Abstract
Hesperidin is a flavonoid glycoside that is frequently found in citrus fruits. Our group have demonstrated that hesperidin has neuroprotective effect in 6-hydroxydopamine (6-OHDA) model of Parkinson’s disease (PD), mainly by antioxidant mechanisms. Although the pathophysiology of PD remains uncertain, a large body of evidence has demonstrated that mitochondrial dysfunction and apoptosis play a critical role in dopaminergic nigrostriatal degeneration. However, the ability of hesperidin in modulating these mechanisms has not yet been investigated. In the present study, we examined the potential of a 28-day hesperidin treatment (50 mg/kg/day, p.o.) in preventing behavioral alterations induced by 6-OHDA injection via regulating mitochondrial dysfunction, apoptosis and dopaminergic neurons in the substantia nigra pars compacta (SNpc) in C57BL/6 mice. Our results demonstrated that hesperidin treatment improved motor, olfactory and spatial memory impairments elicited by 6-OHDA injection. Moreover, hesperidin treatment attenuated the loss of dopaminergic neurons (TH+ cells) in the SNpc and the depletion of dopamine (DA) and its metabolities 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the striatum of 6-OHDA-lesioned mice. Hesperidin also protected against the inhibition of mitochondrial respiratory chain complex-I, -IV and V, the decrease of Na + -K + -ATPase activity and the increase of caspase-3 and -9 activity in the striatum. Taken together, our findings indicate that hesperidin mitigates the degeneration of dopaminergic neurons in the SNpc by preventing mitochondrial dysfunction and modulating apoptotic pathways in the striatum of 6-OHDA-treated mice, thus improving behavioral alterations. These results provide new insights on neuroprotective mechanisms of hesperidin in a relevant preclinical model of PD.
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References
Abushouk AI, Negida A, Ahmed H, Abdel-Daim MM (2017) Neuroprotective mechanisms of plant extracts against MPTP induced neurotoxicity: future applications in Parkinson’s disease. Biomed Pharmacother 85:635–645. https://doi.org/10.1016/j.biopha.2016.11.074
Antunes MS, Goes ATR, Boeira SP, Prigol M, Jesse CR (2014) Protective effect of hesperidin in a model of Parkinson’s disease induced by 6-hydroxydopamine in aged mice. Nutrition 30:1415–1422. https://doi.org/10.1016/j.nut.2014.03.024
Antunes MS, Jesse CR, Ruff JR, de Oliveira Espinosa D, Gomes NS, Altvater EET, Donato F, Giacomeli R, Boeira SP (2016) Hesperidin reverses cognitive and depressive disturbances induced by olfactory bulbectomy in mice by modulating hippocampal neurotrophins and cytokine levels and acetylcholinesterase activity. Eur J Pharmacol 789:411–420. https://doi.org/10.1016/j.ejphar.2016.07.042
Balestrino R, Martinez-Martin P (2017) Neuropsychiatric symptoms, behavioural disorders, and quality of life in Parkinson’s disease. J Neurol Sci 373:173–178. https://doi.org/10.1016/j.jns.2016.12.060
Bose A, Beal MF (2016) Mitochondrial dysfunction in Parkinson’s disease. J Neurochem 139:216–231. https://doi.org/10.1111/jnc.13731
Carabelas R (2016) Parkinson’s disease: old concepts and new challenges. Alzheimers Dis Dement 1. https://doi.org/10.36959/734/36
Chaudhuri KR, Schapira AH (2009) Non-motor symptoms of Parkinson’s disease: dopaminergic pathophysiology and treatment. Lancet Neurol 8:464–474. https://doi.org/10.1016/S1474-4422(09)70068-7
David Adams Jr J (2012) Parkinson’s Disease-Apoptosis and Dopamine Oxidation Open J Apoptosis 1:1–8. https://doi.org/10.4236/ojapo.2012.11.001
Del Fabbro L et al (2019) Chrysin protects against behavioral, cognitive and neurochemical alterations in a 6-hydroxydopamine model of Parkinson’s disease. Neurosci Lett 706:158–163. https://doi.org/10.1016/j.neulet.2019.05.036
Fiske CH, Subbarow Y (1925) The colorimetric determination of phosphorus. J Biol Chem 66:375–400
Garg A, Garg S, Zaneveld LJD, Singla AK (2001) Chemistry and pharmacology of the Citrus bioflavonoid hesperidin. Phyther Res 15:655–669. https://doi.org/10.1002/ptr.1074
