18Dec 2018

A STUDY OF THE EFFECTS OF DIFFERENT DOSES OF SILYMARIN ON ROTENONE-INDUCED RAT MODEL OF PARKINSONISM.

  • Department of medical physiology, Faculty of Medicine, Tanta University, Egypt.
  • Abstract
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Aim of the work: This work was performed to study the effect of different doses of silymarin on rotenone-induced Parkinsonism in rats. Methods:60 rats divided into 3 groups, I- control group (10 rats) received no treatment, II- Positive control group (10 rats) received intraperitoneal injection of silymarin (SM) at a dose of 200 mg/kg daily for 2 weeks, III- Rotenone-treated (RT) group (40 rats) received subcutaneous injection of rotenone at a dose of 1.5 mg/kg/48h for 12 days, then subjected to preliminary behavioral tests. Rats with parkinsonian features were divided into 4 groups (10 rats each), (IIIa- RT group), (IIIb- 100 mg/Kg SM-RT), (IIIc- 200 mg/Kg SM-RT) and (IIId- 300 mg/Kg SM-RT) which received 100, 200, 300 mg/kg intraperitonealsilymarin daily for 2 weeks. Results: Rotenone injection caused significant increase of descent latency time in bar test, brain tissue homogenate levels of malondialdehyde, nitrite/nitrate, tumor necrosis factor-alpha, caspase-3 and serum 8-hydroxy-2'-deoxyguanosine and significant decrease of forepaw stride length, brain tissue homogenate levels of catalase, brain-derived neurotrophic factor and dopamine when compared to control groups. Silymarin treatment reversed rotenone effect significantly in a dose-dependent manner. Conclusion: Silymarin can be used as a promising adjuvant therapy in treatment of Parkinsonism. Its neuroprotective effect is mediated by silymarin?s antioxidant, anti-inflammatory and anti-apoptotic effect which eventually enhanced dopamine level and the characteristic motor deficits of PD in a dose-dependent manner. Further clinical trials are required with special reference to the dose.


