RUTIN FROM RUTA CHALEPENSIS ALLEVIATES ROTENONE-INDUCED DOPAMINE DEPLETION AND MOTOR DEFICITS THROUGH ANTI-OXIDATIVE AND ANTI-APOPTOTIC EFFECTS IN A RAT MODEL OF PARKINSON’S DISEASE
DOI:
https://doi.org/10.22159/ajpcr.2026v19i4.58018Keywords:
Rutin, Nigrostriatal pathway,, Oxidative stress, Apoptotic signaling, α-synuclein,, Rotenone-induced ParkinsonismAbstract
Objectives: Rutin, a flavonol glycoside derived from Ruta chalepensis, has shown antioxidant and anti-apoptotic properties in in vitro models of Parkinson’s disease (PD); however, its neuroprotective mechanisms in vivo remain inadequately characterised. The present study aimed to evaluate the neuroprotective and anti-apoptotic effects of rutin in a rotenone-induced rat model of PD.
Methods: Male albino Wistar rats were administered rotenone (2.5 mg/kg, intraperitoneally) for 28 days to induce Parkinsonian features. Rutin was administered orally at doses of 5, 10, and 20 mg/kg to determine the optimal neuroprotective concentration. Motor performance was assessed using behavioral tests, followed by estimation of striatal dopamine levels, oxidative stress markers, antioxidant enzyme activities, and expression of dopaminergic and apoptotic proteins.
Results: Rotenone administration resulted in significant motor impairment, striatal dopamine depletion, increased oxidative stress, reduced expression of tyrosine hydroxylase, dopamine transporter, and vesicular monoamine transporter-2, elevated α-synuclein levels, and activation of apoptotic signaling characterised by increased Bax, cytochrome c, and caspases-3, -8, and -9, along with decreased Bcl-2 expression. Rutin treatment produced a dose-dependent improvement in motor function, with 10 mg/kg identified as the most effective dose. Co-treatment with rutin (10 mg/kg) significantly restored antioxidant enzyme activities, normalized dopaminergic protein expression, reduced α-synuclein accumulation, and suppressed apoptotic pathways.
Conclusion: These findings demonstrate that rutin confers significant neuroprotection against rotenone-induced dopaminergic neurodegeneration by attenuating oxidative stress and apoptosis in vivo. Rutin may represent a promising candidate for disease-modifying therapy in PD, warranting further investigation of its mitochondrial and anti-inflammatory mechanisms.
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References
1. Schapira AH, Jenner P. Etiology and pathogenesis of Parkinson’s disease. Mov Disord. 2011;26(6):1049-55. doi: 10.1002/mds.23732, PMID 21626550
2. Tambuyzer BR, Ponsaerts P, Nouwen EJ. Microglia: Gatekeepers of central nervous system immunology. J Leukoc Biol. 2009;85(3):352-70. doi: 10.1189/jlb.0608385, PMID 19028958
3. Soldner F, Hockemeyer D, Beard C, Gao Q, Bell GW, Cook EG, et al. Parkinson’s disease patient-derived induced pluripotent stem cells free of viral reprogramming factors. Cell. 2009;136(5):964-77. doi: 10.1016/j.cell.2009.02.013, PMID 19269371
4. Emmrich JV, Hornik TC, Neher JJ, Brown GC. Rotenone induces neuronal death by microglial phagocytosis of neurons. FEBS J. 2013;280(20):5030-8. doi: 10.1111/febs.12401, PMID 23789887
5. Xiong N, Long X, Xiong J, Jia M, Chen C, Huang J. Mitochondrial complex I inhibitor rotenone-induced toxicity and its potential mechanisms in Parkinson’s disease models. Crit Rev Toxicol. 2012 Aug;42(7):613-32. doi: 10.3109/10408444.2012.680431, PMID 22574684.
6. Kandil EA, El-Sheikh AM, Ameen OA. Neuroprotective effect of quercetin against rotenone-induced Parkinson’s disease in rats. Neurochem Res. 2016;41(12):3219-30.
7. Sherer TB, Betarbet R, Testa CM, Seo BB, Richardson JR, Kim JH. Mechanism of toxicity in rotenone models of Parkinson’s disease. J Neurosci. 2003;23(34):10756-64. doi: 10.1523/ JNEUROSCI.23-34-10756.2003, PMID 14645467
8. Thakur P, Nehru B. Anti-inflammatory effects of quercetin on the progression of Parkinson’s disease in rats. Neuropharmacology. 2013;74:173-83.
9. Thakur P, Nehru B. Inhibition of neuroinflammation and mitochondrial dysfunctions by carbenoxolone in rotenone model of Parkinson’s disease. Neurochem Int. 2014;78:1-10.
10. De Almeida LM, Piñeiro CC, Leite MC, Brolese G, Leal RB, Gottfried C. Protective effects of resveratrol on hydrogen peroxide induced toxicity in primary cortical astrocyte cultures. Neurochem Res. 2008;33:8-15. doi: 10.1007/s11064-007-9399-5.
11. Chand J, Kandy AT, Prasad K, Mathew J, Sherin F, Subramanian G. In silico, preparation and in vitro studies of benzylidene-based hydroxy benzyl urea derivatives as free radical scavengers in Parkinson’s disease. Int J Appl Pharm. 2024 May 7;16:217-24.
12. Anandhan A, Tamilselvam K, Radhiga T, Rao S. Curcumin attenuates oxidative stress and mitochondrial dysfunction in rotenone-induced rat model of Parkinson’s disease. Neurochem Res. 2012;37(8):1611-23.
