Advertisement

Tinospora cordifolia Suppresses Neuroinflammation in Parkinsonian Mouse Model

  • Hareram Birla
  • Sachchida Nand Rai
  • Saumitra Sen Singh
  • Walia Zahra
  • Arun Rawat
  • Neeraj Tiwari
  • Rakesh K. Singh
  • Abhishek Pathak
  • Surya Pratap SinghEmail author
Original Paper
  • 66 Downloads

Abstract

Parkinson’s disease (PD), a neurodegenerative central nervous system disorder, is characterised by progressive loss of nigrostriatal neurons in basal ganglia. Previous studies regarding PD have suggested the role of oxidative stress along with neuroinflammation in neurodegeneration. Accordingly, our study explore the anti-inflammatory activity of Tinospora cordifolia aqueous extract (TCAE) in 1-methyl-4-phenyl-1,2,3,6-tetra hydropyridine (MPTP)-intoxicated Parkinsonian mouse model. MPTP-intoxicated mice showed significant behavioral and biochemical abnormalities which were effectively reversed by TCAE. It is evident that TCAE inhibits the MPTP-intoxicated Nuclear factor-κB (NF-κB) activation and its associated pro-inflammatory cytokine tumor necrosis factor-α (TNF-α) from immunohistochemistry and Western blot analysis. In MPTP-intoxicated mice, microglial and astroglial-specific inflammatory markers, ionized calcium binding adaptor molecule 1 (Iba1) and glial fibrillary acidic protein (GFAP), respectively were increased while were significantly reduced in TCAE treatment. Expression of pro-inflammatory cytokine genes, TNF-α, Interleukin-12 (IL-12) and Interleukin-1β (IL-1β) were found to be upregulated in MPTP-intoxicated mice, whereas TCAE treatment restored their levels. Additionally, anti-inflammatory factor Interleukin-10 (IL-10) gene was found to be downregulated in MPTP-intoxicated mice which were significantly restored by TCAE treatment. Tyrosine hydroxylase (TH) expression was reduced in MPTP-intoxicated mice, while its expression was significantly increased in TCAE-treated group. Our result strongly suggests that T. cordifolia protects dopaminergic neurons by suppressing neuroinflammation in MPTP-induced Parkinsonian mouse model.

Keywords

Neuroprotection Parkinson’s disease Tinospora cordifolia Tyrosine hydroxylase Glial cells Neuroinflammation MPTP 

Notes

Acknowledgements

Authors HB, SNR, SSS, NT, and WZ were sincerely thankful to DBT, ICMR, ICMR, CSIR-UGC, UGC India for their respective fellowships. AKR is thankful to D. S. Kothari Post-Doctoral Fellowship, UGC, India. Authors are also thankful to the Head, Department of Biochemistry, B.H.U for providing the basic Departmental Facility and I.S.L.S, B.H.U for their central facility. The authors would also like to acknowledge Anand Prakash, Department of Zoology, B.H.U and Chandra Prakash I.S.L.S. for helping in fluorescence Imaging and Ashok Kumar Yadav, Lab attendant for his help in the animal care and other necessary assistance.

Funding

There is no external funding to carry out this research work.

Compliance with Ethical Standards

Conflict of interest

The authors declare that they have no competing interests.

Supplementary material

12017_2018_8521_MOESM1_ESM.tif (2.4 mb)
Supplementary Figure 1 (TIF 2501 KB)
12017_2018_8521_MOESM2_ESM.docx (13 kb)
Supplementary Table 2 (DOCX 12 KB)

