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01-12-2021 | Parkinson's Disease | Research article

Neuroprotective effects of pomegranate (Punica granatum L.) juice and seed extract in paraquat-induced mouse model of Parkinson’s disease

Authors: Samah M. Fathy, Heba A. El-Dash, Noha I. Said

Published in: BMC Complementary Medicine and Therapies | Issue 1/2021

Abstract

Background

Paraquat, (PQ), an herbicide that can induce Parkinsonian-like symptoms in rodents and humans. The consumption of phytochemical-rich plants can reduce the risk of chronic illnesses such as inflammation and neurodegenerative diseases. The present study aimed to investigate the protective effects of pomegranate seed extract (PSE) and juice (PJ) against PQ-induced neurotoxicity in mice.

Methods

Mice were assigned into 4 groups; three groups received PQ (10 mg/kg, i.p.) twice a week for 3 weeks. Two of the PQ-induced groups pretreated with either PSE or PJ. Detection of phytochemicals, total phenolics, and total flavonoids in PSE and PJ was performed. Tyrosine hydroxylase (TH) level was measured in the substantia nigra (SN) by Western blotting technique. Striatal dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) were detected using high-performance liquid chromatography (HPLC). The levels of adenosine triphosphate (ATP), malondialdehyde (MDA), and the activity of the antioxidant enzymes were estimated in the striatum by colorimetric analysis. Striatal pro-inflammatory and anti-inflammatory markers using enzyme-linked immunosorbent assay (ELISA) as well as DNA fragmentation degree by qualitative DNA fragmentation assay, were evaluated. Real-time polymerase chain reaction (qPCR) assay was performed for the detection of nuclear factor kappa B (NF-кB) gene expression. Moreover, Western blotting analysis was used for the estimation of the cluster of differentiation 11b (CD11b), transforming growth factor β (TGF-β), and glial cell-derived neurotrophic factor (GDNF) levels in the striatum.

Results

Pretreatment with PSE or PJ increased the levels of TH in the SN as well as DA and its metabolite in the striatum that were reduced by PQ injection. PSE and PJ preadministration improved the PQ-induced oxidative stress via a significant reduction of the MDA level and the augmentation of antioxidant enzyme activities. PSE and PJ also significantly downregulated the striatal NF-кB gene expression, reduced the PQ-enhanced apoptosis, decreased the levels of; pro-inflammatory cytokines, CD11b, and TGF-β coupled with a significant increase of; interleukin-10 (IL-10), GDNF, and ATP levels as compared with PQ-treated mice.

Conclusions

The current study indicated that PSE and PJ consumption may exhibit protective effects against PQ-induced neurotoxicity in mice.

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Zeng XS, Geng WS, Jia JJ. Neurotoxin-induced animal models of Parkinson disease: pathogenic mechanism and assessment. ASN neuro. 2018;10:1759091418777438.CrossRefPubMedPubMedCentral

Giasson BI, Ischiropoulos H, Lee VM, Trojanowski JQ. The relationship between oxidative/nitrative stress and pathological inclusions in Alzheimer’s and Parkinson’s diseases. Free Radic Biol Med. 2002;32(12):1264–75. https://doi.org/10.1016/S0891-5849(02)00804-3.CrossRefPubMed

Maiti P, Manna J, Dunbar GL. Current understanding of the molecular mechanisms in Parkinson's disease: targets for potential treatments. Transl Neurodegen. 2017;6(1):28. https://doi.org/10.1186/s40035-017-0099-z.CrossRef

Johnson ME, Zhou XF, Bobrovskaya L. The effects of rotenone on TH, BDNF and BDNF-related proteins in the brain and periphery: relevance to early Parkinson’s disease. J Chem Neuroanat. 2019;97:23–32. https://doi.org/10.1016/j.jchemneu.2019.01.010.CrossRefPubMed

