DOI QR코드

DOI QR Code

The necessity of eliminating the interference of panaxatriol saponins to maximize the preventive effect of panaxadiol saponins against Parkinson's disease in rats

  • Yanwei Wang (College of Pharmaceutical Sciences, Zhejiang University) ;
  • Yufen Zhang (Anhui University of Chinese Medicine) ;
  • Yueyue Li (Anhui University of Chinese Medicine) ;
  • Zhizhen Zhang (Ocean College, Zhoushan Campus, Zhejiang University) ;
  • Xiao-Yuan Lian (College of Pharmaceutical Sciences, Zhejiang University)
  • Received : 2023.11.17
  • Accepted : 2024.05.10
  • Published : 2024.09.01

Abstract

Background: The effects of individual panaxadiol saponin and panaxatriol saponin on rodent models of Parkinson's disease (PD) have been recognized. However, it is not clear whether purified total ginsenosides as an entirety has effect against PD in rat model. This study compared the protective effects of a purified panaxadiol saponin fraction (PDSF), a purified panaxatriol saponin fraction (PTSF), and their mixtures against the rotenone (ROT)-induced PD in rats. Methods: Potential effects of PDSF, PTSF, and their mixtures against motor dysfunction and impairments of nigrostriatal dopaminergic neurons (DN), blood-brain barrier (BBB), cerebrovascular endothelial cells (CEC), and glial cells were measured in the models of ROT-induced PD rats and cell damage. Pro-inflammatory NF-kB p65 (p65) activation was localized in DN and other cells in the striatum. Results: PDSF and PTSF had a dose-dependent effect against motor dysfunction with a larger effective dose range for PDSF. PDSF protected CEC, glial cells, and DN in models of PD rats and cell damage, while PTSF had no such protections. Chronic ROT exposure potently activated p65 in CEC with enhanced pro-inflammatory and decreased anti-inflammatory factors and impaired BBB in the striatum, PDSF almost completely blocked the ROT-induced p65 activation and maintained both anti- and pro-inflammatory factors at normal levels and BBB integrity, but PTSF aggravated the p65 activation with impaired BBB. Furthermore, PTSF nullified all the effects of PDSF when they were co-administrated. Conclusion: PDSF had significant protective effect against the ROT-induced PD in rats by protecting CEC, glial cells, and DN, likely through inhibiting NF-κB p65 in CEC from triggering neuroinflammation, and also directly protecting glial cells and neurons against ROT-induced toxicity. PDSF has great potential for preventing and treating PD.

Keywords

Acknowledgement

This work was supported by the National Natural Science Foundation of China (No. 82074039) and the Zhejiang Provincial Natural Science Foundation (Key project, No. LZ20H280001). We appreciate the Core Facilities of Zhejiang University School of Medicine for providing facilities.