  1. Aebi, H., 1984. Catalase in vitro. Methods Enzymol, Volume 105, 121-126.
  2. Alam, Z., Jenner, A., Daniel, S.E., Lees, A.J., Cairns, N., Marsden, C.D. et al., 1997. Oxidative DNA damage in the parkinsonian brain: an apparent selective increase in 8-hydroxyguanine levels in substantia nigra. J Neurochem, 69(3):1196-1203.
  3. Anusha, C., Sumathi, T. & Joseph, L., 2017. Protective role of apigenin on rotenone induced rat model of Parkinson's disease: Suppression of neuroinflammation and oxidative stress mediated apoptosis. Chem Biol Interact, 269: 67-79.
  4. Ayala, A., Venero, J. & Cano, J., 2007. Mitochondrial toxins and neurodegenerative diseases. Front Biosci, 12:986-1007.
  5. Baker-Herman, T., Fuller, D.D., Bavis, R.W., Zabka, A.G., Golder, F.J., Doperalski, N.J. et al., 2004. BDNF is necessary and sufficient for spinal respiratory plasticity following intermittent hypoxia. Nature Neurosci, 7(1): 48-55.
  6. Baluchnejadmojarad, T., Roghani, M. & Mafakheri, M., 2010. Neuroprotective effect of Silymarin in 6-hydroxydopamine hemi-parkinsonian rat: involvemwnt of estrogen receptors and oxidative stress. Neuroscience Letters, 480:206-210.
  7. Betarbet, R., Sherer, T.B., MacKenzie, G., Garcia-Osuna, M., Panov, A.V. & Greenamyre, J.T., 2000. Chronic systemic pesticide exposure reproduces features of Parkinson?s disease. Nat Neurosci, 3(12):1301-1306.
  8. Block, M. & Hong, J., 2005. Microglia and inflammation-mediated neurodegeneration: multiple triggers with a common mechanism. Prog Neurobiol, 76:77-98.
  9. Brouckaert, P., Libert, C., Everaerdt, B., Takahashi, N., Cauwels, A. & Fiers, W., 1993. Tumor necrosis factor, its receptors and the connection with interleukin 1 and interleukin 6. immunobiol, 187(3-5):317-329.
  10. Cannon, J., Tapias, V., Na, H.M., Honick, A.S., Drolet, R.E. & Greenamyre, J.T., 2009. A highly reproducible rotenone model of Parkinson?s disease. Neurobiol Dis, 34(2):279-290.
  11. Cicchetti, F., Brownell, A.L., Williams, K., Chen, Y.I., Livni, E. & Isacson, O., 2002. Neuroinflammation of the nigrostriatal pathway during progressive 6-OHDA dopamine degeneration in rats monitored by immunohistochemistry and PET imaging. Eur J Neurosci, 15(6):991-998.
  12. Colton, C., Vitek, M.P., Wink, D.A., Xu, Q., Cantillana, V., Previti, M.L. et al., 2006. NO synthase 2 (NOS2) deletion promotes multiple pathologies in a mouse model of Alzheimer?s disease. Proc Natl Acad Sci USA, 103:12867-12872.
  13. Copped?, F. & Migliore, L., 2015. DNA damage in neurodegenerative diseases. Res, 776:84-97.
  14. Di Cesare Mannelli, L., Zanardelli, M., Failli, P. & Ghelardini, C., 2013. Oxaliplatin-induced oxidative stress in nervous system-derived cellular models: could it correlate with in vivo neuropathy? Free Radic Biol Med, 61:143-150.
  15. Dias, V., Junn, E. & Mouradian, M., 2013. The role of oxidative stress in Parkinson?s disease. J Parkinsons Dis, Volume 3, pp. 461-491.
  16. El-Horany, H., El-Latif, R., ElBatsh, M. & Emam, M., 2016. Ameliorative Effect of Quercetin on Neurochemical and Behavioral Deficits in Rotenone Rat Model of Parkinson's Disease: Modulating Autophagy (Quercetin on Experimental Parkinson's Disease). J Biochem Mol Toxicol., 30(7):360-369.
  17. Fathalla, A., Soliman, A., Hammdi, M. & Moustafa, A., 2016. Adenosine A2A receptor blockade prevents rotenone-induced Motor Impairment in a Rat Model of Parkinsonism. Front Behav Neurosci, 10:28-35.
  18. Haddadi, R., Eyvari Brooshghalan, S., Farajniya, S., Mohajjel Nayebi, A. & Sharifi, H., 2015. Short-Term Treatment with Silymarin Improved 6-OHDA-Induced Catalepsy and Motor Imbalance in Hemi-Parkisonian Rats. Adv Pharm Bull., 5(4):463-469.
  19. Haddadi, R., Mohajjel Nayebi, A. & Brooshghalan, S., 2013. Pre-treatment with silymarin reduces brain myeloperoxidase activity and inflammatory cytokines in 6-OHDA hemi-parkinsonian rats. Neurosci Lett, 555: 106-111.
  20. Haddadi, R., Nayebi, A.M., Farajniya, S., Brooshghalan, S.E. & Sharifi, H., 2014. Silymarin improved 6-OHDA-induced motor impairment in hemi-parkisonian rats: behavioral and molecular study. DARU Journal of Pharmaceutical Sciences, 22(1):38-49.