Gaur V, Kumar A (2010) Hesperidin pre-treatment attenuates NO-mediated cerebral ischemic reperfusion injury and memory dysfunction. Pharmacol Reports 62:635–648. https://doi.org/10.1016/S1734-1140(10)70321-2
Goes ATR, Souza LC, Filho CB, del Fabbro L, de Gomes MG, Boeira SP, Jesse CR (2014) Neuroprotective effects of swimming training in a mouse model of Parkinson’s disease induced by 6-hydroxydopamine. Neuroscience 256:61–71. https://doi.org/10.1016/j.neuroscience.2013.09.042
Goes ATR, Jesse CR, Antunes MS, Lobo Ladd FV, Lobo Ladd AAB, Luchese C, Paroul N, Boeira SP (2018) Protective role of chrysin on 6-hydroxydopamine-induced neurodegeneration a mouse model of Parkinson’s disease: involvement of neuroinflammation and neurotrophins. Chem Biol Interact 279:111–120. https://doi.org/10.1016/j.cbi.2017.10.019
Griffiths DE, Houghton RL (1974) Studies on energy-linked reactions: modified mitochondrial ATPase of Oligomycin-resistant mutants of Saccharomyces cerevisiae. Eur J Biochem 46:157–167. https://doi.org/10.1111/j.1432-1033.1974.tb03608.x
Gundersen HJG (2002) The smooth fractionator. J Microsc 207:191–210. https://doi.org/10.1046/j.1365-2818.2002.01054.x
Gundersen HJG, Bagger P, Bendtsen TF, Evans SM, Korbo L, Marcussen N, MØLler A, Nielsen K, Nyengaard JR, Pakkenberg B, SØRensen FB, Vesterby A, West MJ (1988) The new stereological tools: Disector, fractionator, nucleator and point sampled intercepts and their use in pathological research and diagnosis. Apmis 96:857–881. https://doi.org/10.1111/j.1699-0463.1988.tb00954.x
Hauser DN, Hastings TG (2013) Mitochondrial dysfunction and oxidative stress in Parkinson’s disease and monogenic parkinsonism. Neurobiol Dis 51:35–42. https://doi.org/10.1016/j.nbd.2012.10.011
Hernandez-Baltazar D, Zavala-Flores LM, Villanueva-Olivo A (2017) The 6-hydroxydopamine model and parkinsonian pathophysiology: novel findings in an older model. Neurol 32:533–539. https://doi.org/10.1016/j.nrleng.2015.06.019
Huang SG (2002) Development of a high throughput screening assay for mitochondrial membrane potential in living cells. J Biomol Screen 7:383–389. https://doi.org/10.1177/108705710200700411
Kalia LV, Lang AE (2015) Parkinson’s disease. Lancet 386:896–912. https://doi.org/10.1016/S0140-6736(14)61393-3
Kim SR, Kareva T, Yarygina O, Kholodilov N, Burke RE (2012) AAV transduction of dopamine neurons with constitutively active rheb protects from neurodegeneration and mediates axon regrowth. Mol Ther 20:275–286. https://doi.org/10.1038/mt.2011.213
Kozina EA, Khakimova GR, Khaindrava VG, Kucheryanu VG, Vorobyeva NE, Krasnov AN, Georgieva SG, Kerkerian-le Goff L, Ugrumov MV (2014) Tyrosine hydroxylase expression and activity in nigrostriatal dopaminergic neurons of MPTP-treated mice at the presymptomatic and symptomatic stages of parkinsonism. J Neurol Sci 340:198–207. https://doi.org/10.1016/j.jns.2014.03.028
Kumar A, Sharma N, Gupta A, Kalonia H, Mishra J (2012) Neuroprotective potential of atorvastatin and simvastatin (HMG-CoA reductase inhibitors) against 6-hydroxydopamine (6-OHDA) induced Parkinson-like symptoms. Brain Res 1471:13–22. https://doi.org/10.1016/j.brainres.2012.06.050
Kupsch A, Schmidt W, Gizatullina Z, Debska-Vielhaber G, Voges J, Striggow F, Panther P, Schwegler H, Heinze HJ, Vielhaber S, Gellerich FN (2014) 6-Hydroxydopamine impairs mitochondrial function in the rat model of Parkinson’s disease: Respirometric, histological, and behavioral analyses. J Neural Transm 121:1245–1257. https://doi.org/10.1007/s00702-014-1185-3
Li P, Nijhawan D, Budihardjo I, Srinivasula SM, Ahmad M, Alnemri ES, Wang X (1997) Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell 91:479–489. https://doi.org/10.1016/s0092-8674(00)80434-1
Lin MT, Beal MF (2006) Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443:787–795. https://doi.org/10.1038/nature05292
Lowry OH, Rosenborough NJ, Farr AL, Randall RJ (1951) Protein measurement with folin phenol reagente. J Biol Chem 193:265–275.
