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Drug Res (Stuttg) 2015; 65(10): 555-560
DOI: 10.1055/s-0034-1395544
Original Article
© Georg Thieme Verlag KG Stuttgart · New York

Protective Effect of Proanthocyanidins in Cadmium Induced Neurotoxicity in Mice

C. Dong
1   Department of Neurosurgery, Tianjin Huan Hu Hospital, Tianjin, China
› Author Affiliations
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Publication History

received 05 September 2014

accepted 28 October 2014

Publication Date:
02 December 2014 (online)

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Abstract

Cadmium (Cd) is a potent neurotoxic heavy metal, known to induce oxidative stress and membrane disturbances in brain. Proanthocyanidins (PACs), the most abundant polyphenol class in the human diet, have protective effects on oxidative stress and other metabolic disorders. Based on the cellular protective effect of PACs, we aimed to investigate whether PACs could protect the neuronal cells from Cd-induced excitotoxicity. The experiment was carried out on mice model and also in primary culture of hippocampal neurons isolated from neonatal mice. The Cd-induced changes in acetylcholinesterase (AChE) activity, oxidative stress markers (lipid peroxidation/lipid hydroperoxidation), antioxidant status and Akt phosphorylation were measured in the mice brain with or without PACs treatment. Mice intoxicated with cadmium (5 mg/kg/day) for 4 weeks had significantly (p<0.05) reduced the AChE levels, elevated the levels of oxidative stress markers along with the significant (p<0.05) decrease in the levels of both enzymatic antioxidants and non-enzymatic antioxidants in mice brain tissue. In contrast, administration of PACs (100 mg/kg/day) for 4 weeks in cadmium-intoxicated mice had significantly (p<0.05) protected the cadmium-mediated changes. In addition, PACs treatment in cultured mice hippocampal neurons had protected Cd-induced excitotoxicity by activating Akt phosphorylation, decreasing the caspase-3 level and improving the neuronal cell survival rate up to 24 h. Altogether, our data suggest that PACs plays a crucial role on neuroprotection in combating the cadmium induced oxidative neurotoxicity in mice brain by influencing the activation of AChE/Akt phosphorylation, antioxidant status, controlling the membrane damage (lipid peroxidation) and apoptotic protein caspase-3.