Nakashima A, Ota A, Kaneko YS, Mori K, Nagasaki H, Nagatsu T. A possible pathophysiological role of tyrosine hydroxylase in Parkinson’s disease suggested by postmortem brain biochemistry: a contribution for the special 70th birthday symposium in honor of prof. Peter Riederer J Neural Transmission. 2013;120(1):49–54. https://doi.org/10.1007/s00702-012-0828-5.CrossRef

Seet RC, Lee CY, Lim EC, Tan JJ, Quek AM, Chong WL, et al. Oxidative damage in Parkinson disease: measurement using accurate biomarkers. Free Radic Biol Med. 2010;48(4):560–6. https://doi.org/10.1016/j.freeradbiomed.2009.11.026.CrossRefPubMed

Poewe W, Seppi K, Tanner CM, Halliday GM, Brundin P, Volkmann J, et al. Parkinson disease. Nat Rev Dis Primers. 2017;3(1):17013. https://doi.org/10.1038/nrdp.2017.13.CrossRefPubMed

Nisticò R, Mehdawy B, Piccirilli S, Mercuri N. Paraquat-and rotenone-induced models of Parkinson's disease. Int J Immunopathol Pharmacol. 2011;24(2):313–22. https://doi.org/10.1177/039463201102400205.CrossRefPubMed

Shafique H, Blagrove A, Chung A, Logendrarajah R. Causes of Parkinson’s disease: literature review. J Parkinsonism Restless Legs Syndr. 2011;1(1):5–7. https://doi.org/10.2147/JPRLS.S37041.CrossRef

10.

Cha ES, Khang YH, Lee WJ. Mortality from and incidence of pesticide poisoning in South Korea: findings from National Death and Health Utilization Data between 2006 and 2010. PLoS One. 2014;9:4.

11.

Vaccari C, El Dib R, de Camargo JL. Paraquat and Parkinson’s disease: a systematic review protocol according to the OHAT approach for hazard identification. Syst Rev. 2017;6(1):98. https://doi.org/10.1186/s13643-017-0491-x.CrossRefPubMedPubMedCentral

12.

McCormack AL, Thiruchelvam M, Manning-Bog AB, Thiffault C, Langston JW, Cory-Slechta DA, et al. Environmental risk factors and Parkinson’s disease: selective degeneration of nigral dopaminergic neurons caused by the herbicide paraquat. Neurobiol Dis. 2002;10(2):119–27. https://doi.org/10.1006/nbdi.2002.0507.CrossRefPubMed

13.

Rappold PM, Cui M, Chesser AS, Tibbett J, Grima JC, Duan L, et al. Paraquat neurotoxicity is mediated by the dopamine transporter and organic cation transporter-3. Proc Natl Acad Sci. 2011;108(51):20766–71. https://doi.org/10.1073/pnas.1115141108.CrossRefPubMedPubMedCentral

14.

Blanco-Ayala T, Andérica-Romero AC, Pedraza-Chaverri J. New insights into antioxidant strategies against paraquat toxicity. Free Radic Res. 2014;48(6):623–40. https://doi.org/10.3109/10715762.2014.899694.CrossRefPubMed

15.

Hirsch EC, Vyas S, Hunot S. Neuroinflammation in Parkinson’s disease. Parkinsonism Relat Disord. 2012;18:S210–2. https://doi.org/10.1016/S1353-8020(11)70065-7.CrossRefPubMed

16.

Olajide OA, Kumar A, Velagapudi R, Okorji UP, Fiebich BL. Punicalagin inhibits neuroinflammation in LPS-activated rat primary microglia. Mol Nutr Food Res. 2014;58(9):1843–51. https://doi.org/10.1002/mnfr.201400163.CrossRefPubMed

17.

Mitroshina ЕV, Mishchenko TA, Shirokova OM, Astrakhanova TA, Loginova MM, Epifanova EA, et al. Intracellular neuroprotective mechanisms in neuron-glial networks mediated by glial cell line-derived neurotrophic factor. Oxidative Med Cell Longev. 2019;18:2019.

