Polyphenols from Toona sinensis seeds (PTSS) have demonstrated anti-inflammatory effects in various diseases, while the anti-neuroinflammatory effects still remain to be investigated. We aimed to investigate the effects of PTSS on Parkinson’s disease and underlying mechanisms using a rat model. We employed 6-hydroxydopamine (6-OHDA) to male Sprague Dawley (SD) rats and PC12 cells to construct the in vivo and vitro models of PD and dopaminergic (DA) neuron injury, respectively. Cell viability was detected by cell counting kit-8 (CCK-8) assay and protein levels of inflammatory mediators and some p38 MAPK pathway molecules were investigated by immunohistochemistry and Western blot analyses. The results showed that 6-OHDA significantly increased protein levels of inflammatory mediators, such as cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and tumor necrosis factor α (TNF-α), which could be reversed by PTSS through suppressing the p38 MAPK pathway. The anti-inflammatory effects of PTSS were significantly enhanced by the specific p38 inhibitor of SB203580 in vitro. The present work suggests that PTSS can exert anti-inflammatory effects on PD models, which may be attributed to the suppression of p38 MAPK signaling pathway.
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Beitz JM (2014) Parkinson’s disease: a review. Front Biosci (Schol Ed) 6:65–74. https://doi.org/10.2741/s415
Hirsch EC, Jenner P, Przedborski S (2013) Pathogenesis of Parkinson's disease. Mov Disord 28(1):24–30. https://doi.org/10.1002/mds.25032
Wee YV (2010) Inflammation in neurological disorders: a help or a hindrance? Neuroscientist 16(4):408–420. https://doi.org/10.1177/1073858410371379
Niranjan R (2014) The role of inflammatory and oxidative stress mechanisms in the pathogenesis of Parkinson's disease: focus on astrocytes. Mol Neurobiol 49(1):28–38. https://doi.org/10.1007/s12035-013-8483-x
Gupta N, Shyamasundar S, Patnala R, Karthikeyan A, Arumugam TV, Ling EA, Dheen ST (2018) Recent progress in therapeutic strategies for microglia-mediated neuroinflammation in neuropathologies. Expert Opin Ther Targets 22(9):765–781. https://doi.org/10.1080/14728222.2018.1515917
Gagne JJ, Power MC (2010) Anti-inflammatory drugs and risk of Parkinson disease: a meta-analysis. Neurology 74(12):995–1002. https://doi.org/10.1212/WNL.0b013e3181d5a4a3
Ren L, Yi J, Yang J, Li P, Cheng X, Mao P (2018) Nonsteroidal anti-inflammatory drugs use and risk of Parkinson disease: a dose-response meta-analysis. Medicine (Baltimore) 97(37):e12172. https://doi.org/10.1097/MD.0000000000012172
Fu W, Zhuang W, Zhou S, Wang X (2015) Plant-derived neuroprotective agents in Parkinson’s disease. Am J Transl Res 7(7):1189–1202
Little CH, Combet E, McMillan DC, Horgan PG, Roxburgh CS (2017) The role of dietary polyphenols in the moderation of the inflammatory response in early stage colorectal cancer. Crit Rev Food Sci Nutr 57(11):2310–2320. https://doi.org/10.1080/10408398.2014.997866
Limonta P, Moretti RM, Marzagalli M, Fontana F, Raimondi M, Montagnani MM (2019) Role of endoplasmic reticulum stress in the anticancer activity of natural compounds. Int J Mol Sci 20(4):961–984. https://doi.org/10.3390/ijms20040961
González Arbeláez LF, Ciocci Pardo A, Fantinelli JC, Schinella GR, Mosca SM, Ríos JL (2018) Cardioprotection and natural polyphenols: an update of clinical and experimental studies. Food Funct 9(12):6129–6145. https://doi.org/10.1039/c8fo01307a