Key words

cadmium - proanthocyanidins - acetylcholinesterase - oxidative stress
 

  • References

  • 1 Amaral D, Lavenex P. Hippocampal Neuroanatomy. In Andersen P, Morris R, Amaral D, Bliss T, O’Keefe J. The Hippocampus Book. Oxford University Press; 2006
    CrossrefSearch in Google Scholar
  • 2 Rigon AP, Cordova FM, Oliveira CS et al. Neurotoxicity of cadmium on immature hippocampus and a neuroprotective role for p38 MAPK. Neurotoxicology 2008; 29: 727-734
    CrossrefPubMedSearch in Google Scholar
  • 3 Panayi AE, Spyrou NM, Iversen BS et al. Determination of cadmium and zinc in Alzheimer’s brain tissue using inductively coupled plasma mass spectrometry. J Neurol Sci 2002; 195: 1-10
    CrossrefPubMedSearch in Google Scholar
  • 4 Julin B, Wolk A, Bergkvist L et al. Dietary cadmium exposure and risk of postmenopausal breast cancer: a populationbased prospective cohort study. Cancer Res 2012; 72: 1459-1466
    CrossrefPubMedSearch in Google Scholar
  • 5 Sawada N, Iwasaki M, Inoue M et al. Long-term dietary cadmium intake and cancer incidence. Epidemiology 2012; 23: 368-376
    CrossrefPubMedSearch in Google Scholar
  • 6 Wang Y, Fang J, Leonard SS et al. Cadmium inhibits the electron transfer chain and induces reactive oxygen species. Free Radic Biol Med 2004; 36: 1434-1443
    CrossrefPubMedSearch in Google Scholar
  • 7 Abe K, Yuki S, Kogure K. Strong attenuation of ischemic and postischemic brain edema in rats by a novel free radical scavenger. Stroke 1988; 19: 480-485
    CrossrefPubMedSearch in Google Scholar
  • 8 Kaste M, Murayama S, Ford GA et al. Safety, Tolerability and Pharmacokinetics of MCI-186 in Patients with Acute Ischemic Stroke: New Formulation and Dosing Regimen. Cerebrovasc Dis 2013; 36: 196-204
    CrossrefPubMedSearch in Google Scholar
  • 9 Landete JM. Updated knowledge about polyphenols: functions, bioavailability, metabolism, and health. Crit Rev Food Sci Nutr 2012; 52: 936-948
    CrossrefPubMedSearch in Google Scholar
  • 10 Crozier A, Jaganath IB, Clifford MN. Dietary phenolics: chemistry, bioavailability and effects on health. Nat Prod Rep 2009; 26: 1001-1043
    CrossrefPubMedSearch in Google Scholar
  • 11 Serrano J, Puupponen-Pimiä R, Dauer A et al. Current knowledge of food sources, intake, bioavailability and biological effects. Mol Nutr Food Res 2009; 53: 310-329
    CrossrefPubMedSearch in Google Scholar
  • 12 Nakamura Y, Tsuji S, Tonogai Y. Analysis of proanthocyanidins in grape seed extracts, health foods and grape seed oils. J Health Sci 2003; 49: 45-54
    CrossrefPubMedSearch in Google Scholar
  • 13 Bagchi D, Bagchi M, Sj Stohs et al. Cellular protection with proanthocyanidins derived from grape seeds. Ann N Y Acad Sci 2002; 957: 260-270
    CrossrefPubMedSearch in Google Scholar
  • 14 Ashtiyani SC, Najafi H, Firouzifar MR et al. Grape seed extract for reduction of renal disturbances following reperfusion in rats. Iran J Kidney Dis 2013; 7: 28-35
    PubMedSearch in Google Scholar
  • 15 Savaj S. Grape seed for prevention of reperfusion injury. Iran J Kidney Dis 2013; 7: 1-2
    PubMedSearch in Google Scholar
  • 16 Wei R, Ding R, Wang Y et al. Grape seed proanthocyanidin extract reduces renal Ischemia/reperfusion injuries in rats. Am J Med Sci 2012; 343: 452-457
    CrossrefPubMedSearch in Google Scholar
  • 17 Bladé C, Arola L, Salvadó MJ. Hypolipidemic effects of proanthocyanidins and their underlying biochemical and molecular mechanisms. Mol Nutr Food Res 2010; 54: 37-59
    CrossrefPubMedSearch in Google Scholar
  • 18 Nandakumar V, Singh T, Katiyar S. Multi-targeted prevention and therapy of cancer by proanthocyanidins. Cancer Lett 2008; 269: 378-387
    CrossrefPubMedSearch in Google Scholar
  • 19 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: 248-254
    CrossrefPubMedSearch in Google Scholar
  • 20 Ellman GL, Courtney KD, Andres VJ et al. A new and rapid colorimetric determination of acetyl cholinesterase activity. Biochem Pharmacol 1961; 7: 88-95
    CrossrefPubMedSearch in Google Scholar
  • 21 Draper HH, Hadley M. Malondialdehyde determination as index of lipid peroxidation. Method Enzymol 1990; 186: 421-431
    PubMedSearch in Google Scholar
  • 22 Jiang ZY, Hunt JV, Wolff SP. Ferrous ion oxidation in the presence of xylenol orange for detection of lipid hydroperoxides in low density lipoproteins. Anal Biochem 1992; 202: 384-387