18.

Sidorova YA, Saarma M. Small molecules and peptides targeting glial cell line-derived Neurotrophic factor receptors for the treatment of Neurodegeneration. Int J Mol Sci. 2020;21(18):6575. https://doi.org/10.3390/ijms21186575.CrossRefPubMedCentral

19.

Wang H, Liu J, Gao G, Wu X, Wang X, Yang H. Protection effect of piperine and piperlonguminine from Piper longum L alkaloids against rotenone-induced neuronal injury. Brain Res. 2016;1639:214–27. https://doi.org/10.1016/j.brainres.2015.07.029.CrossRefPubMed

20.

Mukherjee S, Dugad S, Bhandare R, Pawar N, Jagtap S, Pawar PK, et al. Evaluation of comparative free-radical quenching potential of Brahmi (Bacopa monnieri) and Mandookparni (Centella asiatica). Ayu. 2011;32(2):258–64. https://doi.org/10.4103/0974-8520.92549.CrossRefPubMedPubMedCentral

21.

Guo S, Yan J, Yang T, Yang X, Bezard E, Zhao B. Protective effects of green tea polyphenols in the 6-OHDA rat model of Parkinson’s disease through inhibition of ROS-NO pathway. Biol Psychiatry. 2007;62(12):1353–62. https://doi.org/10.1016/j.biopsych.2007.04.020.CrossRefPubMed

22.

Doostan F, Vafafar R, Zakeri-Milani P, Pouri A, Afshar RA, Abbasi MM. Effects of pomegranate (Punica granatum L.) seed and peel methanolic extracts on oxidative stress and lipid profile changes induced by methotrexate in rats. Adv Pharm Bull. 2017;7(2):269.CrossRefPubMedPubMedCentral

23.

Prasad D, Kunnaiah R. Punica granatum: a review on its potential role in treating periodontal disease. J Indian soc Periodontol. 2014;18(4):428–32. https://doi.org/10.4103/0972-124X.138678.CrossRefPubMedPubMedCentral

24.

Hartman RE, Shah A, Fagan AM, Schwetye KE, Parsadanian M, Schulman RN, et al. Pomegranate juice decreases amyloid load and improves behavior in a mouse model of Alzheimer’s disease. Neurobiol Dis. 2006;24(3):506–15. https://doi.org/10.1016/j.nbd.2006.08.006.CrossRefPubMed

25.

Rezaee S, Jahromy MH. Potential Effects of Pomegranate Juice in Attenuating LID in Mice Model of Parkinson Disease. Pharm J. 2018;10:4.

26.

Fathy SM, Drees EA. Protective effects of Egyptian cloudy apple juice and apple peel extract on lipid peroxidation, antioxidant enzymes and inflammatory status in diabetic rat pancreas. BMC Complement Altern Med. 2016;16:8.CrossRefPubMedPubMedCentral

27.

Sun AY, Wang Q, Simonyi A, Sun GY. Botanical phenolics and brain health. NeuroMolecular Med. 2008;10(4):259–74. https://doi.org/10.1007/s12017-008-8052-z.CrossRefPubMedPubMedCentral

28.

Velioglu YS, Mazza G, Gao L, Oomah BD. Antioxidant activity and total phenolics in selected fruits, vegetables, and grain products. J Agric Food Chem. 1998;46(10):4113–7. https://doi.org/10.1021/jf9801973.CrossRef

29.

Zhishen J, Mengcheng T, Jianming W. The determination of flavonoid contents in mulberry and their scavenging effects on superoxide radicals. Food Chem. 1999;64(4):555–9. https://doi.org/10.1016/S0308-8146(98)00102-2.CrossRef

30.