References

  1. Arimoto, T., Choi, D.-Y., Lu, X., Liu, M., Nguyen, X. V., Zheng, N., et al. (2007). Interleukin-10 protects against inflammation-mediated degeneration of dopaminergic neurons in substantia nigra. Neurobiology of Aging, 28(6), 894–906.Google Scholar
  2. Blesa, J., Trigo-Damas, I., Quiroga-Varela, A., & Jackson-Lewis, V. R. (2015). Oxidative stress and Parkinson’s disease. Frontiers in Neuroanatomy, 9, 91.  https://doi.org/10.3389/fnana.2015.00091.Google Scholar
  3. Block, M., & Hong, J.-S. (2007). Chronic microglial activation and progressive dopaminergic neurotoxicity. Biochemical Society Transactions, 35, 1127–1132.Google Scholar
  4. Blum, D., Torch, S., Lambeng, N., Nissou, M.-F., Benabid, A.-L., Sadoul, R., et al. (2001). Molecular pathways involved in the neurotoxicity of 6-OHDA, dopamine and MPTP: Contribution to the apoptotic theory in Parkinson’s disease. Progress in Neurobiology, 65(2), 135–172.Google Scholar
  5. Celardo, I., Martins, L. M., & Gandhi, S. (2014). Unravelling mitochondrial pathways to Parkinson’s disease. British Journal of Pharmacology, 171(8), 1943–1957.Google Scholar
  6. Cheng, Y., He, G., Mu, X., Zhang, T., Li, X., Hu, J., et al. (2008). Neuroprotective effect of baicalein against MPTP neurotoxicity: Behavioral, biochemical and immunohistochemical profile. Neuroscience Letters, 441(1), 16–20.Google Scholar
  7. Dauer, W., & Przedborski, S. (2003). Parkinson’s disease: Mechanisms and models. Neuron, 39(6), 889–909.Google Scholar
  8. Duan, W., & Mattson, M. P. (1999). Dietary restriction and 2-deoxyglucose administration improve behavioral outcome and reduce degeneration of dopaminergic neurons in models of Parkinson’s disease. Journal of Neuroscience Research, 57(2), 195–206.Google Scholar
  9. Fiebich, B. L., Lieb, K., Engels, S., & Heinrich, M. (2002). Inhibition of LPS-induced p42/44 MAP kinase activation and iNOS/NO synthesis by parthenolide in rat primary microglial cells. Journal of Neuroimmunology, 132(1), 18–24.Google Scholar
  10. Frankola, A., Greig, K. H., Luo, N. W., & Tweedie, D. (2011). Targeting TNF-alpha to elucidate and ameliorate neuroinflammation in neurodegenerative diseases. CNS & Neurological Disorders-Drug Targets (Formerly Current Drug Targets-CNS & Neurological Disorders), 10(3), 391–403.Google Scholar
  11. Ghosh, A., Roy, A., Liu, X., Kordower, J. H., Mufson, E. J., Hartley, D. M., et al. (2007). Selective inhibition of NF-κB activation prevents dopaminergic neuronal loss in a mouse model of Parkinson’s disease. Proceedings of the National Academy of Sciences, 104(47), 18754–18759.Google Scholar
  12. Glass, C. K., Saijo, K., Winner, B., Marchetto, M. C., & Gage, F. H. (2010). Mechanisms underlying inflammation in neurodegeneration. Cell, 140(6), 918–934.Google Scholar
  13. Gorbatyuk, O. S., Li, S., Sullivan, L. F., Chen, W., Kondrikova, G., Manfredsson, F. P., et al. (2008). The phosphorylation state of Ser-129 in human α-synuclein determines neurodegeneration in a rat model of Parkinson disease. Proceedings of the National Academy of Sciences, 105(2), 763–768.Google Scholar
  14. Gupta, S. P., Patel, S., Yadav, S., Singh, A. K., Singh, S., & Singh, M. P. (2010). Involvement of nitric oxide in maneb-and paraquat-induced Parkinson’s disease phenotype in mouse: Is there any link with lipid peroxidation? Neurochemical Research, 35(8), 1206–1213.Google Scholar
  15. Haavik, J., & Toska, K. (1998). Tyrosine hydroxylase and Parkinson’s disease. Molecular neurobiology, 16(3), 285–309.Google Scholar
  16. Hirsch, E. C., Vyas, S., & Hunot, S. (2012). Neuroinflammation in Parkinson’s disease. Parkinsonism & Related Disorders, 18, S210–S212.Google Scholar
  17. Kalia, L. V., & Lang, A. E. (2015). Parkinson’s disease. The Lancet, 386(9996), 896–912.  https://doi.org/10.1016/s0140-6736(14)61393-3.Google Scholar
  18. Katzenschlager, R., Evans, A., Manson, A., Patsalos, P., Ratnaraj, N., Watt, H., et al. (2004). Mucuna pruriens in Parkinson’s disease: A double blind clinical and pharmacological study. Journal of Neurology, Neurosurgery & Psychiatry, 75(12), 1672–1677.Google Scholar
  19. Kosaraju, J., Chinni, S., Roy, P. D., Kannan, E., Antony, A. S., & Kumar, M. S. (2014). Neuroprotective effect of Tinospora cordifolia ethanol extract on 6-hydroxy dopamine induced Parkinsonism. Indian Journal of Pharmacology, 46(2), 176.Google Scholar
