Yuan Y. Zhai Y. Chen J. Xu X. Wang H. Kaempferol Ameliorates Oxygen-Glucose Deprivation/Reoxygenation-Induced Neuronal Ferroptosis by Activating Nrf2/SLC7A11/GPX4 Axis. Biomolecules 2021 11 7 923 10.3390/biom11070923 34206421
    [Google Scholar]
  44. Liu H. Zhang T. Zhang W.Y. Huang S.R. Hu Y. Sun J. Rhein attenuates cerebral ischemia-reperfusion injury via inhibition of ferroptosis through NRF2/SLC7A11/GPX4 pathway. Exp. Neurol. 2023 369 114541 10.1016/j.expneurol.2023.114541 37714424
    [Google Scholar]
  45. Yang S. Wang L. Zeng Y. Wang Y. Pei T. Xie Z. Xiong Q. Wei H. Li W. Li J. Su Q. Wei D. Cheng W. Salidroside alleviates cognitive impairment by inhibiting ferroptosis via activation of the Nrf2/GPX4 axis in SAMP8 mice. Phytomedicine 2023 114 154762 10.1016/j.phymed.2023.154762 36965372
    [Google Scholar]
  46. Yang S. xie Z. Pei T. zeng Y. Xiong Q. Wei H. Wang Y. Cheng W. Salidroside attenuates neuronal ferroptosis by activating the Nrf2/HO1 signaling pathway in Aβ1-42-induced Alzheimer’s disease mice and glutamate-injured HT22 cells. Chin. Med. 2022 17 1 82 10.1186/s13020‑022‑00634‑3 35787281
    [Google Scholar]
  47. Kong L. Wang Y. Tong Z. Dai R. Yusuf A. Du L. Liu B. Huang Z. Hu L. Granulathiazole A protects 6-OHDA-induced Parkinson’s disease from ferroptosis via activating Nrf2/HO-1 pathway. Bioorg. Chem. 2024 147 107399 10.1016/j.bioorg.2024.107399 38678778
    [Google Scholar]
  48. Xie R. Zhao W. Lowe S. Bentley R. Hu G. Mei H. Jiang X. Sun C. Wu Y. Liu Y. Corrigendum to“Quercetin alleviates kainic acid-induced seizure by inhibiting the Nrf2-mediated ferroptosis pathway” [Free Radic. Biol. Med. 191 (2022) 212–226]. Free Radic. Biol. Med. 2022 193 Pt 1 80 10.1016/j.freeradbiomed.2022.10.275 36252463
    [Google Scholar]
  49. Wang J. Shi J. Xiao Y. Chen G. Yang C. Duan L. Zhao W. Wang Q. Fo-Shou-San Ameliorates Chronic Cerebral Hypoperfusion-Induced Cognitive Impairment in Mice by Regulating NRF2/HO-1 Pathway Against Ferroptosis. J. Integr. Neurosci. 2023 22 2 41 10.31083/j.jin2202041 36992577
    [Google Scholar]
  50. Dang R. Wang M. Li X. Wang H. Liu L. Wu Q. Zhao J. Ji P. Zhong L. Licinio J. Xie P. Edaravone ameliorates depressive and anxiety-like behaviors via Sirt1/Nrf2/HO-1/Gpx4 pathway. J. Neuroinflammation 2022 19 1 41 10.1186/s12974‑022‑02400‑6 35130906
    [Google Scholar]
  51. Seiler A. Schneider M. Förster H. Roth S. Wirth E.K. Culmsee C. Plesnila N. Kremmer E. Rådmark O. Wurst W. Bornkamm G.W. Schweizer U. Conrad M. Glutathione peroxidase 4 senses and translates oxidative stress into 12/15-lipoxygenase dependent- and AIF-mediated cell death. Cell Metab. 2008 8 3 237 248 10.1016/j.cmet.2008.07.005 18762024
    [Google Scholar]
  52. Wang F. Wang J. Shen Y. Li H. Rausch W.D. Huang X. Iron Dyshomeostasis and Ferroptosis: A New Alzheimer’s Disease Hypothesis? Front. Aging Neurosci. 2022 14 830569 10.3389/fnagi.2022.830569 35391749
    [Google Scholar]