Mattioli R, Francioso A, d’Erme M, Trovato M, Mancini P, Piacentini L, Casale AM, Wessjohann L, Gazzino R, Costantino P, Mosca L (2019) Anti-inflammatory activity of a polyphenolic extract from Arabidopsis thaliana in in vitro and in vivo models of Alzheimer's disease. Int J Mol Sci 20(3):708–726. https://doi.org/10.3390/ijms20030708
Ghaffari F, Hajizadeh Moghaddam A, Zare M (2018) Neuroprotective effect of quercetin nanocrystal in a 6-hydroxydopamine model of Parkinson disease: biochemical and behavioral evidence. Basic Clin Neurosci 9(5):317–324. https://doi.org/10.32598/bcn.9.5.317
Figueira I, Menezes R, Macedo D, Costa I, Dos Santos CN (2017) Polyphenols beyond barriers: a glimpse into the brain. Curr Neuropharmacol 15(4):562–594. https://doi.org/10.2174/1570159X14666161026151545
Zhang Y, Guo Y, Wang M, Dong H, Zhang J, Zhang L (2017) Quercetrin from Toona sinensis leaves induces cell cycle arrest and apoptosis via enhancement of oxidative stress in human colorectal cancer SW620 cells. Oncol Rep 38(6):3319–3326. https://doi.org/10.3892/or.2017.6042
Truong VL, Ko SY, Jun M, Jeong WS (2016) Quercitrin from Toona sinensis (Juss.) M.Roem. Attenuates acetaminophen-induced acute liver toxicity in HepG2 cells and mice through induction of antioxidant machinery and inhibition of inflammation. Nutrients. 8(7):431–446. https://doi.org/10.3390/nu8070431
Kakumu A, Ninomiya M, Efdi M, Adfa M, Hayashi M, Tanaka K, Koketsu M (2014) Phytochemical analysis and antileukemic activity of polyphenolic constituents of Toona sinensis. Bioorg Med Chem Lett 24(17):4286–4290. https://doi.org/10.1016/j.bmcl.2014.07.022
Yan Y, Min Y, Min H, Chao C, Ying Q, Zhi H (2014) n-Butanol soluble fraction of the water extract of Chinese toon fruit ameliorated focal brain ischemic insult in rats via inhibition of oxidative stress and inflammation. J Ethnopharmacol 151(1):176–182. https://doi.org/10.1016/j.jep.2013.10.026
Chen JY, Zhu GY, Su XH, Wang R, Liu J, Liao K, Ren R, Li T, Liu L (2017) 7-deacetylgedunin suppresses inflammatory responses through activation of Keap1/Nrf2/HO-1 signaling. Oncotarget. 8(33):55051–55063. https://doi.org/10.18632/oncotarget.19017
Li WZ, Wang XH, Zhang HX, Mao SM, Zhao CZ (2016) Protective effect of the n-butanol Toona sinensis seed extract on diabetic nephropathy rat kidneys. Genet Mol Res 15(1):1000. https://doi.org/10.4238/gmr.15017403
Wang XH, Li WZ (2016) Antioxidant activity of polyphenols from Toona sinensis roem seeds and the inhibition of aldose reductase. Afr J Tradit Complement Altern Med 13(1):99–104
Hwang CJ, Kim YE, Son DJ, Park MH, Choi DY, Park PH, Hellström M, Han SB, Oh KW, Park EK, Hong JT (2017) Parkin deficiency exacerbate ethanol-induced dopaminergic neurodegeneration by P38 pathway dependent inhibition of autophagy and mitochondrial function. Redox Biol 11:456–468. https://doi.org/10.1016/j.redox.2016.12.008
Jiang P, Dickson DW (2018) Parkinson's disease: experimental models and reality. Acta Neuropathol 135(1):13–32. https://doi.org/10.1007/s00401-017-1788-5
Paxinos G, Watson C (1985) The rat brain stereotaxic coordinates. Academic Press Sydney 25:87–92
Shah A, Han P, Wong MY, Chang RC, Legido-Quigley C (2019) Palmitate and stearate are increased in the plasma in a 6-OHDA model of Parkinson’s disease. Metabolites 9(2):E31. https://doi.org/10.3390/metabo9020031