  20. Kumar, A., Ahmad, I., Shukla, S., Singh, B. K., Patel, D. K., Pandey, H. P., et al. (2010). Effect of zinc and paraquat co-exposure on neurodegeneration: Modulation of oxidative stress and expression of metallothioneins, toxicant responsive and transporter genes in rats. Free Radical Research, 44(8), 950–965.Google Scholar
  21. Manna, S., Bhattacharyya, D., Mandal, T., & Dey, S. (2006). Neuropharmacological effects of deltamethrin in rats. Journal of Veterinary Science, 7(2), 133–136.Google Scholar
  22. Matejuk, A., & Shamsuddin, A. (2010). IP6 in cancer therapy: Past, present and future. Current Cancer Therapy Reviews, 6(1), 1–12.Google Scholar
  23. Miquel, J. (2009). An update of the oxidation-inflammation theory of aging: The involvement of the immune system in oxi-inflamm-aging. Current Pharmaceutical Design, 15(26), 3003–3026.Google Scholar
  24. Mishra, R., & Kaur, G. (2013). Aqueous ethanolic extract of Tinospora cordifolia as a potential candidate for differentiation based therapy of glioblastomas. PLoS ONE, 8(10), e78764.Google Scholar
  25. Mishra, R., Manchanda, S., Gupta, M., Kaur, T., Saini, V., Sharma, A., et al. (2016). Tinospora cordifolia ameliorates anxiety-like behavior and improves cognitive functions in acute sleep deprived rats. Scientific Reports, 6, 25564.Google Scholar
  26. Mohanasundari, M., Srinivasan, M., Sethupathy, S., & Sabesan, M. (2006). Enhanced neuroprotective effect by combination of bromocriptine and Hypericum perforatum extract against MPTP-induced neurotoxicity in mice. Journal of the Neurological Sciences, 249(2), 140–144.Google Scholar
  27. Moron, M. S., Depierre, J. W., & Mannervik, B. (1979). Levels of glutathione, glutathione reductase and glutathione S-transferase activities in rat lung and liver. Biochimica et Biophysica Acta (BBA)-General Subjects, 582(1), 67–78.Google Scholar
  28. Nishikimi, M., Rao, N. A., & Yagi, K. (1972). The occurrence of superoxide anion in the reaction of reduced phenazine methosulfate and molecular oxygen. Biochemical and Biophysical Research Communications, 46(2), 849–854.Google Scholar
  29. Ohkawa, H., Ohishi, N., & Yagi, K. (1979). Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Analytical Biochemistry, 95(2), 351–358.Google Scholar
  30. Ojha, R. P., Rastogi, M., Devi, B. P., Agrawal, A., & Dubey, G. (2012). Neuroprotective effect of curcuminoids against inflammation-mediated dopaminergic neurodegeneration in the MPTP model of Parkinson’s disease. Journal of Neuroimmune Pharmacology, 7(3), 609–618.Google Scholar
  31. Olson, K. E., & Gendelman, H. E. (2016). Immunomodulation as a neuroprotective and therapeutic strategy for Parkinson’s disease. Current Opinion in Pharmacology, 26, 87–95.Google Scholar
  32. Peinnequin, A., Mouret, C., Birot, O., Alonso, A., Mathieu, J., Clarençon, D., et al. (2004). Rat pro-inflammatory cytokine and cytokine related mRNA quantification by real-time polymerase chain reaction using SYBR green. BMC Immunology, 5(1), 3.Google Scholar
  33. Pendse, V., Dadhich, A., Mathur, P., Bal, M., & Madan, B. (1977). Antiinflammatory, immunosuppressive and some related pharmacological actions of the water extract of Neem Giloe (Tinospora cordifolia): A preliminary report. Indian Journal of Pharmacology, 9(3), 221.Google Scholar
  34. Pigeolet, E., Corbisier, P., Houbion, A., Lambert, D., Michiels, C., Raes, M., et al. (1990). Glutathione peroxidase, superoxide dismutase, and catalase inactivation by peroxides and oxygen derived free radicals. Mechanisms of Ageing and Development, 51(3), 283–297.Google Scholar
  35. Pisa, M. (1988). Regional specialization of motor functions in the rat striatum: Implications for the treatment of parkinsonism. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 12(2), 217–224.Google Scholar
  36. Rai, S. N., Birla, H., Singh, S. S., Zahra, W., Patil, R. R., Jadhav, J. P., et al. (2017a). Mucuna pruriens protects against MPTP intoxicated neuroinflammation in Parkinson’s disease through NF-κB/pAKT signaling pathways. Frontiers in Aging Neuroscience, 9, 421.Google Scholar
  37. Rai, S. N., Birla, H., Zahra, W., Singh, S. S., & Singh, S. P. (2017b). Immunomodulation of Parkinson’s disease using Mucuna pruriens (Mp). Journal of Chemical Neuroanatomy, 85, 27–35.Google Scholar
