Abstract
Parkinson's disease (PD) is a multifactorial neurodegenerative disease manifesting mitochondrial damages and neuroinflammation. Qi is defined as a natural power that can regulate the energy flow in Oriental medicine, whereas mitochondria generate energy power in Western medicine. We investigated whether Qi-enhancing component in Oriental herb medicines could activate mitochondrial activities. Quercetin was found as a major bioactive compound in most Qi-activating Oriental herb medicines through online search for active compounds in several Oriental Medicine databases. We then investigated if quercetin could reverse 1-methyl-4-phenylpyridinium (MPP+)-induced mitochondrial dysfunction and lipopolysaccharide (LPS)-induced neuroinflammation. Mitochondrial activities were monitored based on complex 1 NADH dehydrogenase activities, ATP contents, mitochondrial membrane potential, cellular/mitochondrial reactive oxygen species, and oxygen consumption rate in SH-SY5Y cells. Quercetin at concentration up to 20 µg/ml was not cytotoxic to SH-SY5Y cells. Pre-treatment with quercetin significantly protected mitochondrial damages in 1 mM MPP+- or 100 ng/ml LPS-treated cells. Quercetin increased expression levels of tyrosine hydroxylase and mitochondria controlling proteins. When in vivo effects of quercetin were assessed by immunohistochemical staining of tissue sections from LPS-injected mice brains, quercetin reduced the activation of microglia and astrocytes in the hippocampus and substantia nigra of LPS-injected mice. Our data suggest that Qi-activating quercetin might be therapeutically effective for neuroinflammation-mediated neurodegeneration by alleviating mitochondrial damages.
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References
Ahn SY, Choi YS, Koo HJ, Jeong JH, Park WH, Kim M, Piao Y, Pak YK (2010) Mitochondrial dysfunction enhances the migration of vascular smooth muscles cells via suppression of akt phosphorylation. Biochim Biophys Acta 1800(3):275–281. https://doi.org/10.1016/j.bbagen.2009.09.005
Ay M, Luo J, Langley M, Jin H, Anantharam V, Kanthasamy A, Kanthasamy AG (2017) Molecular mechanisms underlying protective effects of quercetin against mitochondrial dysfunction and progressive dopaminergic neurodegeneration in cell culture and mitopark transgenic mouse models of parkinson’s disease. J Neurochem 141(5):766–782. https://doi.org/10.1111/jnc.14033
Comalada M, Camuesco D, Sierra S, Ballester I, Xaus J, Galvez J, Zarzuelo A (2005) In vivo quercitrin anti-inflammatory effect involves release of quercetin, which inhibits inflammation through down-regulation of the nf-kappab pathway. Eur J Immunol 35(2):584–592. https://doi.org/10.1002/eji.200425778
Dauer W, Przedborski S (2003) Parkinson’s disease: mechanisms and models. Neuron 39(6):889–909. https://doi.org/10.1016/s0896-6273(03)00568-3
De Oliveira MR, Nabavi SM, Braidy N, Setzer WN, Ahmed T, Nabavi SF (2016) Quercetin and the mitochondria: a mechanistic view. Biotechnol Adv 34(5):532–549. https://doi.org/10.1016/j.biotechadv.2015.12.014
Denny Joseph KM, Muralidhara (2015) Combined oral supplementation of fish oil and quercetin enhances neuroprotection in a chronic rotenone rat model: relevance to Parkinson’s disease. Neurochem Res 40(5):894–905. https://doi.org/10.1007/s11064-015-1542-0
Ebadi M, Govitrapong P, Sharma S, Muralikrishnan D, Shavali S, Pellett L, Schafer R, Albano C, Eken J (2001) Ubiquinone (coenzyme q10) and mitochondria in oxidative stress of parkinson’s disease. Biol Signals Recept 10(3–4):224–253. https://doi.org/10.1159/000046889
Elumalai P, Lakshmi S (2016) Role of quercetin benefits in neurodegeneration. Adv Neurobiol, 12: 229–245. https://doi.org/10.1007/978-3-319-28383-8$412
Henchcliffe C, Beal MF (2008) Mitochondrial biology and oxidative stress in parkinson disease pathogenesis. Nat Clin Pract Neurol 4(11):600–609. https://doi.org/10.1038/ncpneuro0924
Hirsch EC, Hunot S (2009) Neuroinflammation in parkinson’s disease: a target for neuroprotection? Lancet Neurol 8(4):382–397. https://doi.org/10.1016/S1474-4422(09)70062-6
Hsieh CL, Cheng CY, Tsai TH, Lin IH, Liu CH, Chiang SY, Lin JG, Lao CJ, Tang NY (2006) Paeonol reduced cerebral infarction involving the superoxide anion and microglia activation in ischemia-reperfusion injured rats. J Ethnopharmacol 106(2):208–215. https://doi.org/10.1016/j.jep.2005.12.027
