Skip to main content
SpringerLink
Log in

Naringin Exhibits Neuroprotection Against Rotenone-Induced Neurotoxicity in Experimental Rodents

  • Original Paper
  • Published:
NeuroMolecular Medicine Aims and scope Submit manuscript

Abstract

Parkinson’s disease (PD) is a neurodegenerative disease that is accompanied with the loss of dopaminergic neurons in the substantia nigra pars compacta which subsequently leads to a reduction in the dopamine level in the striatum. The flavonoids are gaining critical attention in the management of PD due to the toxic effects of the synthetic drugs. Naringin, a potent flavonoid, exerts neuroprotective activity against experimental animal models of PD. It also exhibits protective activity against rotenone-induced neurotoxicity in cell line studies. Therefore, the present study was designed to evaluate the therapeutic potential of naringin against rotenone-induced animal model of PD. The rotenone was injected through intracerebroventricular route into substantia nigra pars compacta (SNpc) to induce PD-like manifestations in the male rats. The behavioral deficits of the animals due to dopaminergic toxicity were evaluated in actophotometer, OFT, bar catalepsy, narrow beam walk, rota-rod, grip strength and foot print analysis. Naringin-attenuated rotenone-induced behavioral abnormalities in the experimental rats. Further, naringin reduced the rotenone-induced dopaminergic toxicity in striatum and SNpc the animals. At the sub-cellular level, naringin attenuated the rotenone-induced decrease in the mitochondrial function, integrity and bioenergetics in the SNpc of the animals. Furthermore, naringin reduced the rotenone-induced mitochondria-dependent apoptosis in the rat SNpc. However, Trigonelline significantly abolished the therapeutic effects of naringin on behavioral, biochemical and molecular observations in rotenone-induced PD-like animals. These observations indicate that naringin may exert neuroprotective activity against rotenone-induced toxicity in the animals possibly through Nrf2-mediated pathway. Thus, it can be presumed that naringin could be an alternative option in the management of PD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10

Similar content being viewed by others

References

  • Anusha, C., Sumathi, T., & Joseph, L. D. (2017). Protective role of apigenin on rotenone induced rat model of Parkinson's disease: Suppression of neuroinflammation and oxidative stress mediated apoptosis. Chemico-Biological Interactions,269, 67–79.

    CAS  PubMed  Google Scholar 

  • Bradford, M. M. (1976). A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Analytical Biochemistry,72, 248–254.

    CAS  PubMed  Google Scholar 

  • Burke, R. E., & O’Malley, K. (2013). Axon degeneration in Parkinson’s disease. Experimental Neurology,246, 72–83.

    CAS  PubMed  Google Scholar 

  • Burton, N. C., Kensler, T. W., & Guilarte, T. R. (2006). In vivo modulation of the Parkinsonian phenotype by Nrf2. Neurotoxicology,27(6), 1094–1100.

    CAS  PubMed  Google Scholar 

  • Cadenas, S., Rojas, C., Perez-Campo, R., Lopez-Torres, M., & Barja, G. (1995). Vitamin E protects guinea pig liver from lipid peroxidation without depressing levels of antioxidants. International Journal of Biochemistry & Cell Biology,27, 1175–1181.

    CAS  Google Scholar 

  • Camara, A. K., Lesnefsky, E. J., & Stowe, D. F. (2010). Potential therapeutic benefits of strategies directed to mitochondria. Antioxidants & Redox Signal,13(3), 279–347.

    CAS  Google Scholar 

  • Chance, B., & Williams, G. R. (1956). Respiratory enzymes in oxidative phosphorylation.VI. The effects of adenosine diphosphate on azide-treated mitochondria. The Journal of Biological Chemistry,221(1), 477–490.

    CAS  PubMed  Google Scholar 

  • Choi, H. J., Lee, S. Y., Cho, Y., No, H., Kim, S. W., & Hwang, O. (2006). Tetrahydrobiopterin causes mitochondrial dysfunction in dopaminergic cells: Implications for Parkinson's disease. Neurochemistry Inernational,48(4), 255–262.

    CAS  Google Scholar 

  • Darbinyan, L. V., Hambardzumyan, L. E., Simonyan, K. V., Chavushyan, V. A., Manukyan, L. P., Badalyan, S. A., et al. (2017). Protective effects of curcumin against rotenone-induced rat model of Parkinson’s disease: In vivo electrophysiological and behavioral study. Metabolic Brain Disease,32(6), 1791–1803.