Fu W, Zheng Z, Zhuang W, Chen D, Wang X, Sun X, Wang X (2013) Neural metabolite changes in corpus striatum after rat multipotent mesenchymal stem cells transplanted in hemiparkinsonian rats by magnetic resonance spectroscopy. Int J Neurosci 123:883–891. https://doi.org/10.3109/00207454.2013.814132
Mansouri MT, Farbood Y, Sameri MJ, Sarkaki A, Naghizadeh B, Rafeirad M (2013) Neuroprotective effects of oral gallic acid against oxidative stress induced by 6-hydroxydopamine in rats. Food Chem 138(2–3):1028–1233. https://doi.org/10.1016/j.foodchem.2012.11.022
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
Baluchnejadmojarad T, Jamali-Raeufy N, Zabihnejad S, Rabiee N, Roghani M (2017) Troxerutin exerts neuroprotection in 6-hydroxydopamine lesion rat model of Parkinson's disease: possible involvement of PI3K/ERβ signaling. Eur J Pharmacol 801:72–78. https://doi.org/10.1016/j.ejphar.2017.03.002
Yang YL, Cheng X, Li WH, Liu M, Wang YH, Du GH (2019) Kaempferol attenuates LPS-induced striatum injury in mice involving anti-neuroinflammation, maintaining BBB Integrity, and down-regulating the HMGB1/TLR4 pathway. Int J Mol Sci 20(3):491–501. https://doi.org/10.3390/ijms20030491
Tan L, Li J, Wang Y, Tan R (2019) Anti-neuroinflammatory effect of alantolactone through the suppression of the NF-κB and MAPK signaling pathways. Cells 8(7):739–760. https://doi.org/10.3390/cells8070739
Lee Y, Lee S, Chang SC, Lee J (2019) Significant roles of neuroinflammation in Parkinson’s disease: therapeutic targets for PD prevention. Arch Pharm Res 42(5):416–425. https://doi.org/10.1007/s12272-019-01133-0
Oliveira-Junior MS, Pereira EP, de Amorim VCM, Reis LTC, do Nascimento RP, da Silva VDA, Costa SL (2019) Lupeol inhibits LPS-induced neuroinflammation in cerebellar cultures and induces neuroprotection associated to the modulation of astrocyte response and expression of neurotrophic and inflammatory factors. Int Immunopharmacol 70:302–312. https://doi.org/10.1016/j.intimp.2019.02.055
de Wit NM, den Hoedt S, Martinez-Martinez P, Rozemuller AJ, Mulder MT, de Vries HE (2019) Astrocytic ceramide as possible indicator of neuroinflammation. J Neuroinflammation 16(1):48–58. https://doi.org/10.1186/s12974-019-1436-1
Lv R, Du L, Liu X, Zhou F, Zhang Z, Zhang L (2019) Polydatin alleviates traumatic spinal cord injury by reducing microglial inflammation via regulation of iNOS and NLRP3 inflammasome pathway. Int Immunopharmacol 70:28–36. https://doi.org/10.1016/j.intimp.2019.02.006
Singh G, Kaur A, Kaur J, Bhatti MS, Singh P, Bhatti R (2019) Bergapten inhibits chemically induced nociceptive behavior and inflammation in mice by decreasing the expression of spinal PARP, iNOS, COX-2 and inflammatory cytokines. Inflammopharmacology 27(4):749–760. https://doi.org/10.1007/s10787-019-00585-6
Aggarwal BB, Gupta SC, Kim JH (2012) Historical perspectives on tumor necrosis factor and its superfamily: 25 years later, a golden journey. Blood 119(3):651–665. https://doi.org/10.1182/blood-2011-04-325225
Olianas MC, Dedoni S, Onali P (2019) Inhibition of TNF-α-induced neuronal apoptosis by antidepressants acting through the lysophosphatidic acid receptor LPA1. Apoptosis 24(5–6):478–498. https://doi.org/10.1007/s10495-019-01530-2
Li N, Liu BW, Ren WZ, Liu JX, Li SN, Fu SP, Zeng YL, Xu SY, Yan X, Gao YJ, Liu DF, Wang W (2016) GLP-2 Attenuates LPS-induced inflammation in BV-2 cells by inhibiting ERK1/2, JNK1/2 and NF-κB signaling pathways. Int J Mol Sci 17(2):190–200. https://doi.org/10.3390/ijms17020190