Jeong JH, Cheol Kang Y, Piao Y, Kang S, Pak YK (2017) Mir-24-mediated knockdown of h2ax damages mitochondria and the insulin signaling pathway. Exp Mol Med 49(4):e313. https://doi.org/10.1038/emm.2016.174
Jeong JS, Piao Y, Kang S, Son M, Kang YC, Du XF, Ryu J, Cho YW, Jiang HH, Oh MS, Hong SP, Oh YJ, Pak YK (2018) Triple herbal extract da-9805 exerts a neuroprotective effect via amelioration of mitochondrial damage in experimental models of parkinson’s disease. Sci Rep 8(1):15953. https://doi.org/10.1038/s41598-018-34240-x
Karuppagounder SS, Madathil SK, Pandey M, Haobam R, Rajamma U, Mohanakumar KP (2013) Quercetin up-regulates mitochondrial complex-i activity to protect against programmed cell death in rotenone model of parkinson’s disease in rats. Neuroscience 236:136–148. https://doi.org/10.1016/j.neuroscience.2013.01.032
Keeney PM, Xie J, Capaldi RA, Bennett JP Jr (2006) Parkinson’s disease brain mitochondrial complex i has oxidatively damaged subunits and is functionally impaired and misassembled. J Neurosci 26(19):5256–5264. https://doi.org/10.1523/JNEUROSCI.0984-06.2006
Khan A, Ali T, Rehman SU, Khan MS, Alam SI, Ikram M, Muhammad T, Saeed K, Badshah H, Kim MO (2018) Neuroprotective effect of quercetin against the detrimental effects of lps in the adult mouse brain. Front Pharmacol 9:1383. https://doi.org/10.3389/fphar.2018.01383
Lei X, Chao H, Zhang Z, Lv J, Li S, Wei H, Xue R, Li F, Li Z (2015) Neuroprotective effects of quercetin in a mouse model of brain ischemic/reperfusion injury via anti-apoptotic mechanisms based on the akt pathway. Mol Med Rep 12(3):3688–3696. https://doi.org/10.3892/mmr.2015.3857
Lestienne P, Nelson J, Riederer P, Jellinger K, Reichmann H (1990) Normal mitochondrial genome in brain from patients with Parkinson’s disease and complex i defect. J Neurochem 55(5):1810–1812
Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative pcr and the 2(-delta delta c(t)) method. Methods 25(4):402–408. https://doi.org/10.1006/meth.2001.1262
Luoma P, Melberg A, Rinne JO, Kaukonen JA, Nupponen NN, Chalmers RM, Oldfors A, Rautakorpi I, Peltonen L, Majamaa K, Somer H, Suomalainen A (2004) Parkinsonism, premature menopause, and mitochondrial DNA polymerase gamma mutations: clinical and molecular genetic study. Lancet 364(9437):875–882. https://doi.org/10.1016/S0140-6736(04)16983-3
Mattson MP (2000) Apoptosis in neurodegenerative disorders. Nat Rev Mol Cell Biol 1(2):120–129. https://doi.org/10.1038/35040009
Moore DJ, West AB, Dawson VL, Dawson TM (2005) Molecular pathophysiology of Parkinson’s disease. Annu Rev Neurosci 28:57–87. https://doi.org/10.1146/annurev.neuro.28.061604.135718
Obeso JA, Rodriguez-Oroz MC, Goetz CG, Marin C, Kordower JH, Rodriguez M, Hirsch EC, Farrer M, Schapira AH, Halliday G (2010) Missing pieces in the Parkinson’s disease puzzle. Nat Med 16(6):653–661. https://doi.org/10.1038/nm.2165
Park WH, Kang S, Piao Y, Pak CJ, Oh MS, Kim J, Kang MS, Pak YK (2015) Ethanol extract of bupleurum falcatum and saikosaponins inhibit neuroinflammation via inhibition of nf-kappab. J Ethnopharmacol 174:37–44. https://doi.org/10.1016/j.jep.2015.07.039
Piao Y, Kim HG, Oh MS, Pak YK (2012) Overexpression of tfam, nrf-1 and myr-akt protects the mpp(+)-induced mitochondrial dysfunctions in neuronal cells. Biochim Biophys Acta 1820(5):577–585. https://doi.org/10.1016/j.bbagen.2011.08.007
Pietta PG (2000) Flavonoids as antioxidants. J Nat Prod 63(7):1035–1042. https://doi.org/10.1021/np9904509
Prasad J, Baitharu I, Sharma AK, Dutta R, Prasad D, Singh SB (2013) Quercetin reverses hypobaric hypoxia-induced hippocampal neurodegeneration and improves memory function in the rat. High Alt Med Biol 14(4):383–394. https://doi.org/10.1089/ham.2013.1014
Sabogal-Guaqueta AM, Munoz-Manco JI, Ramirez-Pineda JR, Lamprea-Rodriguez M, Osorio E, Cardona-Gomez GP (2015) The flavonoid quercetin ameliorates Alzheimer’s disease pathology and protects cognitive and emotional function in aged triple transgenic Alzheimer’s disease model mice. Neuropharmacology 93:134–145. https://doi.org/10.1016/j.neuropharm.2015.01.027
Schapira AH (2006) Mitochondrial disease. Lancet 368(9529):70–82. https://doi.org/10.1016/S0140-6736(06)68970-8
