Proanthocyanidins exert a neuroprotective effect via ROS/JNK signaling in MPTP‑induced Parkinson's disease models in vitro and in vivo

Chen,Hucheng; Xu,Jiyu; Lv,Yuan; He,Ping; Liu,Chunyan; Jiao,Jie; Li,Shiwei; Mao,Xuhua; Xue,Xue

doi:10.3892/mmr.2018.9509

Proanthocyanidins exert a neuroprotective effect via ROS/JNK signaling in MPTP‑induced Parkinson's disease models in vitro and in vivo

Authors:
- Hucheng Chen
- Jiyu Xu
- Yuan Lv
- Ping He
- Chunyan Liu
- Jie Jiao
- Shiwei Li
- Xuhua Mao
- Xue Xue
View Affiliations

Affiliations: Department of Nuclear Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210006, P.R. China, Department of Clinical Laboratory, Yixing People Hospital, Affiliated Jiangsu University, Yixing, Jiangsu 214200, P.R. China
Published online on: September 25, 2018 https://doi.org/10.3892/mmr.2018.9509
Pages: 4913-4921
Copyright: © Chen et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The pathological alterations of Parkinson's disease (PD) predominantly manifest as a loss of dopaminergic neurons in the substantia nigra, which may be caused by oxidative stress damage. Proanthocyanidins (PCs) are a class of compounds found in various plants, which have significant antioxidant and free radical‑scavenging activity. The present study investigated the protective effects and underlying mechanisms of PCs in a 1‑methyl‑4‑phenyl‑1,2,3,6‑tetrahydropyridine (MPTP)‑induced PD model in vitro and in vivo. MTT assays were used to detect cell viability, and flow cytometry and TUNEL assays were used to detect cell apoptosis. Mitochondrial membrane potential (MMP) alterations were investigated using a JC‑1 MMP Assay kit. The pole test was used to measure motor behavior in a mouse model of PD. Levels of reactive oxygen species (ROS) were measured using the fluorescent probe, 2',7'‑dichlorodihydrofluorescein diacetate. Immunohistochemistry and western blotting were performed to detect the expression levels of proteins associated with PD. In vitro, it was demonstrated that in MPTP‑treated PC12 cells, PCs increased cell viability and reduced cell apoptosis in a dose‑dependent manner. In vivo, it was revealed that PC treatment inhibited striatal dopamine depletion, which resulted in significant improvements in PD‑like movement impairment. Reactive oxygen species (ROS) production and MPTP‑induced apoptosis were also inhibited. Furthermore, the results demonstrated that the neuroprotective activity of PCs may be mediated via the inhibition of ROS generation, as well as modulation of c‑Jun N‑terminal kinase activation. Taken together, these data revealed that PCs may exert neuroprotective effects in in vivo and in vitro PD models, and may have potential in the prevention or treatment of PD.