Ying H, Wang Y, Gao Z, Zhang Q (2019) Long non-coding RNA activated by transforming growth factor beta alleviates lipopolysaccharide-induced inflammatory injury via regulating microRNA-223 in ATDC5 cells. Int Immunopharmacol 69:313–320. https://doi.org/10.1016/j.intimp.2019.01.056
Pan Z, Niu Y, Liang Y, Zhang X, Dong M (2016) β-Ecdysterone protects SH-SY5Y cells against 6-hydroxydopamine-induced apoptosis via mitochondria-dependent mechanism: involvement of p38 (MAPK)-p53 signaling pathway. Neurotox Res 30(3):453–466. https://doi.org/10.1007/s12640-016-9631-7
Liu Q, Zhang Y, Liu S, Liu Y, Yang X, Liu G, Shimizu T, Ikenaka K, Fan K, Ma J (2019) Cathepsin C promotes microglia M1 polarization and aggravates neuroinflammation via activation of Ca2+-dependent PKC/p38MAPK/NF-κB pathway. J Neuroinflammation 16(1):10–27. https://doi.org/10.1186/s12974-019-1398-3
Giovannini MG, Scali C, Prosperi C, Bellucci A, Vannucchi MG, Rosi S, Pepeu G, Casamenti F (2002) Beta-amyloid-induced inflammation and cholinergic hypofunction in the rat brain in vivo: involvement of the p38 MAPK pathway. Neurobiol Dis 11(2):257–274. https://doi.org/10.1006/nbdi.2002.0538
Choi WS, Eom DS, Han BS, Kim WK, Han BH, Choi EJ, Oh TH, Markelonis GJ, Cho JW, Oh YJ (2004) Phosphorylation of p38 MAPK induced by oxidative stress is linked to activation of both caspase-8-and-9-mediated apoptotic pathways in domaminergic neurons. J Biol Chem 279(19):20451–20460. https://doi.org/10.1074/jbc.M311164200
Yan X, Liu DF, Zhang XY, Liu D, Xu SY, Chen GX, Huang BX, Ren WZ, Wang W, Fu SP, Liu JX (2017) Vanillin protects dopaminergic neurons against inflammation-mediated cell death by inhibiting ERK1/2, P38 and the NF-κB signaling pathway. Int J Mol Sci 18(2):389–400. https://doi.org/10.3390/ijms18020389
Wang CC, Tsai YJ, Hsieh YC, Lin RJ, Lin CL (2014) The aqueous extract from Toona sinensis leaves inhibits microglia-mediated neuroinflammation. Kaohsiung J Med Sci 30(2):73–81. https://doi.org/10.1016/j.kjms.2013.09.012
Yang HL, Huang PJ, Liu YR, Kumar KJ, Hsu LS, Lu TL, Chia YC, Takajo T, Kazunori A, Hseu YC (2014) Toona sinensis inhibits LPS-induced inflammation and migration in vascular smooth muscle cells via suppression of reactive oxygen species and NF-κB signaling pathway. Oxid Med Cell Longev 2014:901315. https://doi.org/10.1155/2014/901315
This research project was supported by the National Natural Science Foundation of China (Grant Number 81870943), the Shandong Province Natural Science Foundation of China (Grant NUMBER ZR2014HL043, and ZR2018LH006), the Shandong Province Science and Technology Development Program of China (Grant Number 2012GSF11827), the Shandong Provincial Education Department of China (Grant Number J11LF16), the Shandong Traditional Chinese Medicine Technology Development Project of China (Grant Number 2017-214), the Shandong Medical and Health Science and Technology Development Program of China (Grant Number 2015WS0063).
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Zhuang, W., Cai, M., Li, W. et al. Polyphenols from Toona sinensiss Seeds Alleviate Neuroinflammation Induced by 6-Hydroxydopamine Through Suppressing p38 MAPK Signaling Pathway in a Rat Model of Parkinson’s Disease. Neurochem Res (2020). https://doi.org/10.1007/s11064-020-03067-2
- Parkinson’s disease
- Polyphenols from toona sinensis seeds
- p38 MAPK