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      Naringin Chelates Excessive Iron and Prevents the Formation of Amyloid-Beta Plaques in the Hippocampus of Iron-Overloaded Mice

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          Abstract

          Metal chelating agents are antioxidant agents, which decrease the reductive potential and stabilize the oxidized metal ion form. In this study, we evaluated the naringin capacity in chelating iron and preventing amyloid-beta plaque formation in the hippocampus of iron-overloaded mice. Thirty-five NMRI male mice (8–10 weeks old) were provided. The mice were classified into five groups. Iron dextran was administered as i.p. injection (100 mg/kg/day) four times a week for four subsequent weeks. The treated groups received 30 and 60 mg/kg/day naringin for a month. After histological processing, the brain sections were stained with Perls’ stain kit for iron spots, and Congo red was used to stain the brain and hippocampus for amyloid-beta plaques. 30 mg/kg/day of naringin was shown to decrease nonheme iron in an efficient manner; iron content in this group decreased to 16.83 ± 0.57 μg/g wet weight, a quantity as low as that observed in the normal saline-receiving group. The nonheme iron content in the mice receiving 60 mg/kg/day of naringin was 20.73 ± 0.65 μg/g wet weight. In addition, Aβ plaque numbers in CA1, CA3, and DG areas of the hippocampus decreased significantly following treatment with 30 or 60 mg/kg/day naringin. Naringin has a strong iron chelation capacity and is able to reduce the formation of amyloid plaques. So it can be useful for neuroprotection and prevention of Alzheimer’s disease.

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          Most cited references46

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          Prevention of cytotoxicity and inhibition of intercellular communication by antioxidant catechins isolated from Chinese green tea.

          An antioxidant fraction of Chinese green tea (green tea antioxidant; GTA), containing several catechins, has been previously shown to inhibit 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced tumor promotion in mouse skin. In the present study, GTA was shown to have antioxidative activity toward hydrogen peroxide (H2O2) and the superoxide radical (O2-). GTA also prevented oxygen radical and H2O2-induced cytotoxicity and inhibition of intercellular communication in cultured B6C3F1 mouse hepatocytes and human keratinocytes (NHEK cells). GTA (0.05-50 micrograms/ml) prevented the killing of hepatocytes (measured by lactate dehydrogenase release) by paraquat (1-10 mM) and glucose oxidase (0.8-40 micrograms/ml) in a concentration-dependent fashion. GTA (50 micrograms/ml) also prevented the inhibition of hepatocyte intercellular communication by paraquat (5 mM), glucose oxidase (0.8 micrograms/ml), and phenobarbital (500 micrograms/ml). In addition, GTA (50 micrograms/ml) prevented the inhibition of intercellular communication in human keratinocytes by TPA (100 ng/ml). Cytotoxicity and inhibition of intercellular communication, two possible mechanisms by which tumor promoters may produce their promoting effects were therefore prevented by GTA. The inhibition of these two effects of pro-oxidant compounds may suggest a mechanism by which GTA inhibits tumor promotion in vivo.
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            Iron, brain ageing and neurodegenerative disorders.

            There is increasing evidence that iron is involved in the mechanisms that underlie many neurodegenerative diseases. Conditions such as neuroferritinopathy and Friedreich ataxia are associated with mutations in genes that encode proteins that are involved in iron metabolism, and as the brain ages, iron accumulates in regions that are affected by Alzheimer's disease and Parkinson's disease. High concentrations of reactive iron can increase oxidative-stress induced neuronal vulnerability, and iron accumulation might increase the toxicity of environmental or endogenous toxins. By studying the accumulation and cellular distribution of iron during ageing, we should be able to increase our understanding of these neurodegenerative disorders and develop new therapeutic strategies.
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              Copper, iron and zinc in Alzheimer's disease senile plaques.

              Concentrations of copper (Cu), iron (Fe) and zinc (Zn) were measured in the rims and cores of senile plaques (SP) and in the neuropil of the amygdala of nine Alzheimer's disease (AD) patients and in the neuropil of the amygdala of five neurologically normal control subjects using micro particle-induced X-ray emission (micro-PIXE). Comparison of SP rim and core values revealed no significant differences between levels of Cu, Fe or Zn. Zinc and Fe in SP rims and cores were significantly elevated in AD compared with AD neuropil (P<0.05). Copper was significantly elevated (P<0.05) in the rim of SP compared with AD neuropil. Comparison of AD and control neuropil revealed a significant (P<0.05) elevation of Zn in AD subjects. The elevation of these elements in SP in AD is of interest in light of the observation that Cu, Fe and particularly Zn, can accelerate aggregation of amyloid beta peptide.
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                Author and article information

                Contributors
                Journal
                Front Pharmacol
                Front Pharmacol
                Front. Pharmacol.
                Frontiers in Pharmacology
                Frontiers Media S.A.
                1663-9812
                02 July 2021
                2021
                : 12
                : 651156
                Affiliations
                [ 1 ]Neuroscience Research Center, Department of Anatomy, Faculty of Medicine, Golestan University of Medical Sciences, Gorgan, Iran
                [ 2 ]Neuroscience Research Center, Golestan University of Medical Sciences, Gorgan, Iran
                [ 3 ]Infectious Diseases Research Center, Golestan University of Medical Sciences, Gorgan, Iran
                Author notes

                Edited by: Philippe De Deurwaerdere, Université de Bordeaux, France

                Reviewed by: Nikhil Baban Ghate, University of Southern California, United States

                Somdet Srichairatanakool, Chiang Mai University, Thailand

                This article was submitted to Neuropharmacology, a section of the journal Frontiers in Pharmacology

                Article
                651156
                10.3389/fphar.2021.651156
                8283124
                34276359
                8689c23b-f6a5-4afb-81ec-c2f04821f521
                Copyright © 2021 Jahanshahi, Khalili and Margedari.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 15 January 2021
                : 04 June 2021
                Funding
                Funded by: Golestan University of Medical Sciences 10.13039/501100008091
                Categories
                Pharmacology
                Original Research

                Pharmacology & Pharmaceutical medicine
                iron chelation,brain,hippocampus,naringin,amyloid-β plaque
                Pharmacology & Pharmaceutical medicine
                iron chelation, brain, hippocampus, naringin, amyloid-β plaque

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