View Figures

View References

1	Keeney PM, Xie J, Capaldi RA and Bennett JP Jr: Parkinson's disease brain mitochondrial complex I has oxidatively damaged subunits and is functionally impaired and misassembled. J Neurosci. 26:5256–5264. 2006. View Article : Google Scholar : PubMed/NCBI
2	Jenner P: Oxidative stress in Parkinson's disease. Ann Neurol. 53 Suppl 3:S26–S38. 2003. View Article : Google Scholar : PubMed/NCBI
3	Reynolds A, Laurie C, Mosley RL and Gendelman HE: Oxidative stress and the pathogenesis of neurodegenerative disorders. Int Rev Neurobiol. 82:297–325. 2007. View Article : Google Scholar : PubMed/NCBI
4	Sharpe MA, Han J, Baskin AM and Baskin DS: Design and synthesis of a MAO-B-selectively activated prodrug based on MPTP: A mitochondria-targeting chemotherapeutic agent for treatment of human malignant gliomas. ChemMedChem. 10:621–628. 2015. View Article : Google Scholar : PubMed/NCBI
5	Chalimoniuk M, Snoek GT, Adamczyk A, Małecki A and Strosznajder JB: Phosphatidylinositol transfer protein expression altered by aging and Parkinson disease. Cell Mol Neurobiol. 26:1151–1164. 2006. View Article : Google Scholar
6	Lee WS, Tsai WJ, Yeh PH, Wei BL and Chiou WF: Divergent role of calcium on Abeta- and MPTP-induced cell death in SK-N-SH neuroblastoma. Life Sci. 78:1268–1275. 2006. View Article : Google Scholar : PubMed/NCBI
7	Dalia A, Neff NH and Hadjiconstantinou M: Tyrosine hydroxylase and aromatic L-amino acid decarboxylase in mesencephalic cultures after MPP+: The consequences of treatment with GM1 ganglioside. Brain Res. 742:260–264. 1996. View Article : Google Scholar : PubMed/NCBI
8	Kim MJ, Kim DW, Jeong HJ, Sohn EJ, Shin MJ, Ahn EH, Kwon SW, Kim YN, Kim DS, Park J, et al: Tat-Frataxin protects dopaminergic neuronal cells against MPTP-induced toxicity in a mouse model of Parkinson's disease. Biochimie. 94:2448–2456. 2012. View Article : Google Scholar : PubMed/NCBI
9	Rocarodríguez MM, Lópeztinoco C, Murri M, Fernández-Deudero A, García-Palacios MV, García-Valero MA, Tinahones-Madueño FJ and Aguilar-Diosdado M: Postpartum development of endothelial dysfunction and oxidative stress markers in women with previous gestational diabetes mellitus. J Endocrinol Invest. 37:503–509. 2014. View Article : Google Scholar : PubMed/NCBI
10	Prasad R, Vaid M and Katiyar SK: Grape proanthocyanidin inhibit pancreatic cancer cell growth in vitro and in vivo through induction of apoptosis and by targeting the PI3K/Akt pathway. PLoS One. 7:e430642012. View Article : Google Scholar : PubMed/NCBI
11	Gao X, Cassidy A, Schwarzschild MA, Rimm EB and Ascherio A: Habitual intake of dietary flavonoids and risk of Parkinson disease. Neurology. 78:1138–1145. 2012. View Article : Google Scholar : PubMed/NCBI
12	Strathearn KE, Yousef GG, Grace MH, Roy SL, Tambe MA, Ferruzzi MG, Wu QL, Simon JE, Lila MA and Rochet JC: Neuroprotective effects of anthocyanin- and proanthocyanidin-rich extracts in cellular models of Parkinson's disease. Brain Res. 1555:60–77. 2014. View Article : Google Scholar : PubMed/NCBI
13	Saad AA, Youssef MI and Elshennawy LK: Cisplatin induced damage in kidney genomic DNA and nephrotoxicity in male rats: The protective effect of grape seed proanthocyanidin extract. Food Chem Toxicol. 47:14992009. View Article : Google Scholar : PubMed/NCBI
14	Basli A, Soulet S, Chaher N, Mérillon JM, Chibane M, Monti JP and Richard T: Wine polyphenols: Potential agents in neuroprotection. Oxid Med Cell Longev. 2012:8057622012. View Article : Google Scholar : PubMed/NCBI
15	Park G, Park YJ, Yang HO and Oh MS: Ropinirole protects against 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced neurotoxicity in mice via anti-apoptotic mechanism. Pharmacol Biochem Behav. 104:163–168. 2013. View Article : Google Scholar : PubMed/NCBI
16	Kim HG, Ju MS, Shim JS, Kim MC, Lee SH, Huh Y, Kim SY and Oh MS: Mulberry fruit protects dopaminergic neurons in toxin-induced Parkinson's disease models. Br J Nutr. 104:8–16. 2010. View Article : Google Scholar : PubMed/NCBI