Sharma DR, Wani WY, Sunkaria A, Kandimalla RJ, Sharma RK, Verma D, Bal A, Gill KD (2016) Quercetin attenuates neuronal death against aluminum-induced neurodegeneration in the rat hippocampus. Neuroscience 324:163–176. https://doi.org/10.1016/j.neuroscience.2016.02.055
Shults CW, Haas RH, Beal MF (1999) A possible role of coenzyme q10 in the etiology and treatment of Parkinson’s disease. Biofactors 9(2–4):267–272. https://doi.org/10.1002/biof.5520090223
Shutenko Z, Henry Y, Pinard E, Seylaz J, Potier P, Berthet F, Girard P, Sercombe R (1999) Influence of the antioxidant quercetin in vivo on the level of nitric oxide determined by electron paramagnetic resonance in rat brain during global ischemia and reperfusion. Biochem Pharmacol 57(2):199–208. https://doi.org/10.1016/s0006-2952(98)00296-2
Sikorska M, Lanthier P, Miller H, Beyers M, Sodja C, Zurakowski B, Gangaraju S, Pandey S, Sandhu JK (2014) Nanomicellar formulation of coenzyme q10 (ubisol-q10) effectively blocks ongoing neurodegeneration in the mouse 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model: potential use as an adjuvant treatment in Parkinson’s disease. Neurobiol Aging 35(10):2329–2346. https://doi.org/10.1016/j.neurobiolaging.2014.03.032
Sim Y, Park G, Eo H, Huh E, Gu PS, Hong SP, Pak YK, Oh MS (2017) Protective effects of a herbal extract combination of bupleurum falcatum, paeonia suffruticosa, and angelica dahurica against mptp-induced neurotoxicity via regulation of nuclear receptor-related 1 protein. Neuroscience 340:166–175. https://doi.org/10.1016/j.neuroscience.2016.10.029
Sohmiya M, Tanaka M, Tak NW, Yanagisawa M, Tanino Y, Suzuki Y, Okamoto K, Yamamoto Y (2004) Redox status of plasma coenzyme q10 indicates elevated systemic oxidative stress in Parkinson’s disease. J Neurol Sci 223(2):161–166. https://doi.org/10.1016/j.jns.2004.05.007
Solesio ME, Prime TA, Logan A, Murphy MP, Del Mar Arroyo-Jimenez M, Jordan J, Galindo MF (2013) The mitochondria-targeted anti-oxidant mitoq reduces aspects of mitochondrial fission in the 6-ohda cell model of Parkinson’s disease. Biochim Biophys Acta 1832(1):174–182. https://doi.org/10.1016/j.bbadis.2012.07.009
Trifunovic A, Larsson NG (2008) Mitochondrial dysfunction as a cause of ageing. J Intern Med 263(2):167–178. https://doi.org/10.1111/j.1365-2796.2007.01905.x
Wang XM, Li XB, Peng Y (2017) Impact of qi-invigorating traditional Chinese medicines on intestinal flora: a basis for rational choice of prebiotics. Chin J Nat Med 15(4):241–254. https://doi.org/10.1016/S1875-5364(17)30041-9
Wang GH, Chen CY, Tsai TH, Chen CK, Cheng CY, Huang YH, Hsieh MC, Chung YC (2017a) Evaluation of tyrosinase inhibitory and antioxidant activities of angelica dahurica root extracts for four different probiotic bacteria fermentations. J Biosci Bioeng 123(6):679–684. https://doi.org/10.1016/j.jbiosc.2017.01.003
Weyemi U, Paul BD, Bhattacharya D, Malla AP, Boufraqech M, Harraz MM, Bonner WM, Snyder SH (2019) Histone h2ax promotes neuronal health by controlling mitochondrial homeostasis. Proc Natl Acad Sci USA 116(15):7471–7476. https://doi.org/10.1073/pnas.1820245116
Yao RQ, Qi DS, Yu HL, Liu J, Yang LH, Wu XX (2012) Quercetin attenuates cell apoptosis in focal cerebral ischemia rat brain via activation of bdnf-trkb-pi3k/akt signaling pathway. Neurochem Res 37(12):2777–2786. https://doi.org/10.1007/s11064-012-0871-5
Acknowledgements
This research was supported by the Korean Health Technology R&D Project (HI14C2700) through the Korea Health Industry Development Institute (KHIDI) and by the Basic Science Research Program (2018R1A6A1A03025124 and 2020R1A2C1008699) through the National Research Foundation of Korea (NRF) funded by the Korean government (MSIT). The funding source had no role in the collection of data or in the decision to submit this manuscript for publication. Authors thank Hyun Soo Jeon and Hyung Seok Roh for starting the project on Qi and mitochondria when they were students of Korean Minjok Leadership Academy High School, Gangwon-do, Korea.
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Kang, S., Piao, Y., Kang, Y.C. et al. Qi-activating quercetin alleviates mitochondrial dysfunction and neuroinflammation in vivo and in vitro. Arch. Pharm. Res. 43, 553–566 (2020). https://doi.org/10.1007/s12272-020-01238-x
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DOI: https://doi.org/10.1007/s12272-020-01238-x