  21. Hegde, M., 2006. Studies on genomic DNA topology and stability in brain regions of Parkinson?s disease. Arch Biochem Biophys, 449(2):143-156.
  22. Huang, J.Y., Yuan, Y.H., Yan, J.Q., Wang, Y.N., Chu, S.F., Zhu, C.G. et al., 2016. 20C, a bibenzyl compound isolated from Gastrodia elata, protects PC12 cells against rotenone-induced apoptosis via activation of the Nrf2/ARE/HO-1 signaling pathway. Acta Pharmacol Sin, 37(6):731-740.
  23. Hwang, O., 2013. Role of oxidative stress in Parkinson?s disease. Neurobiol, 22:11-17.
  24. Jacobowitz, D. & Richardson, J., 1978. Method for the rapid determination of norepinephrine, dopamine, and serotonin in the same brain region. Pharmacol Biochem Behav, 8(5):515-519.
  25. Jangra, A., Kasbe, P., Pandey, S.N., Dwivedi, S., Gurjar, S.S., Kwatra, M. et al., 2015. Hesperidin and Silibinin Ameliorate Aluminum-Induced Neurotoxicity: Modulation of Antioxidants and Inflammatory Cytokines Level in Mice Hippocampus. Biol Trace Elem Res, 168(2):462-471.
  26. Johnson, V., He, Q., Osuchowski, M. & Sharma, R., 2003. Physiological responses of a natural antioxidant flavonoid mixture, silymarin, in BALB/c mice: III. Silymarin inhibits T-lymphocyte function at low doses but stimulates inflammatory processes at high doses. Planta Med, 69(1):44-49.
  27. Jung, U., Jeon, M., Choi, M. & Kim, S., 2014. Silibinin Attenuates MPP1-Induced Neurotoxicity in the Substantia Nigra In Vivo. J Med Food, 17(5):599-605.
  28. Lee, Y., Park, H., Chun, H. & Lee, J., 2015. Silibinin Prevents Dopaminergic Neuronal Loss in a Mouse Model of Parkinson?s Disease Via Mitochondrial Stabilization. J Neurosci Res. 93(5):755-765.
  29. Lu, P., Mamiya, T., Lu, L., Mouri, A., Niwa, M., Kim, H.C. et al., 2010. Silibinin attenuates cognitive deficits and decreases of dopamine and serotonin induced by repeated methamphetamine treatment. Behav Brain Res, 207:387-393.
  30. Malekinejad, H., Rahmani, F., Valivande-Azar, S., Taheri-Broujerdi, M. & Bazargani-Gilani, B., 2012. Long-term administration of Silymarin augments proinflammatory mediators in the hippocampus of rats: evidence for antioxidant and pro-oxidant effects. Hum Exp Toxicol., 31(9):921-930.
  31. Malekinejad, H., Rahmani, F., Valivande-Azar, S., Taheri-Broujerdi, M. & Bazargani-Gilani, B., 2012. Long-term administration of Silymarin augments proinflammatory mediators in the hippocampus of rats: evidence for antioxidant and pro-oxidant effects. Hum Exp Toxicol., 31(9):921-930.
  32. Manna, S., Mukhopadhyay, A., Van, N. & Aggarwal, B., 1999. Silymarin suppresses TNF-induced activation of NF-kappa B, c-Jun N-terminal kinase, and apoptosis. J Immunol, 163(12): 6800-6809.
  33. Marella, M., Seo, B.B., Nakamaru-Ogiso, E., Greenamyre, J.T., Matsuno-Yagi, A. & Yagi, T.l., 2008. Protection by the NDI1 gene against neurodegeneration in a rotenone rat model of Parkinson?s disease. PLoS One, 3(1):1433-1439.
  34. Montgomery, H. & Dymock, J., 1961. Colorimetric determination of nitric oxide. In Analyst, 86:414-416.
  35. M?ller, T. & Kohlhepp, W., 2016. Hypomethylation in Parkinson?s disease: an epigenetic drug effect? Mov Disord, 31(4):605?607.
  36. M?ller, T. & M?hr, J.D., 2018. Long-term management of Parkinson?s disease using levodopa combinations. Expert Opin on Pharmacother, 19(9):1003-1011.
  37. Nencini, C., Giorgi, G. & Micheli, I., 2007. Protective effect of silymarin on oxidative stress in rat brains. Phytomedicine, 14:129-135.
  38. Ohkawa, H., Ohishi, N. & Yagi, K., 1979. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem, 95(2)351-358.
  39. Perez, H.J., Carrillo, S.C., Garcia, E., Ruiz-Mar, G., Perez-Tamayo, R. & Chavarria, A., 2014. Neuroprotective effect of silymarin in an MPTP mouse model of Parkinson?s disease. Toxicology, 319:38-43.
  40. Plang?r, I., Z?dori, D., Szal?rdy, L., V?csei, L. & Kliv?nyi, P., 2013. Assessment of the role of multidrug resistance-associated proteins in MPTP neurotoxicity in mice. Ideggyogy Sz, 66(11-12):407-414.
  41. Porter, A. & Janicke, R., 1999. Emerging role of caspase-3 in apoptosis. Cell Death Differ, 6(2):99-104.