    CAS  PubMed  Google Scholar 

  • Deacon, R. M., Koros, E., Bornemann, K. D., & Rawlins, J. N. (2009). Aged Tg2576 mice are impaired on social memory and open field habituation tests. Behavioural Brain Research,197(2), 466–468.

    CAS  PubMed  Google Scholar 

  • Dexter, D. T., Sian, J., Rose, S., Hindmarsh, J. G., Mann, V. M., Cooper, J. M., et al. (1994). Indices of oxidative stress and mitochondrial function in individuals with incidental Lewy body disease. Annals of Neurology,35(1), 38–44.

    CAS  PubMed  Google Scholar 

  • Diederich, N. J., Moore, C. G., Leurgans, S. E., Chmura, T. A., & Goetz, C. G. (2003). Parkinson disease with old-age onset: A comparative study with subjects with middle-age onset. Archives of Neurology,60(4), 529–533.

    PubMed  Google Scholar 

  • Ferro, M. M., Bellissimo, M. I., Anselmo-Franci, J. A., Angellucci, M. E., Canteras, N. S., & Da Cunha, C. (2005). Comparison of bilaterally 6-OHDA-and MPTP-lesioned rats as models of the early phase of Parkinson's disease: histological, neurochemical, motor and memory alterations. Journal of Neuroscience Methods,148(1), 78–87.

    CAS  PubMed  Google Scholar 

  • Fu, M. H., Wu, C. W., Lee, Y. C., Hung, C. Y., Chen, I. C., & Wu, K. L. (2018). Nrf2 activation attenuates the early suppression of mitochondrial respiration due to the α-synuclein overexpression. Biomedical Journal,41(3), 169–183.

    PubMed  PubMed Central  Google Scholar 

  • Garabadu, D., Shah, A., Ahmad, A., Joshi, V. B., Saxena, B., Palit, G., et al. (2011). Eugenol as an anti-stress agent: modulation of hypothalamic–pituitary–adrenal axis and brain monoaminergic systems in a rat model of stress. Stress,14(2), 145–155.

    CAS  PubMed  Google Scholar 

  • Geibl, F. F., Henrich, M. T., & Oertel, W. H. (2019). Mesencephalic and extramesencephalic dopaminergic systems in Parkinson’s disease. Journal of Neural Transmission (Vienna, Austria: 1996),126(4), 377–396.

    CAS  Google Scholar 

  • Golechha, M., Chaudhry, U., Bhatia, J., Saluja, D., & Arya, D. S. (2011). Naringin protects against kainic acid-induced status epilepticus in rats: evidence for an antioxidant, anti-inflammatory and neuroprotective intervention. Biological & Pharmaceutical Bulletin,34(3), 360–365.

    CAS  Google Scholar 

  • Gopinath, K., & Sudhandiran, G. (2012). Naringin modulates oxidative stress and inflammation in 3-nitropropionic acid-induced neurodegeneration through the activation of nuclear factor-erythroid 2-related factor-2 signalling pathway. Neuroscience,227, 134–143.

    CAS  PubMed  Google Scholar 

  • Gopinath, K., Prakash, D., & Sudhandiran, G. (2011). Neuroprotective effect of naringin, a dietary flavonoid against 3-nitropropionic acid-induced neuronal apoptosis. Neurochemistry Inernatinal,59(7), 1066–1073.

    CAS  Google Scholar 

  • Griffiths, D. E., & Houghton, R. L. (1974). Studies on energy-linked reactions: Modified mitochondrial ATPase of oligomycin-resistant mutants of Saccharomyces cerevisiae. European Journal of Biochemistry,46(1), 157–167.

    CAS  PubMed  Google Scholar 

  • Hall, C. S. (1934). Emotional behavior in the rat. I. Defecation and urination as measures of individual differences in emotionality. Journal of Comparative Psychology,18(3), 385–403.

    Google Scholar 

  • Henderson, J. M., Stanic, D., Tomas, D., Patch, J., Horne, M. K., Bourke, D., et al. (2005). Postural changes after lesions of the substantia nigra pars reticulata in hemiparkinsonian monkeys. Behavioural Brain Research,160(2), 267–276.