13. Sowmya Priya M, Sangilimuthu A, Karpagavalli M, Ramkumar M, Josphin Nirmala A. Antioxidant potentials and simultaneous estimation of quercetin, Rutin, and gallic acid in Curcuma species. Asian J Pharm Clin Res. 2017 Dec 1;10(12):387. doi: 10.22159/ajpcr.2017. v10i12.14093
14. Niehaus WG Jr., Samuelsson B. Formation of malonaldehyde from phospholipid arachidonate during microsomal lipid peroxidation. Eur J Biochem. 1968;6(1):126-30. doi: 10.1111/j.1432-1033.1968.tb00428.x, PMID 4387188
15. Eldalawy R. Quantitative estimation of Rutin in rue (Ruta graveolens L.) cultivated in Iraq with the evaluation of its antioxidant activity. Asian J Pharm Clin Res. 2017 Feb 1;10(2):353-5. doi: 10.22159/ajpcr.2017. v10i2.15726
16. Rotruck JT, Pope AL, Ganther HE, Swanson AB, Hafeman DG, Hoekstra WG. Selenium: Biochemical role as a component of glutathione peroxidase. Science. 1973;179(4073):588-90. doi: 10.1126/ science.179.4073.588, PMID 4686466
17. Li N, Ragheb K, Lawler G, Sturgis J, Rajwa B, Melendez JA. Mitochondrial complex I inhibitor rotenone induces apoptosis through enhancing mitochondrial reactive oxygen species production. J Biol Chem. 2003;278(10):8516-25. doi: 10.1074/jbc.M210432200, PMID 12496265
18. Ding Y, Qiao A, Wang Z, Goodwin JS, Lee ES, Block ML. Retinoic acid attenuates beta-amyloid deposition and rescues memory deficits in an Alzheimer’s disease transgenic mouse model. J Neurosci. 2008 Nov 5;28(45):11622-34. doi: 10.1523/JNEUROSCI.3153-08.2008, PMID 18987198, PMCID PMC3844785.
19. Kelsey NA, Wilkins HM, Linseman DA. Nutraceutical antioxidants as novel neuroprotective agents. Molecules. 2010;15(11):7792-814. doi: 10.3390/molecules15117792, PMID 21060289
20. Craggs LJ, Kalaria RN. Revisiting dietary antioxidants in neurological disease. Neurochem Res. 2011;36(12):2329-41.
21. Blume SR, Cass DK, Tseng KY, Steketee JD. Repeated exposure to cocaine alters dopamine signaling in the nucleus accumbens. J Neurochem. 2009;109(4):1127-37.
22. Nehru B, Verma R, Khanna P. Behavioral and biochemical alterations in rotenone model of Parkinson’s disease. Neurochem Res. 2008;33(10):1932-8.
23. Abdel-Salam O, Mohammed N, Youness E, Khadrawy Y, Omara E, Sleem A. Cerebrolysin protects against rotenone-induced oxidative stress and neurodegeneration. J Neurorestoratol. 2014;2:47-63. doi: 10.2147/JN.S50114.
24. Balakrishnan R, Elangovan N, Mohankumar T, Nataraj J, Manivasagam T, Justin Thenmozhi A. Isolongifolene attenuates rotenone-induced mitochondrial dysfunction, oxidative stress and apoptosis. Front Biosci (Schol Ed). 2018 Jan1;10(2):248-261. doi: 10.2741/s513, PMID 28930531.
25. Choi WS, Palmiter RD, Xia Z. Loss of dopamine neurons due to proteasome inhibition. J Neurosci. 2015;35(24):8970-81.
26. Lin TK, Liou CW, Chen SD, Chuang YC, Tiao MM, Wang PW. Mitochondrial dysfunction and biogenesis in the pathogenesis of Parkinson’s disease. Chang Gung Med J. 2009 Nov-Dec;32(6):589-99. PMID 20035637
27. Johnson ME, Stecher B, Labrie V, Brundin L, Brundin P. Triggers, facilitators, and aggravators: Redefining Parkinson’s disease pathogenesis. Trends Neurosci. 2019 Jan;42(1):4-13. doi: 10.1016/j. tins.2018.09.007, PMID 30342839, PMCID PMC6623978.
28. Kumbhar PS, Manwatkar S, Kumar B, Raje SB, Chavan AS. Pharmacological impact of Rutin and quercetin in alcohol-induced neuropathy in rats. Asian J Pharm Clin Res. 2025 May 7;18:175-83.
29. Watanabe Y, Tateishi T, Itoh K, Oyanagi T, Takahashi S, Nishikawa N. Decreased dopamine transporter levels in Parkinson’s disease. Neurobiol Aging. 2005;26(4):523-8.
30. García-Yagüe ÁJ, Rada P, Rojo AI, Lastres-Becker I, Cuadrado A. Dopamine transporter andVMAT2 dysfunction in Parkinson’s disease. Neuropharmacology. 2013;73:47-59.
31. Kim C, Ho DH, Suk JE, You S, Michael S, Kang J. Neuron-released oligomeric α-synuclein is an endogenous agonist of TLR2 for paracrine activation of microglia. Nat Commun. 2013;4(1):1562. doi: 10.1038/ ncomms2534
32. Quik M, Perez XA, Bordia T. Nicotine as a potential neuroprotective agent for Parkinson’s disease. Mov Disord. 2013;28(7):947-57.
33. Singh S, Jamwal S, Kumar P. Neuroprotective role of VMAT2 modulators in Parkinson’s disease. CNS Neurol Disord Drug Targets. 2008;7(6):459-66.
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