  42. Rangel-L?pez, A., Paniagua-Medina, M.E., Urb?n-Reyes, M., Cortes-Arredondo, M., Alvarez-Aguilar, C., L?pez-Meza, J. et al., 2013. Genetic damage in patients with chronic kidney disease, peritoneal dialysis and haemodialysis: a comparative study. Mutagenesis, 28(2): 219-225.
  43. Robert, C., Wilson, C.S., Lipton, R.B. & Arreto C.D., 2018. Parkinson?s disease: Evolution of the scientific literature from 1983 to 2017 by countries and journals. Parkinsonism Relat Disord, 8020(18):30495-30504.
  44. Samson F., Colip F. & Patterson J. (1957). Procedure for the Use of Sodium Pentobarbital (Nembutal?) Anesthesia in Classroom Experiments with Rats. Transactions of the Kansas Academy of Science, (1903), 425-428.
  45. Saravanan, K., Sindhu, K. & Mohanakumar, K., 2005. Acute intranigral infusion of rotenone in rats causes progressive biochemical lesions in the striatum similar to Parkinson's disease. Brain Res, 1049(2):147-155.
  46. Serrano-Garc?a, N., Fern?ndez-Valverde, F., Luis-Garcia, E. R., Granados-Rojas, L., Ju?rez-Zepeda, T. E., Orozco-Su?rez, S. A. et al., 2018. Docosahexaenoic acid protection in a rotenone induced Parkinson?s model: Prevention of tubulin and synaptophysin loss, but no association with mitochondrial function. Neurochem Int, 121:26-37.
  47. Siddiqui, M.A., Kashyap, M.P., Khanna, V.K., Yadav, S., Al-Khedhairy, A.A., Musarrat, J. et al., 2010. Association of dopamine DA-D2 receptor in rotenone-induced cytotoxicity in PC12 cells. Toxicol Ind Health, 26(8):533-542.
  48. Soliman, A., Fathalla, A. & Moustafa, A., 2016. Dose-dependent neuroprotective effect of caffeine on a rotenone-induced rat model of parkinsonism: A histological study. Neurosci Lett, 3940(16):30279-30288.
  49. Song, X., Zhou, B., Zhang, P., Lei, D., Wang, Y., Yao, G. et al., 2016. Protective Effect of Silibinin on Learning and Memory Impairment in LPS-Treated Rats via ROS-BDNF-TrkB Pathway. Neurochem Res, 41(7):1662-72.
  50. Taylor, T., Greene, J. & Miller, G., 2010. Behaviouralphenotyping of mouse models of Parkinson?s disease. Behav Brain Res, 211(1):1-10.
  51. Ullah, H. & Khan, H., 2018. Anti-Parkinson?Potential of?Silymarin: Mechanistic Insight and Therapeutic Standing.Front Pharmacol., 9:422-4329.
  52. Vivekanandan, L., Sheik, H., Singaravel, S. & Thangavel, S., 2018. Ameliorative effect of silymarin against linezolid-induced hepatotoxicity in methicillin-resistant Staphylococcus aureus (MRSA) infected Wistar rats. Biomed Pharmacother, 108:1303?1312.
  53. Wichmann, T., Bergman, H. & DeLong, M. R., 2018. Basal ganglia, movement disorders and deep brain stimulation: advances made through non-human primate research. J Neural Transm. 125(3):419-430.
  54. Xiong, N., Huang, J., Zhang, Z., Zhang, Z., Xiong, J., Liu, X. et al., 2009. Stereotaxical Infusion of Rotenone: A Reliable Rodent Model for Parkinson?s Disease. PLoS ONE, 4(11):e7878.
  55. Yu, H., Wu, F., Lin, S. & Shen, L., 2008. Recombinant arginine dei- minase reduces inducible nitric oxide synthase iNOS-mediated neurotoxicity in a coculture of neurons and microglia. J Neurosci Res, 86:2963-2972.
  56. Zelko, I., Mariani, T. & Folz, R., 2002. Superoxide dismutase multigene family: a comparison of the CuZn-SOD (SOD1), Mn-SOD (SOD2), and EC-SOD (SOD3) gene structures, evolution, and expression. Free Radic Biol Med, 33(3):337-349.
  57. Zhang, J., Perry, G., Smith, M.A., Robertson, D., Olson, S.J., Graham, D.G. et al., 1999. Parkinson?s disease is associated with oxidative damage to cytoplasmic DNA and RNA in substantia nigra neurons. Am J Pathol, 154(5):1423?1429.

[Yasmeen Mohamed El-Harty, Rizk Mahmoud El-Khouly, Hala Fouad El-Baradey and Ahmed El-Sayed Abdelfattah. (2018); A STUDY OF THE EFFECTS OF DIFFERENT DOSES OF SILYMARIN ON ROTENONE-INDUCED RAT MODEL OF PARKINSONISM. Int. J. of Adv. Res. 6 (Dec). 925-937] (ISSN 2320-5407). www.journalijar.com


Yasmeen Mohamed El-Harty
Department of medical physiology, Faculty of Medicine, Tanta University, Egypt

DOI:


Article DOI: 10.21474/IJAR01/8218      
DOI URL: https://dx.doi.org/10.21474/IJAR01/8218