    CrossrefPubMedSearch in Google Scholar
  • 23 Kakkar P, Das B, Viswanathan PN. A modified spectroscopic assay of superoxide dismutase. Ind J Biochem Biophys 1984; 21: 130-132
    PubMedSearch in Google Scholar
  • 24 Sinha AK. Colorimetric assay of catalase. Anal Biochem 1972; 47: 389-394
    CrossrefPubMedSearch in Google Scholar
  • 25 Rotruck JT, Pope AL, Ganther HE. Selenium: biochemical role as a component of glutathione peroxidase purification assay. Science 1973; 179: 588-590
    CrossrefPubMedSearch in Google Scholar
  • 26 Habig WH, Pabst MJ, Jakoby WB. Glutathione transferase: a first enzymatic step in mercapturic acid and formation. J Biol Chem 1974; 249: 7130-7139
    PubMedSearch in Google Scholar
  • 27 Moron MS, Despierre JW, Minnervik B. Levels of glutathione, glutathione reductase and glutathione S-transferase activities in rat lung and liver. Biochim Biophys Acta 1979; 582: 67-78
    CrossrefPubMedSearch in Google Scholar
  • 28 Omaye ST, Turbull TD, Sauberlich HC. Selected method for the determination of ascorbic acid in animal cells, tissues and fluids. In: McCormic DB, Wright DL. (eds.) Methods in Enzymology. Academic Press; New York, USA: 1979: 3-11
    Search in Google Scholar
  • 29 Desai ID. Vitamin E analysis method for animal tissues. Method Enzymol 1984; 105: 138-143
    PubMedSearch in Google Scholar
  • 30 Berbari NF, Bishop GA, Askwith CC et al. Hippocampal neurons possess primary cilia in culture. J Neurosci Res 2007; 85: 1095-1100
    CrossrefPubMedSearch in Google Scholar
  • 31 Halliwell B. Oxidative stress and neurodegeneration: Where are we now?. J Neurochem 2006; 97: 1634-1658
    CrossrefPubMedSearch in Google Scholar
  • 32 Lopez E, Arce C, Oset-Gasque MJ et al. Cadmium induces reactive oxygen species generation and lipid peroxidation in cortical neurons in culture. Free Radical Biol Med 2006; 40: 940-951
    CrossrefPubMedSearch in Google Scholar
  • 33 Kumar R, Agarwal AK, Seth PK. Oxidative stress mediated neurotoxicity of cadmium. Toxicol Lett 1996; 89: 65-69
    CrossrefPubMedSearch in Google Scholar
  • 34 Antonio MT, Corredor L, Leret ML. Study of the activity of several brain enzymes like markers of the neurotoxicity induced by perinatal exposure to lead and/or cadmium. Toxicol Lett 2003; 143: 331-340
    CrossrefPubMedSearch in Google Scholar
  • 35 Tsakiris S, Angelogianni P, Schulpis KH et al. Protective effect of L-phenylalanine on rat brain acetylcholinesterase inhibition induced by free radicals. Clin Biochem 2000; 33: 103-106
    CrossrefPubMedSearch in Google Scholar
  • 36 Ashokkumar N, Pari L, Ramkumar KM. N-Benzoyl-D-phenylalanine attenuates brain acetylcholinesterase in neonatal streptozotocin-diabetic rats. Basic Clin Pharmacol Toxicol 2006; 99: 246-250
    CrossrefPubMedSearch in Google Scholar
  • 37 German JB. Food processing and lipid oxidation. Adv Exp Med Biol 1999; 459: 23-50
    PubMedSearch in Google Scholar
  • 38 Gutteridge JMC, Halliwell B. Antioxidants in Nutrition, Health and Disease. Oxford University Press; Oxford, UK: 1994
    Search in Google Scholar
  • 39 Buettner GR. The pecking order of free radicals and antioxidants: lipid peroxidation, alpha-tocopherol, and ascorbate. Arch Biochem Biophys 1993; 300: 535-543
    CrossrefPubMedSearch in Google Scholar
  • 40 Shukla A, Shukla GS, Srimal RC. Cadmium-induced alterations in blood-brain barrier permeability microvessel antioxidant potential in rat. Hum Exp Toxicol 1996; 15: 400-405
    CrossrefPubMedSearch in Google Scholar
  • 41 Feng Z, Wei RB, Hong Q et al. Grape seed extract enhances eNOS expression and NO production through regulating calcium-mediated AKT phosphorylation in H2O2-treated endothelium. Cell Biol Int 2010; 34: 1055-1061
    CrossrefPubMedSearch in Google Scholar
  • 42 Gao D, Xu Z, Qiao P et al. Cadmium induces liver cell apoptosis through caspase-3A activation in purse red common carp (Cyprinus carpio). PLoS One 2013; 8: e83423
    CrossrefPubMedSearch in Google Scholar
  • 43 Wang H, Zhang C, Lu D et al. Oligomeric proanthocyanidin protects retinal ganglion cells against oxidative stress-induced apoptosis. Neural Regen Res 2013; 8: 2317-2326
    PubMedSearch in Google Scholar