17	Lamine A, Létourneau M, Doan ND, Maucotel J, Couvineau A, Vaudry H, Chatenet D, Vaudry D and Fournier A: Characterizations of a synthetic pituitary adenylate cyclase-activating polypeptide analog displaying potent neuroprotective activity and reduced in vivo cardiovascular side effects in a Parkinson's disease model. Neuropharmacology. 108:440–450. 2015. View Article : Google Scholar : PubMed/NCBI
18	Ariga T and Asao Y: Isolation, identification and organoleptic astringency of dimeric proanthocyanidins occurring in Azuki Beans. J Agric Chem Soc Japan. 45:2709–2712. 2014.
19	Celardo I, Martins LM and Gandhi S: Unravelling mitochondrial pathways to Parkinson's disease. Br J Pharmacol. 171:1943–1957. 2014. View Article : Google Scholar : PubMed/NCBI
20	Leppä S and Bohmann D: Diverse functions of JNK signaling and c-Jun in stress response and apoptosis. Oncogene. 18:6158–6162. 1999. View Article : Google Scholar : PubMed/NCBI
21	Freund TF, Bolam JP, Björklund A, Stenevi U, Dunnett SB, Powell JF and Smith AD: Efferent synaptic connections of grafted dopaminergic neurons reinnervating the host neostriatum: A tyrosine hydroxylase immunocytochemical study. J Neurosci. 5:603–16. 1985. View Article : Google Scholar : PubMed/NCBI
22	Dragicevic N, Smith A, Lin X, Yuan F, Copes N, Delic V, Tan J, Cao C, Shytle RD and Bradshaw PC: Green tea epigallocatechin-3-gallate (EGCG) and other flavonoids reduce Alzheimer's amyloid-induced mitochondrial dysfunction. J Alzheimers Dis. 26:507–521. 2011. View Article : Google Scholar : PubMed/NCBI
23	Laschober GT, Ruli D, Hofer E, Muck C, Carmona-Gutierrez D, Ring J, Hutter E, Ruckenstuhl C, Micutkova L, Brunauer R, et al: Identification of evolutionarily conserved genetic regulators of cellular aging. Aging Cell. 9:1084–1097. 2010. View Article : Google Scholar : PubMed/NCBI
24	Hartley A, Stone JM, Heron C, Cooper JM and Schapira AH: Complex I inhibitors induce dose-dependent apoptosis in PC12 cells: Relevance to Parkinson's disease. J Neurochem. 63:1987–1990. 1994. View Article : Google Scholar : PubMed/NCBI
25	Kuchta K, Qiao HX, Huang HB, Fang L, Chen Y and Wang RW: The neuroprotective activity of a proanthocyanidin enriched Ginkgo biloba L. leaves extract in vitro and in vivo. Planta Medica. 81 Suppl 1:S1–S381. 2016.
26	Li L, Zhang Y, Sun B, Zhang H, Tao W, Tian J, Ye X and Chen S: The neuroprotective effects of Chinese bayberry leaves proanthocyanidins. J Funct Foods. 40:554–563. 2018. View Article : Google Scholar
27	Agrawal S, Singh A, Tripathi P, Mishra M, Singh PK and Singh MP: Cypermethrin-induced nigrostriatal dopaminergic neurodegeneration alters the mitochondrial function: A proteomics study. Mol Neurobiol. 51:448–465. 2015. View Article : Google Scholar : PubMed/NCBI
28	Huang QR, Li Q, Chen YH, Li L, Liu LL, Lei SH, Chen HP, Peng WJ and He M: Involvement of anion exchanger-2 in apoptosis of endothelial cells induced by high glucose through an mPTP-ROS-Caspase-3 dependent pathway. Apoptosis. 15:693–704. 2010. View Article : Google Scholar : PubMed/NCBI
29	Lu M, Su C, Qiao C, Bian Y, Ding J and Hu G: Metformin prevents dopaminergic neuron death in MPTP/P-induced mouse model of Parkinson's disease via autophagy and mitochondrial ROS clearance. Int J Neuropsychopharmacol. 19:pyw0472016. View Article : Google Scholar : PubMed/NCBI
30	Stefanis L, Burke RE and Greene LA: Apoptosis in neurodegenerative disorders. Curr Opin Neurol. 10:299–305. 1997. View Article : Google Scholar : PubMed/NCBI
31	Hoehn MM and Yahr MD: Parkinsonism: Onset, progression, and mortality. Neurology. 17:427–442. 1967. View Article : Google Scholar : PubMed/NCBI
32	Kim SY, Kim MY, Mo JS, Park JW and Park HS: SAG protects human neuroblastoma SH-SY5Y cells against 1-methyl-4-phenylpyridinium ion (MPP+)-induced cytotoxicity via the downregulation of ROS generation and JNK signaling. Neurosci Lett. 413:132–136. 2007. View Article : Google Scholar : PubMed/NCBI
33	Voss T and Ravina B: Neuroprotection in Parkinson's disease: Myth or reality? Curr Neurol Neurosci Rep. 8:304–309. 2008. View Article : Google Scholar : PubMed/NCBI
34	Zhang L, Xing Y, Ye CF, Ai HX, Wei HF and Li L: Learning-memory deficit with aging in APP transgenic mice of Alzheimer's disease and intervention by using tetrahydroxystilbene glucoside. Behav Brain Res. 173:246–254. 2006. View Article : Google Scholar : PubMed/NCBI