References

  1. Bloem BR, Okun MS, Klein C. Parkinson's disease. Lancet 2021;397:2284-303.
  2. Armstrong MJ, Okun MS. Diagnosis and treatment of Parkinson Disease: a review. JAMA 2020;323:548-60.
  3. Klingelhoefer L, Reichmann H. Pathogenesis of Parkinson disease-the gut-brain axis and environmental factors. Nat Rev Neurol 2015;11:625-36.
  4. Ascherio A, Schwarzschild MA. The epidemiology of Parkinson's disease: risk factors and prevention. Lancet Neurol 2016;15:1257-72.
  5. Radad K, Al-Shraim M, Al-Emam A, Wang F, Kranner B, Rausch WD, Moldzio R. Rotenone: from modelling to implication in Parkinson's disease. Folia Neuropathol 2019;57:317-26.
  6. Betarbet R, Sherer TB, MacKenzie G, Garcia-Osuna M, Panov AV, Greenamyre JT. Chronic systemic pesticide exposure reproduces features of Parkinson's disease. Nat Neurosci 2000;3:1301-6.
  7. Przedborski S. The two-century journey of Parkinson disease research. Nat Rev Neurosci 2017;18:251-9.
  8. Majlath Z, Toldi J, Fulop F, Vecsei L. Excitotoxic mechanisms in non-motor dysfunctions and levodopa- induced dyskinesia in Parkinson's disease: the role of the interaction between the dopaminergic and the kynurenine system. Curr Med Chem 2016;23:874-83.
  9. Marino BLB, de Souza LR, Sousa KPA, Ferreira JV, Padilha EC, da Silva C, Taft CA, Hage-Melim LIS. Parkinson's disease: a review from pathophysiology to treatment. Mini Rev Med Chem 2020;20:754-67.
  10. Rascol O, Fabbri M, Poewe W. Amantadine in the treatment of Parkinson's disease and other movement disorders. Lancet Neurol 2021;20:1048-56.
  11. Narasimhan M, Schwartz R, Halliday G. Parkinsonism and cerebrovascular disease. J Neurol Sci 2022;433:120011.
  12. Jacob MA, Cai M, Bergkamp M, Darweesh SKL, Gelissen LMY, Marques J, Norris DG, Duering M, Esselink RAJ, Tuladhar AM, et al. Cerebral small vessel disease progression increases risk of incident parkinsonism. Ann Neurol 2023;93:1130-41.
  13. Lee DY, Cho JG, Lee MK, Lee JW, Lee YH, Yang DC, Baek NI. Discrimination of Panax ginseng roots cultivated in different areas in Korea using HPLC-ELSD and principal component analysis. J Ginseng Res 2011;35:31-8.
  14. Liu J, Liu Y, Zhao L, Zhang ZH, Tang ZH. Profiling of ginsenosides in the two medicinal Panax herbs based on ultra-performance liquid chromatography-electrospray ionization-mass spectrometry. SpringerPlus 2016;5:1770.
  15. Kim HJ, Kim P, Shin CYA. Comprehensive review of the therapeutic and pharmacological effects of ginseng and ginsenosides in central nervous system. J Ginseng Res 2013;37:8-29.
  16. Lu J, Wang X, Wu A, Cao Y, Dai X, Liang Y, Li X. Ginsenosides in central nervous system diseases: pharmacological actions, mechanisms, and therapeutics. Phytother Res 2022;36:1523-44.
  17. Zhu G, Wang Y, Li J, Wang J. Chronic treatment with ginsenoside Rg1 promotes memory and hippocampal long-term potentiation in middle-aged mice. Neuron 2015;292:81-9.
  18. Jin Y, Peng J, Wang X, Zhang D, Wang T. Ameliorative effect of ginsenoside Rg1 on lipopolysaccharide-induced cognitive impairment: role of cholinergic system. Neurochem Res 2017;42:1299-307.
  19. Chen H, Shen J, Li H, Zheng X, Kang D, Xu Y, Chen C, Guo H, Xie L, Wang G, et al. Ginsenoside Rb1 exerts neuroprotective effects through regulation of Lactobacillus helveticus abundance and GABA(A) receptor expression. J Ginseng Res 2020;44:86-95.
  20. Chen WZ, Liu S, Chen FF, Zhou CJ, Yu J, Zhuang CL, Shen X, Chen BC, Yu Z. Prevention of postoperative fatigue syndrome in rat model by ginsenoside Rb1 via down-regulation of inflammation along the NMDA receptor pathway in the hippocampus. Biol Pharm Bull 2015;38:239-47.
  21. Gonzalez-Burgos E, Fernandez-Moriano C, Gomez-Serranillos MP. Potential neuroprotective activity of ginseng in Parkinson's disease: a review. J Neuroimmune Pharmacol 2015;10:14-29.
  22. Xie W, Wang X, Xiao T, Cao Y, Wu Y, Yang D, Zhang S. Protective effects and network analysis of ginsenoside Rb1 against cerebral ischemia injury: a pharmacological review. Front Pharmacol 2021;12:604811.
  23. Zhao A, Liu N, Yao M, Zhang Y, Yao Z, Feng Y, Liu J, Zhou GA. Review of neuroprotective effects and mechanisms of ginsenosides from Panax ginseng in treating ischemic stroke. Front Pharmacol 2022;13:946752.
  24. Lian XY, Zhang Z, Stringer JL. Protective effects of ginseng components in a rodent model of neurodegeneration. Ann Neurol 2005;57:642-8.
  25. Xu K, Zhang Y, Wang Y, Ling P, Xie X, Jiang C, Zhang Z, Lian XY. Ginseng Rb fraction protects glia, neurons and cognitive function in a rat model of neurodegeneration. PLoS One 2014;9:e101077.