  53. Baruah P. Moorthy H. Ramesh M. Padhi D. Govindaraju T. A natural polyphenol activates and enhances GPX4 to mitigate amyloid-β induced ferroptosis in Alzheimer’s disease. Chem. Sci. (Camb.) 2023 14 35 9427 9438 10.1039/D3SC02350H 37712018
    [Google Scholar]
  54. Liao W. Zhang R. Chen G. Zhu X. Wu W. Chen Z. Jiang C. Lin Z. Ma L. Yu H. Berberine synergises with ferroptosis inducer sensitizing NSCLC to ferroptosis in p53-dependent SLC7A11-GPX4 pathway. Biomed. Pharmacother. 2024 176 116832 10.1016/j.biopha.2024.116832 38850659
    [Google Scholar]
  55. Li C. Wu Z. Xue H. Gao Q. Zhang Y. Wang C. Zhao P. Ferroptosis contributes to hypoxic–ischemic brain injury in neonatal rats: Role of the SIRT1 /Nrf2/ GPx4 signaling pathway. CNS Neurosci. Ther. 2022 28 12 2268 2280 10.1111/cns.13973 36184790
    [Google Scholar]
  56. Kwon H. Lee E.H. Park S.Y. Park J.Y. Hong J.H. Kim E.K. Shin T.S. Kim Y.K. Han P.L. Lactobacillus-derived extracellular vesicles counteract Aβ42-induced abnormal transcriptional changes through the upregulation of MeCP2 and Sirt1 and improve Aβ pathology in Tg-APP/PS1 mice. Exp. Mol. Med. 2023 55 9 2067 2082 10.1038/s12276‑023‑01084‑z 37704750
    [Google Scholar]
  57. Tang H. Wen J. Qin T. Chen Y. Huang J. Yang Q. Jiang P. Wang L. Zhao Y. Yang Q. New insights into Sirt1: potential therapeutic targets for the treatment of cerebral ischemic stroke. Front. Cell. Neurosci. 2023 17 1228761 10.3389/fncel.2023.1228761 37622049
    [Google Scholar]
  58. Hassanein E.H.M. Saleh F.M. Ali F.E.M. Rashwan E.K. Atwa A.M. Abd El-Ghafar O.A.M. Neuroprotective effect of canagliflozin against cisplatin-induced cerebral cortex injury is mediated by regulation of HO-1/PPAR-γ, SIRT1/FOXO-3, JNK/AP-1, TLR4/iNOS, and Ang II/Ang 1–7 signals. Immunopharmacol. Immunotoxicol. 2023 45 3 304 316 10.1080/08923973.2022.2143371 36326099
    [Google Scholar]
  59. Zhao N. Zhu X. Xie L. Guan X. Tang L. Jiang G. Pang T. The Combination of Citicoline and Nicotinamide Mononucleotide Induces Neurite Outgrowth and Mitigates Vascular Cognitive Impairment via SIRT1/CREB Pathway. Cell. Mol. Neurobiol. 2023 43 8 4261 4277 10.1007/s10571‑023‑01416‑7 37812361
    [Google Scholar]
  60. Gu X. Xie Y. Cao Q. Hou Z. Zhang Y. Wang W. Fisetin alleviates cerebral ischemia/reperfusion injury by regulating Sirt1/Foxc1/Ubqln1 pathway-mediated proteostasis. Int. Immunopharmacol. 2024 130 111742 10.1016/j.intimp.2024.111742 38452414
    [Google Scholar]
  61. Ma J. Chen T. Wang R. Astragaloside IV ameliorates cognitive impairment and protects oligodendrocytes from antioxidative stress via regulation of the SIRT1/Nrf2 signaling pathway. Neurochem. Int. 2023 167 105535 10.1016/j.neuint.2023.105535 37209830
    [Google Scholar]
/content/journals/cnr/10.2174/0115672026348862241003042336
Loading
/content/journals/cnr/10.2174/0115672026348862241003042336
Loading

Data & Media loading...


  • Article Type:
    Research Article
Keywords: SIRT1 ; Aloe-emodin ; ferroptosis ; WDCI
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test