Nishi A, Fisone G, Snyder GL, Dulubova I, Aperia A, Nairn AC, Greengard P (1999) Regulation of Na+, K+-ATPase isoforms in rat neostriatum by dopamine and protein kinase C. J Neurochem 73:1492–1501
Oorschot DE (1996) Total number of neurons in the neostriatal, pallidal, subthalamic, and substantia nigral nuclei of the rat basal ganglia: a stereological study using the cavalieri and optical disector methods. J Comp Neurol 366:580–599
Paxinos G, Franklin, KBJ (2001). The mouse brain in stereotaxic coordinates: second edition (deluxe) by academic press, New York, ISBN 0-12-547637-X
Pedersen PL, Greenawalt JW, Reynafarje B, Hullihen J, Decker GL, Soper JW, Bustamente E (1978) Preparation and characterization of mitochondria and submitochondrial particles of rat liver and liver-derived tissues. Methods Cell Biol 20:411–481. https://doi.org/10.1016/s0091-679x(08)62030-0
Perier C, Bové J, Wu DC, Dehay B, Choi DK, Jackson-Lewis V, Rathke-Hartlieb S, Bouillet P, Strasser A, Schulz JB, Przedborski S, Vila M (2007) Two molecular pathways initiate mitochondria-dependent dopaminergic neurodegeneration in experimental Parkinson’s disease. Proc Natl Acad Sci U S A 104:8161–8166. https://doi.org/10.1073/pnas.0609874104
Prediger RDS, Aguiar AS Jr, Rojas-Mayorquin AE, Figueiredo CP, Matheus FC, Ginestet L, Chevarin C, Bel ED, Mongeau R, Hamon M, Lanfumey L, Raisman-Vozari R (2010) Single intranasal administration of 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine in C57BL/6 mice models early preclinical phase of Parkinson’s disease. Neurotox Res 17:114–129. https://doi.org/10.1007/s12640-009-9087-0
Prut L, Belzung C (2003) The open field as a paradigm to measure the effects of drugs on anxiety-like behaviors: a review. Eur J Pharmacol 463:3–33. https://doi.org/10.1016/S0014-2999(03)01272-X
Rocha EM, De Miranda B, Sanders LH (2018) Alpha-synuclein: pathology, mitochondrial dysfunction and neuroinflammation in Parkinson’s disease. Neurobiol Dis 109:249–257. https://doi.org/10.1016/j.nbd.2017.04.004
Ross GW, Petrovitch H, Abbott RD, Tanner CM, Popper J, Masaki K, Launer L, White LR (2008) Association of olfactory dysfunction with risk for future Parkinson’s disease. Ann Neurol 63:167–173. https://doi.org/10.1002/ana.21291
Schmitz C, Hof PR (2005) Design-based stereology in neuroscience. Neuroscience 130:813–831. https://doi.org/10.1016/j.neuroscience.2004.08.050
Shapiro BL, Feigal RJ, Lam LFH (1979) Mitochondrial NADH dehydrogenase in cystic fibrosis. Proc Natl Acad Sci U S A 76:2979–2983. https://doi.org/10.1073/pnas.76.6.2979
Silva LFA, Hoffmann MS, Gerbatin RR, Fiorin FS, Dobrachinski F, Mota BC, Wouters ATB, Pavarini SP, Soares FAA, Fighera MR, Royes LFF (2013) Treadmill exercise protects against pentylenetetrazol-induced seizures and oxidative stress after traumatic brain injury. J Neurotrauma 30:1278–1287. https://doi.org/10.1089/neu.2012.2577
Solanki I, Parihar P, Parihar MS (2016) Neurodegenerative diseases: From available treatments to prospective herbal therapy. Neurochem Int 95:100–108. https://doi.org/10.1016/j.neuint.2015.11.001
Soto-Otero R, Méndez-Álvarez E, Hermida-Ameijeiras Á, Muñoz-Patiño AM, Labandeira-Garcia JL (2000) Autoxidation and neurotoxicity of 6-hydroxydopamine in the presence of some antioxidants: potential implication in relation to the pathogenesis of Parkinson’s disease. J Neurochem 74:1605–1612. https://doi.org/10.1046/j.1471-4159.2000.0741605.x