  26. Lian, XY, Zhang, ZZ, Zhao, Y, Wu, YY, Zheng, WT, Wang, ZW. Active ginsenoside composition and its preparation method and application in the preparation of drugs for preventing and/or treating diseases or health products with health benefits. Chinse patent, CN116019819A 2023-04-28.
  27. Yun SP, Kam TI, Panicker N, Kim S, Oh Y, Park JS, Kwon SH, Park YJ, Karuppagounder SS, Park H, et al. Block of A1 astrocyte conversion by microglia is neuroprotective in models of Parkinson's disease. Nat Med 2018;24:931-8.
  28. Chotibut T, Meadows S, Kasanga EA, McInnis T, Cantu MA, Bishop C, Salvatore MF. Ceftriaxone reduces L-dopa-induced dyskinesia severity in 6-hydroxydopamine Parkinson's disease model. Mov Disord 2017;32:1547-56.
  29. Wiatrak B, Kubis-Kubiak A, Piwowar A, Barg E. PC12 cell Line: cell types, coating of culture vessels, differentiation and other culture conditions. Cells 2020;9:958.
  30. Bramanti V, Bronzi D, Tomassoni D, Li Volti G, Cannavo' G, Raciti G, Napoli M, Vanella A, Campisi A, Ientile R, et al. Effect of choline-containing phospholipids on transglutaminase activity in primary astroglial cell cultures. Clin Exp Hypertens 2008;30:798-807.
  31. Vichai V, Kirtikara K. Sulforhodamine B colorimetric assay for cytotoxicity screening. Nat Protoc 2006;1:1112-6.
  32. Halliday GM, Stevens CH. Glia: initiators and progressors of pathology in Parkinson's disease. Mov Disord 2011;26:6-17.
  33. Tremblay ME, Cookson MR, Civiero L. Glial phagocytic clearance in Parkinson's disease. Mol Neurodegener 2019;14:16.
  34. Kwon HS, Koh SH. Neuroinflammation in neurodegenerative disorders: the roles of microglia and astrocytes. Transl Neurodegener 2020;9:42.
  35. Wang Q, Zheng J, Pettersson S, Reynolds R, Tan EK. The link between neuroinflammation and the neurovascular unit in synucleinopathies. Sci Adv 2023;9:eabq1141.
  36. Belarbi K, Cuvelier E, Bonte MA, Desplanque M, Gressier B, Devos D, Chartier-Harlin MC. Glycosphingolipids and neuroinflammation in Parkinson's disease. Mol Neurodegener 2020;15:59.
  37. Iadecola C. The neurovascular unit coming of age: a journey through neurovascular coupling in health and disease. Neuron 2017;96:17-42.
  38. Lian XY, Zhang ZZ, Stringer JL. Anticonvulsant activity of ginseng on seizures induced by chemical convulsants. Epilepsia 2005;46:15-22.
  39. Lian XY, Zhang Z, Stringer JL. Anticonvulsant and neuroprotective effects of ginsenosides in rats. Epilepsy Res 2006;70:244-56.
  40. Liu Y, Yang H. Environmental toxins and alpha-synuclein in Parkinson's disease. Mol Neurobiol 2005;31:273-82.
  41. Pang SY, Ho PW, Liu HF, Leung CT, LiL Chang EES, Ramsden DB, Ho SL. The interplay of aging, genetics and environmental factors in the pathogenesis of Parkinson's disease. Transl Neurodegener 2019;8:23.
  42. van Horssen J, van Schaik P, Witte M. Inflammation and mitochondrial dysfunction: a vicious circle in neurodegenerative disorders? Neurosci Lett 2019;710:132931.
  43. La Vitola P, Balducci C, Baroni M, Artioli L, Santamaria G, Castiglioni M, Cerovic M, Colombo L, Caldinelli L, Pollegioni L, et al. Peripheral inflammation exacerbates α-synuclein toxicity and neuropathology in Parkinson's models. Neuropathol Appl Neurobiol 2021;47:43-60.
  44. Yu W, Li Y, Hu J, Wu J, Huang YA. Study on the pathogenesis of vascular cognitive impairment and dementia: the chronic cerebral hypoperfusion hypothesis. J Clin Med 2022;11:4742.
  45. de Rus Jacquet A, Alpaugh M, Denis HL, Tancredi JL, Boutin M, Decaestecker J, Beauparlant C, Herrmann L, Saint-Pierre M, Parent M, et al. The contribution of inflammatory astrocytes to BBB impairments in a brain-chip model of Parkinson's disease. Nat Commun 2023;14:3651.
  46. Sheng L, Stewart T, Yang D, Thorland E, Soltys D, Aro P, Khrisat T, Xie Z, Li N, Liu Z, et al. Erythrocytic α-synuclein contained in microvesicles regulates astrocytic glutamate homeostasis: a new perspective on Parkinson's disease pathogenesis. Acta Neuropathol Commun 2020;8:102.
  47. Xiong Y, Fu Y, Li Z, Zheng Y, Cui M, Zhang C, Huang XY, Jian Y, Chen BH. Laquinimod inhibits microglial activation, astrogliosis, BBB damage, and infarction and improves neurological damage after ischemic stroke. ACS Chem Neurosci 2023;14:1992-2007.
  48. Kummer BR, Diaz I, Wu X, Aaroe AE, Chen ML, Iadecola C, Kamel H, Navi BB. Associations between cerebrovascular risk factors and Parkinson disease. Ann Neurol 2019;86:572-81.