    PubMed  Google Scholar 

  • Huang, S. G. (2002). Development of a high throughput screening assay for mitochondrial membrane potential in living cells. Journal of Biomolecular Screening,7(4), 383–389.

    CAS  PubMed  Google Scholar 

  • Huang, H., Wu, K., You, Q., Huang, R., & Li, S. (2013). Naringin inhibits high glucose-induced cardiomyocyte apoptosis by attenuating mitochondrial dysfunction and modulating the activation of the p38 signaling pathway. International Journal of Molecular Medicine,32(2), 396–402.

    CAS  PubMed  Google Scholar 

  • Jagetia, G. C., & Reddy, T. K. (2002). The grapefruit flavanone naringin protects against the radiation-induced genomic instability in the mice bone marrow: A micronucleus study. Mutation Research,519(1–2), 37–48.

    CAS  PubMed  Google Scholar 

  • Jakel, R. J., Townsend, J. A., Kraft, A. D., & Johnson, J. A. (2007). Nrf2-mediated protection against 6-hydroxydopamine. Brain Research,1144, 192–201.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Jung, U. J., & Kim, S. R. (2014). Effects of naringin, a flavanone glycoside in grapefruits and citrus fruits, on the nigrostriatal dopaminergic projection in the adult brain. Neural Regeneration Research,9(16), 1514–1517.

    PubMed  PubMed Central  Google Scholar 

  • Kamboj, S. S., Kumar, V., Kamboj, A., & Sandhir, R. (2008). Mitochondrial oxidative stress and dysfunction in rat brain induced by carbofuran exposure. Cellular & Molecular Neurobiology,28(7), 961–969.

    CAS  Google Scholar 

  • Kim, C., Speisky, M. B., & Kharouba, S. N. (1987). Rapid and sensitive method for measuring norepinephrine, dopamine, 5-hydroxytryptamine and their major metabolites in rat brain by high-performance liquid chromatography. Differential effect of probenecid, haloperidol and yohimbine on the concentrations of biogenic amines and metabolites in various regions of rat brain. Journal of Chromatography,386, 25–35.

    CAS  PubMed  Google Scholar 

  • Kim, H. J., Song, J. Y., Park, H. J., Park, H. K., Yun, D. H., & Chung, J. H. (2009). Naringin protects against rotenone-induced apoptosis in human neuroblastoma SH-SY5Y cells. The Korean Journal of Physiology and Pharmacology,13(4), 281–285.

    CAS  PubMed  Google Scholar 

  • Kim, H. D., Jeong, K. H., Jung, U. J., & Kim, S. R. (2016). Naringin treatment induces neuroprotective effects in a mouse model of Parkinson's disease in vivo, but not enough to restore the lesioned dopaminergic system. The Journal of Nutritional Biochemistry,28, 140–146.

    CAS  PubMed  Google Scholar 

  • Klapdor, K., Dulfer, B. G., Hammann, A., & Van der Staay, F. J. (1997). A low-cost method to analyse footprint patterns. Journal of Neuroscience Methods,75, 49–54.

    CAS  PubMed  Google Scholar 

  • Leem, E., Nam, J. H., Jeon, M. T., Shin, W. H., Won, S. Y., Park, S. J., et al. (2014). Naringin protects the nigrostriatal dopaminergic projection through induction of GDNF in a neurotoxin model of Parkinson's disease. The Journal of Nutritional Biochemistry,25(7), 801–806.

    CAS  PubMed  Google Scholar 

  • Leung, K. W., Yung, K. K., Mak, N. K., Chan, Y. S., Fan, T. P., & Wong, R. N. (2007). Neuroprotective effects of ginsenoside-Rg1 in primary nigral neurons against rotenone toxicity. Neuropharmacology,52(3), 827–835.

    CAS  PubMed  Google Scholar 

  • Liu, D., Xiao, B., Han, F., Wang, E., & Shi, Y. (2012). Single-prolonged stress induces apoptosis in dorsal raphe nucleus in the rat model of post-traumatic stress disorder. BMC Psychiatry,12, 211.

    PubMed  PubMed Central  Google Scholar 

  • Lowry, O. H., Rosebrough, N. J., Farr, A. L., & Randall, R. J. (1951). Protein measurement with the Folin phenol reagent. The Journal of Biological Chemistry,193(1), 265–275.