Shah TA, Parikh M, Patel KV, Patel KG, Joshi CG, Gandhi TR. Evaluation of the effect of Punica granatum juice and punicalagin on NFκB modulation in inflammatory bowel disease. Mol Cell Biochem. 2016;419(1–2):65–74. https://doi.org/10.1007/s11010-016-2750-x.CrossRefPubMed

31.

Jiao Y, Lu L, Williams RW, Smeyne RJ. Genetic dissection of strain dependent paraquat-induced neurodegeneration in the substantia nigra pars compacta. PLoS One. 2012;7:1.

32.

Smeyne RJ, Breckenridge CB, Beck M, Jiao Y, Butt MT, Wolf JC, et al. Assessment of the effects of MPTP and paraquat on dopaminergic neurons and microglia in the substantia nigra pars compacta of C57BL/6 mice. PLoS One. 2016;11:10.CrossRef

33.

Cristóvão AC, Campos FL, Je G, Esteves M, Guhathakurta S, Yang L, et al. Characterization of a Parkinson’s disease rat model using an upgraded paraquat exposure paradigm. Eur J Neurosci. 2020;00(4):1–13. https://doi.org/10.1111/ejn.14683.CrossRef

34.

Paxinos G, Franklin KBJ. The mouse brain in stereotaxic coordinates. 2nd ed. San Diego: Academic Press; 2001.

35.

Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976;72(1-2):248–54. https://doi.org/10.1016/0003-2697(76)90527-3.CrossRefPubMed

36.

Chi JD, Odontiadis J, Franklin M. Simultaneous determination of catecholamines in rat brain tissue by high-performance liquid chromatography. J Chromatogr B Biomed Sci Appl. 1999;731(2):361–7. https://doi.org/10.1016/S0378-4347(99)00255-8.CrossRefPubMed

37.

Esterbauer H, Cheeseman KH. Determination of aldehydic lipid peroxidation products: malonaldehyde and 4-hydroxynonenal. Methods Enzymol. 1990;186:407–21. https://doi.org/10.1016/0076-6879(90)86134-H.CrossRefPubMed

38.

Paglia DE, Valentine WN. Studies on the quantitative and qualitative characterization of erythrocyte glutathione peroxidase. J Lab Clin Med. 1967;70(1):158–69. https://doi.org/10.5555/uri:pii:0022214367900765.CrossRefPubMed

39.

Sambrook J, Fritsch EF, Maniatis T. Molecular cloning: a laboratory manual. 2nd ed. New York: CSH Cold Spring Harbor Press; 1989.

40.

Fathy S, Said N. Immunomodulation and antigenotoxic effects of propolis in paclitaxel-treated rats. Egyptian J Zool. 2019;72(72):45–56. https://doi.org/10.12816/ejz.2019.18937.1017.CrossRef

41.

Wu T, Yin J, Zhang G, Long H, Zheng X. Mulberry and cherry anthocyanin consumption prevents oxidative stress and inflammation in diet-induced obese mice. Mol Nutr Food Res. 2016 Mar;60(3):687–94. https://doi.org/10.1002/mnfr.201500734.CrossRefPubMed

42.

Yamamoto H, Omelchenko I, Shi X, Nuttall AL. The influence of NF-κB signal-transduction pathways on the murine inner ear by acoustic overstimulation. J Neurosci Res. 2009 Jun;87(8):1832–40. https://doi.org/10.1002/jnr.22018.CrossRefPubMedPubMedCentral

43.

Lee J, Jo DG, Park D, Chung HY, Mattson MP. Adaptive cellular stress pathways as therapeutic targets of dietary phytochemicals: focus on the nervous system. Pharmacol Rev. 2014;66(3):815–68. https://doi.org/10.1124/pr.113.007757.CrossRefPubMedPubMedCentral

44.

Kang MJ, Gil SJ, Koh HC. Paraquat induces alternation of the dopamine catabolic pathways and glutathione levels in the substantia nigra of mice. Toxicol Lett. 2009;188(2):148–52. https://doi.org/10.1016/j.toxlet.2009.03.026.CrossRefPubMed

45.