  38. Rai, S. N., Yadav, S. K., Singh, D., & Singh, S. P. (2016). Ursolic acid attenuates oxidative stress in nigrostriatal tissue and improves neurobehavioral activity in MPTP-induced Parkinsonian mouse model. Journal of Chemical Neuroanatomy, 71, 41–49.Google Scholar
  39. Saijo, K., Winner, B., Carson, C. T., Collier, J. G., Boyer, L., Rosenfeld, M. G., et al. (2009). A Nurr1/CoREST transrepression pathway attenuates neurotoxic inflammation in activated microglia and astrocytes. Cell, 137(1), 47.Google Scholar
  40. Scapagnini, G., Butterfield, D. A., Colombrita, C., Sultana, R., Pascale, A., & Calabrese, V. (2004). Ethyl ferulate, a lipophilic polyphenol, induces HO-1 and protects rat neurons against oxidative stress. Antioxidants & Redox Signaling, 6(5), 811–818.Google Scholar
  41. Sengupta, M., Sharma, G. D., & Chakraborty, B. (2011). Effect of aqueous extract of Tinospora cordifolia on functions of peritoneal macrophages isolated from CCl 4 intoxicated male albino mice. BMC Complementary and Alternative Medicine, 11(1), 102.Google Scholar
  42. Singh, S., Singh, K., Patel, D. K., Singh, C., Nath, C., Singh, V. K., et al. (2009). The expression of CYP2D22, an ortholog of human CYP2D6, in mouse striatum and its modulation in 1-methyl 4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinson’s disease phenotype and nicotine-mediated neuroprotection. Rejuvenation Research, 12(3), 185–197.Google Scholar
  43. Singh, S. S., Rai, S. N., Birla, H., Zahra, W., Kumar, G., Gedda, M. R., et al. (2018). Effect of chlorogenic acid supplementation in MPTP-intoxicated mouse. Frontiers in pharmacology. 9, 757.Google Scholar
  44. Song, J.-X., Sze, S. C.-W., Ng, T.-B., Lee, C. K.-F., Leung, G. P., Shaw, P.-C., et al. (2012). Anti-Parkinsonian drug discovery from herbal medicines: What have we got from neurotoxic models? Journal of Ethnopharmacology, 139(3), 698–711.Google Scholar
  45. Subramaniam, S. R., & Chesselet, M.-F. (2013). Mitochondrial dysfunction and oxidative stress in Parkinson’s disease. Progress in Neurobiology, 106, 17–32.Google Scholar
  46. Sutachan, J. J., Casas, Z., Albarracin, S. L., Stab, B. R., Samudio, I., Gonzalez, J., et al. (2012). Cellular and molecular mechanisms of antioxidants in Parkinson’s disease. Nutritional Neuroscience, 15(3), 120–126.Google Scholar
  47. Teismann, P., & Schulz, J. B. (2004). Cellular pathology of Parkinson’s disease: Astrocytes, microglia and inflammation. Cell and Tissue Research, 318(1), 149–161.Google Scholar
  48. Upadhyay, A. K., Kumar, K., Kumar, A., & Mishra, H. S. (2010). Tinospora cordifolia (Willd.) Hook. f. and Thoms. (Guduchi)—validation of the Ayurvedic pharmacology through experimental and clinical studies. International Journal of Ayurveda Research, 1(2), 112–121.  https://doi.org/10.4103/0974-7788.64405.Google Scholar
  49. Wilms, H., Rosenstiel, P., Sievers, J., Deuschl, G., Zecca, L., & Lucius, R. (2003). Activation of microglia by human neuromelanin is NF-κB dependent and involves p38 mitogen-activated protein kinase: Implications for Parkinson’s disease. The FASEB Journal, 17(3), 500–502.Google Scholar
  50. Yadav, S. K., Prakash, J., Chouhan, S., & Singh, S. P. (2013). Mucuna pruriens seed extract reduces oxidative stress in nigrostriatal tissue and improves neurobehavioral activity in paraquat-induced Parkinsonian mouse model. Neurochemistry International, 62(8), 1039–1047.Google Scholar
  51. Yadav, S. K., Rai, S. N., & Singh, S. P. (2017). Mucuna pruriens reduces inducible nitric oxide synthase expression in Parkinsonian mice model. Journal of Chemical Neuroanatomy, 80, 1–10.Google Scholar
  52. Zhang, F., Shi, J.-S., Zhou, H., Wilson, B. C., Hong, J.-S., & Gao, H.-M. (2010). Resveratrol protects dopamine neurons against lipopolysaccharide-induced neurotoxicity through its anti-inflammatory actions. Molecular Pharmacology.  https://doi.org/10.1124/mol.110.064535 Google Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Hareram Birla
    • 1
  • Sachchida Nand Rai
    • 1
  • Saumitra Sen Singh
    • 1
  • Walia Zahra
    • 1
  • Arun Rawat
    • 1
  • Neeraj Tiwari
    • 1
  • Rakesh K. Singh
    • 1
  • Abhishek Pathak
    • 2
  • Surya Pratap Singh
    • 1
    Email author
  1. 1.Department of Biochemistry, Institute of ScienceBanaras Hindu UniversityVaranasiIndia
  2. 2.Department of Neurology, Institute of Medical ScienceBanaras Hindu UniversityVaranasiIndia

Personalised recommendations