    CAS  PubMed  Google Scholar 

  • Madiha, S., Tabassum, S., Batool, Z., Liaquat, L., Sadir, S., Shahzad, S., et al. (2017). Assessment of gait dynamics in rotenone-induced rat model of Parkinson's disease by footprint method. Pakistan Journal of Pharmaceutical Sciences,30(3(Suppl.)), 943–948.

    CAS  PubMed  Google Scholar 

  • Medeiros-Linard, C. F., Andrade-da-Costa, B. L. D. S., Augusto, R. L., Sereniki, A., Trevisan, M. T. S., Perreira, R. C. R., et al. (2018). Anacardic acids from cashew nuts prevent behavioral changes and oxidative stress induced by rotenone in a rat model of Parkinson’s disease. Neurotoxicity Research,34(2), 250–262.

    CAS  PubMed  Google Scholar 

  • Middleton, E., Kandaswami, C., & Theoharides, T. C. (2000). The effects of plant flavonoids on mammalian cells: Implications for inflammation, heart disease, and cancer. Pharmacological Reviews,52(4), 673–751.

    CAS  PubMed  Google Scholar 

  • Moran, P. M., Higgins, L. S., Cordell, B., & Moser, P. C. (1995). Age-related learning deficits in transgenic mice expressing the 751-amino acid isoform of human beta-amyloid precursor protein. Proceedings of the National Academy of Sciences of the United States of America,92(12), 5341–5345.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Nakhate, K. T., Bharne, A. P., Verma, V. S., Aru, D. N., & Kokare, D. M. (2018). Plumbagin ameliorates memory dysfunction in streptozotocin induced Alzheimer’s disease via activation of Nrf2/ARE pathway and inhibition of β-secretase. Biomedicine & Pharmacothererapy,101, 379–390.

    CAS  Google Scholar 

  • Olanow, C. W., Perl, D. P., DeMartino, G. N., & McNaught, K. S. (2004). Lewy-body formation is an aggresome-related process: A hypothesis. The Lancet. Neurology,3(8), 496–503.

    PubMed  Google Scholar 

  • Old, S. L., & Johnson, M. A. (1989). Methods of microphotometric assay of succinate dehydrogenase and cytochrome c oxidase activities for use on human skeletal muscle. The Histochemical Journal,21(9–10), 545–555.

    CAS  PubMed  Google Scholar 

  • Pari, L., & Amudha, K. (2011). Hepatoprotective role of naringin on nickel-induced toxicity in male Wistar rats. European Journal of Pharmacology,650(1), 364–370.

    CAS  PubMed  Google Scholar 

  • Paxinos, G., & Watson, C. (1998). The rat brain in stereotaxic coordinates (p. 4). San Diego. p: Acadamic Press.

    Google Scholar 

  • Pedersen, P. L., Greenawalt, J. W., Reynafarje, B., Hullihen, J., Decker, G. L., Soper, J. W., et al. (1978). Preparation and characterization of mitochondria and sub-mitochondrial particles of rat liver-derived tissues. Methods in Cell Biology,20, 411–481.

    CAS  PubMed  Google Scholar 

  • Prajapati, S. K., Garabadu, D., & Krishnamurthy, S. (2017). Coenzyme Q10 prevents mitochondrial dysfunction and facilitates pharmacological activity of atorvastatin in 6-OHDA induced dopaminergic toxicity in rats. Neurotoxicity Research,31(4), 478–492.

    PubMed  Google Scholar 

  • Reddy, D. S., & Kulkarni, S. K. (1998). Possible role of nitric oxide in the nootropic and antiamnesic effects of neurosteroids on aging-and dizocilpine-induced learning impairment. Brain Research,799(2), 215–229.

    CAS  PubMed  Google Scholar 

  • Requejo-Aguilar, R., & Bolanos, J. P. (2016). Mitochondrial control of cell bioenergetics in Parkinson’s disease. Free Radical Biology & Medicine,100, 123–137.

    CAS  Google Scholar 

  • Rojo, A. I., Innamorato, N. G., Martín-Moreno, A. M., De Ceballos, M. L., Yamamoto, M., & Cuadrado, A. (2010). Nrf2 regulates microglial dynamics and neuroinflammation in experimental Parkinson's disease. Glia,58(5), 588–598.