Kuter K, Śmiałowska M, Wierońska J, Zięba B, Wardas J, Pietraszek M, et al. Toxic influence of subchronic paraquat administration on dopaminergic neurons in rats. Brain Res. 2007;1155:196–207. https://doi.org/10.1016/j.brainres.2007.04.018.CrossRefPubMed

46.

Ortega-Arellano HF, Jimenez-Del-Rio M, Velez-Pardo C. Dmp53, basket and drICE gene knockdown and polyphenol gallic acid increase life span and locomotor activity in a Drosophila Parkinson’s disease model. Genet Mol Biol. 2013;36(4):608–15. https://doi.org/10.1590/S1415-47572013000400020.CrossRefPubMedPubMedCentral

47.

Calabrese V, Santoro A, Monti D, Crupi R, Di Paola R, Latteri S, et al. Aging and Parkinson's disease: Inflammaging, neuroinflammation and biological remodeling as key factors in pathogenesis. Free Radic Biol Med. 2018;115:80–91. https://doi.org/10.1016/j.freeradbiomed.2017.10.379.CrossRefPubMed

48.

Zhang X, Shang P, Qin F, Zhou Q, Gao B, Huang H, et al. Chemical composition and antioxidative and anti-inflammatory properties of ten commercial mung bean samples. LWT-food Sci Technol. 2013;54(1):171–8. https://doi.org/10.1016/j.lwt.2013.05.034.CrossRef

49.

Ortiz MS, Forti KM, Martinez EB, Muñoz LG, Husain K, Muñiz WH. Effects of antioxidant N-acetylcysteine against paraquat-induced oxidative stress in vital tissues of mice. Int J Sci Basic Appl Res. 2016;26(1):26–46.PubMedPubMedCentral

50.

Chaudhuri A, Bowling K, Funderburk C, Lawal H, Inamdar A, Wang Z, et al. Interaction of genetic and environmental factors in a Drosophila parkinsonism model. J Neurosci. 2007;27(10):2457–67. https://doi.org/10.1523/JNEUROSCI.4239-06.2007.CrossRefPubMedPubMedCentral

51.

Schwartz M, Kipnis J, Rivest S, Prat A. How do immune cells support and shape the brain in health, disease, and aging? J Neurosci. 2013;33(45):17587–96. https://doi.org/10.1523/JNEUROSCI.3241-13.2013.CrossRefPubMedPubMedCentral

52.

Stojkovska I, Wagner BM, Morrison BE. Parkinson’s disease and enhanced inflammatory response. Exp Biol Med. 2015;240(11):1387–95. https://doi.org/10.1177/1535370215576313.CrossRef

53.

Sanchez-Guajardo V, Barnum CJ, Tansey MG, Romero-Ramos M. Neuroimmunological processes in Parkinson's disease and their relation to α-synuclein: microglia as the referee between neuronal processes and peripheral immunity. ASN Neuro. 2013;5(2):AN20120066. https://doi.org/10.1042/AN20120066.CrossRef

54.

Ben Youssef S, Brisson G, Doucet-Beaupré H, Castonguay AM, Gora C, Amri M, et al. Neuroprotective benefits of grape seed and skin extract in a mouse model of Parkinson’s disease. Nutr Neurosci. 2019;1:1–15.

55.

Hostetler GL, Ralston RA, Schwartz SJ. Flavones: food sources, bioavailability, metabolism, and bioactivity. Adv Nutr. 2017;8(3):423–35. https://doi.org/10.3945/an.116.012948.CrossRefPubMedPubMedCentral

56.

Nonaka M, Chen XH, Pierce JE, Leoni MJ, Mcintosh TK, Wolf JA, et al. Prolonged activation of NF-κB following traumatic brain injury in rats. J Neurotrauma. 1999;16(11):1023–34. https://doi.org/10.1089/neu.1999.16.1023.CrossRefPubMed

57.