Storrie B, Madden EA (1990) Isolation of subcellular organelles. Methods Enzymol 182:203–225. https://doi.org/10.1016/0076-6879(90)82018-W
Ungerstedt U (1971) Postsynaptic Supersensitivity after 6-Hydroxy-dopamine induced degeneration of the Nigrostriatal dopamine system. Acta Physiol Scand 82:69–93. https://doi.org/10.1111/j.1365-201X.1971.tb11000.x
Valle-Leija P, Drucker-Colín R (2014) Unilateral olfactory deficit in a hemiparkinson’s disease mouse model. Neuroreport 25:948–953. https://doi.org/10.1097/WNR.0000000000000218
Vauzour D, Vafeiadou K, Rodriguez-Mateos A, Rendeiro C, Spencer JPE (2008) The neuroprotective potential of flavonoids: a multiplicity of effects. Genes Nutr 3:115–126. https://doi.org/10.1007/s12263-008-0091-4
Vianello R, Domene C, Mavri J (2016) The use of multiscale molecular simulations in understanding a relationship between the structure and function of biological systems of the brain: the application to monoamine oxidase enzymes. Front Neurosci 10:327. https://doi.org/10.3389/fnins.2016.00327
Walker JM, Fowler SW, Miller DK, Sun AY, Weisman GA, Wood WG, Sun GY, Simonyi A, Schachtman TR (2011) Spatial learning and memory impairment and increased locomotion in a transgenic amyloid precursor protein mouse model of Alzheimer’s disease. Behav Brain Res 222:169–175. https://doi.org/10.1016/j.bbr.2011.03.049
Wang XQ et al (2003) Apoptotic insults impair Na+, K+-ATPase activity as a mechanism of neuronal death mediated by concurrent ATP deficiency and oxidant stress. J Cell Sci 116:2099–2110. https://doi.org/10.1242/jcs.00420
Xie A, Gao J, Xu L, Meng D (2014) Shared mechanisms of neurodegeneration in alzheimer’s disease and parkinson’s disease. Biomed Res Int 2014:648740–648748. https://doi.org/10.1155/2014/648740
Yang C, Garrett-Mayer E, Schneider JS, Gollomp SM, Tilley BC (2009) Repeatable battery for assessment of neuropsychological status in early Parkinson’s disease. Mov Disord 24:1453–1460. https://doi.org/10.1002/mds.22552
Zhang Z, Hou L, Li X, Ju C, Zhang J, Li X, Wang X, Liu C, Lv Y, Wang Y (2016) Neuroprotection of inositol hexaphosphate and changes of mitochondrion mediated apoptotic pathway and α-synuclein aggregation in 6-OHDA induced Parkinson’s disease cell model. Brain Res 1633:87–95. https://doi.org/10.1016/j.brainres.2015.12.035
Acknowledgments
The authors are grateful for financial support by FAPERGS (#16/2551-0000526-5 (PRONUPEQ) and CNPq (#430841/2016-7 (Universal)) Research Grants. LCS is recipient by CNPq fellowship [150560/2019–2]. We would like to thank professor Cristiano Ricardo Jesse for the study design, interpretation of the data and for provided their thoughts and his contribution to the development of the experiments.
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Antunes, M.S., Ladd, F.V.L., Ladd, A.A.B.L. et al. Hesperidin protects against behavioral alterations and loss of dopaminergic neurons in 6-OHDA-lesioned mice: the role of mitochondrial dysfunction and apoptosis. Metab Brain Dis 36, 153–167 (2021). https://doi.org/10.1007/s11011-020-00618-y
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DOI: https://doi.org/10.1007/s11011-020-00618-y