    PubMed  Google Scholar 

  • Rozas, G., Guerra, M. J., & Labandeira-Garcıa, J. L. (1997). An automated rotarod method for quantitative drug-free evaluation of overall motor deficits in rat models of parkinsonism. Brain Research. Brain Research Protocols,2(1), 75–84.

    CAS  PubMed  Google Scholar 

  • Savitt, J. M., Dawson, V. L., & Dawson, T. M. (2006). Diagnosis and treatment of Parkinson disease: Molecules to medicine. The Journal of Clinical Investigation,116(7), 1744–1754.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Schapira, A. H., Gu, M., Taanman, J. W., Tabrizi, S. J., Seaton, T., Cleeter, M., et al. (1998). Mitochondria in the etiology and pathogenesis of Parkinson's disease. Annals of Neurology,44(3 Suppl 1), S89–98.

    CAS  PubMed  Google Scholar 

  • Schulz, D., Mirrione, M. M., & Henn, F. A. (2010). Cognitive aspects of congenital learned helplessness and its reversal by the monoamine oxidase (MAO)-B inhibitor deprenyl. Neurobiology of Learning and Memory,93(2), 291–301.

    CAS  PubMed  Google Scholar 

  • Shapiro, B. L., Feigal, R. J., & Lam, L. F. (1979). Mitrochondrial NADH dehydrogenase in cystic fibrosis. Proceeding of the National Academy of sciences of the United States of America,76(6), 2979–2983.

    CAS  Google Scholar 

  • Singh, D., Chander, V., & Chopra, K. (2004). Protective effect of naringin, a bioflavonoid on glycerol-induced acute renal failure in rat kidney. Toxicology,201(1–3), 143–151.

    CAS  PubMed  Google Scholar 

  • Storrie, B., & Madden, E. A. (1990). Isolation of subcellular organelles. Methods of Enzymology,182, 203–225.

    CAS  Google Scholar 

  • Subaraja, M., & Vanisree, A. J. (2016). Rotenone causing dysfunctional mitochondria and lysosomes in cerebral ganglions of Lumbricus terrestris degenerate giant fibers and neuromuscular junctions. Chemosphere,152, 468–480.

    CAS  PubMed  Google Scholar 

  • Teerapattarakan, N., Benya-Aphikul, H., Tansawat, R., Wanakhachornkrai, O., Tantisira, M. H., & Rodsiri, R. (2018). Neuroprotective effect of a standardized extract of Centella asiatica ECa233 in rotenone-induced parkinsonism rats. Phytomedicine: International Journal of Phytotherapy and Phytopharmacology,44, 65–73.

    CAS  Google Scholar 

  • Vauzour, D., Vafeiadou, K., Rodriguez-Mateos, A., Rendeiro, C., & Spencer, J. P. (2008). The neuroprotective potential of flavonoids: A multiplicity of effects. Genes & Nutrition,3(3–4), 115–126.

    CAS  Google Scholar 

  • Wendel, A. (1981). Glutathione peroxidase. Methods of Enzymology,77, 325–333.

    CAS  Google Scholar 

  • Xiong, N., Long, X., Xiong, J., Jia, M., Chen, C., Huang, J., et al. (2012). Mitochondrial complex I inhibitor rotenone-induced toxicity and its potential mechanisms in Parkinson’s disease models. Critical Reviews in Toxicology,42(7), 613–632.

    CAS  PubMed  Google Scholar 

  • Zhang, L., Hao, J., Zheng, Y., Su, R., Liao, Y., Gong, X., et al. (2018). Fucoidan protects dopaminergic neurons by enhancing the mitochondrial function in a rotenone-induced rat model of Parkinson’s disease. Aging and Disease,9(4), 590–604.

    PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

NA is thankful to GLA University, Mathura, Uttar Pradesh, India for the financial assistantship.

Author information

Authors and Affiliations

  1. Division of Pharmacology, Institute of Pharmaceutical Research, GLA University, Mathura, 281 406, India

    Debapriya Garabadu & Nidhi Agrawal

Authors
  1. Debapriya Garabadu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nidhi Agrawal
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Debapriya Garabadu.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Garabadu, D., Agrawal, N. Naringin Exhibits Neuroprotection Against Rotenone-Induced Neurotoxicity in Experimental Rodents. Neuromol Med 22, 314–330 (2020). https://doi.org/10.1007/s12017-019-08590-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12017-019-08590-2

Keywords

Search

Navigation