Chen AC, Arany PR, Huang YY, Tomkinson EM, Sharma SK, Kharkwal GB, et al. Low-level laser therapy activates NF-kB via generation of reactive oxygen species in mouse embryonic fibroblasts. PLoS One. 2011;6:7.

58.

Ilbey YO, Ozbek E, Simsek A, Cekmen M, Somay A, Tasci AI. Effects of pomegranate juice on hyperoxaluria-induced oxidative stress in the rat kidneys. Ren Fail. 2009;31(6):522–31. https://doi.org/10.1080/08860220902963871.CrossRefPubMed

59.

Li LY, Zhao XL, Fei XF, Gu ZL, Qin ZH, Liang ZQ. Bilobalide inhibits 6-OHDA-induced activation of NF-κB and loss of dopaminergic neurons in rat substantia nigra. Acta Pharmacol Sin. 2008;29(5):539–47. https://doi.org/10.1111/j.1745-7254.2008.00787.x.CrossRefPubMed

60.

Lin CM, Huang ST, Liang YC, Lin MS, Shih CM, Chang YC, et al. Isovitexin suppresses lipopolysaccharide-mediated inducible nitric oxide synthase through inhibition of NF-kappa B in mouse macrophages. Planta Med. 2005;71(08):748–53. https://doi.org/10.1055/s-2005-871287.CrossRefPubMed

61.

Kessler JA, Von De Water TR. Growth factors as drugs for neurological and sensory disorders. Introduction Ciba Foundation Symposium. 1996;196:1–2.PubMed

62.

Buckwalter MS, Wyss-Coray T. Modelling neuroinflammatory phenotypes in vivo. J Neuroinflammation. 2004;1(1):10. https://doi.org/10.1186/1742-2094-1-10.CrossRefPubMedPubMedCentral

63.

Taylor A, Verhagen J, Blaser K, Akdis M, Akdis CA. Mechanisms of immune suppression by interleukin-10 and transforming growth factor-beta: the role of T regulatory cells. Immunology. 2006;117(4):433–42. https://doi.org/10.1111/j.1365-2567.2006.02321.x.CrossRefPubMedPubMedCentral

64.

Cacheaux LP, Ivens S, David Y, Lakhter AJ, Bar-Klein G, Shapira M, et al. Transcriptome profiling reveals TGF-beta signaling involvement in ep./..ileptogenesis. J Neurosci. 2009;29:8927–35. https://doi.org/10.1523/JNEUROSCI.0430-09.2009.CrossRefPubMedPubMedCentral

65.

David Y, Cacheaux LP, Ivens S, Lapilover E, Heinemann U, Kaufer D, et al. Astrocytic dysfunction in epileptogenesis: consequence of altered potassium and glutamate homeostasis? J Neurosci. 2009;29(34):10588–99. https://doi.org/10.1523/JNEUROSCI.2323-09.2009.CrossRefPubMedPubMedCentral

66.

Schuster N, Krieglstein K. Mechanisms of TGF-β-mediated apoptosis. Cell Tissue Res. 2002;307(1):1–4. https://doi.org/10.1007/s00441-001-0479-6.CrossRefPubMed

Title: Neuroprotective effects of pomegranate (Punica granatum L.) juice and seed extract in paraquat-induced mouse model of Parkinson’s disease
Authors: Samah M. Fathy
Heba A. El-Dash
Noha I. Said
Publication date: 01-12-2021
Publisher: BioMed Central
Keyword: Parkinson's Disease
Published in: BMC Complementary Medicine and Therapies / Issue 1/2021
Electronic ISSN: 2662-7671
DOI: https://doi.org/10.1186/s12906-021-03298-y

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Neuroprotective effects of pomegranate (Punica granatum L.) juice and seed extract in paraquat-induced mouse model of Parkinson’s disease

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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