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Sailer J, Nagel J, Akdogan B, Jauch AT, Engler J, Knolle PA, Zischka H. Deadly excess copper. Redox Biol 2024; 75:103256. [PMID: 38959622 PMCID: PMC11269798 DOI: 10.1016/j.redox.2024.103256] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2024] [Revised: 06/13/2024] [Accepted: 06/23/2024] [Indexed: 07/05/2024] Open
Abstract
Higher eukaryotes' life is impossible without copper redox activity and, literally, every breath we take biochemically demonstrates this. However, this dependence comes at a considerable price to ensure target-oriented copper action. Thereto its uptake, distribution but also excretion are executed by specialized proteins with high affinity for the transition metal. Consequently, malfunction of copper enzymes/transporters, as is the case in hereditary Wilson disease that affects the intracellular copper transporter ATP7B, comes with serious cellular damage. One hallmark of this disease is the progressive copper accumulation, primarily in liver but also brain that becomes deadly if left untreated. Such excess copper toxicity may also result from accidental ingestion or attempted suicide. Recent research has shed new light into the cell-toxic mechanisms and primarily affected intracellular targets and processes of such excess copper that may even be exploited with respect to cancer therapy. Moreover, new therapies are currently under development to fight against deadly toxic copper.
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Affiliation(s)
- Judith Sailer
- Institute of Toxicology and Environmental Hygiene, Technical University Munich, School of Medicine and Health, Munich, Germany
| | - Judith Nagel
- Institute of Toxicology and Environmental Hygiene, Technical University Munich, School of Medicine and Health, Munich, Germany
| | - Banu Akdogan
- Institute of Molecular Toxicology and Pharmacology, Helmholtz Munich, German Research Center for Environmental Health, Neuherberg, Germany
| | - Adrian T Jauch
- Institute of Toxicology and Environmental Hygiene, Technical University Munich, School of Medicine and Health, Munich, Germany
| | - Jonas Engler
- Institute of Toxicology and Environmental Hygiene, Technical University Munich, School of Medicine and Health, Munich, Germany
| | - Percy A Knolle
- Institute of Molecular Immunology and Experimental Oncology, Technical University Munich, School of Medicine and Health, Munich, Germany
| | - Hans Zischka
- Institute of Toxicology and Environmental Hygiene, Technical University Munich, School of Medicine and Health, Munich, Germany; Institute of Molecular Toxicology and Pharmacology, Helmholtz Munich, German Research Center for Environmental Health, Neuherberg, Germany.
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Raschke S, Bornhorst J, Schwerdtle T. Se supplementation to an in vitro blood-brain barrier does not affect Cu transfer into the brain. J Trace Elem Med Biol 2023; 78:127180. [PMID: 37201367 DOI: 10.1016/j.jtemb.2023.127180] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Revised: 03/26/2023] [Accepted: 04/26/2023] [Indexed: 05/20/2023]
Abstract
BACKGROUND Dyshomeostasis of copper (Cu) accompanied by Cu accumulation in certain brain areas has been associated with neurodegenerative diseases. One proposed toxic mode of action following Cu overload is oxidative stress associated with neuronal damage, whereas Selenium (Se) is assumed to play here a protective role. This study investigates the relationship between adequate Se supplementation and the respective consequences for Cu transfer into the brain applying an in vitro model of the blood-brain barrier (BBB). METHODS Primary porcine brain capillary endothelial cells (PBCECs) seeded on Transwell® inserts were supplemented with selenite starting at cultivation in both compartments. After apical application of 15 or 50 µM CuSO4, transfer of Cu to the basolateral compartment, the brain facing side, was assessed by ICP-MS/MS. RESULTS Incubation with Cu did not negatively affect the barrier properties, whereas Se had a positive effect. Additionally, Se status improved after selenite supplementation. Transfer of Cu was not affected by selenite supplementation. Under Se-deficient conditions, Cu permeability coefficients decreased with increasing Cu concentrations. CONCLUSION The results of this study do not indicate that under suboptimal Se supplementation more Cu transfers across the BBB to the brain.
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Affiliation(s)
- Stefanie Raschke
- Institute of Nutritional Science, University of Potsdam, Arthur-Scheunert-Allee 114-116, 14558 Nuthetal, Germany
| | - Julia Bornhorst
- Food Chemistry, Faculty of Mathematics and Natural Sciences, University of Wuppertal, Gaußstraße 20, 42119 Wuppertal, Germany; TraceAge - DFG Research Unit on Interactions of Essential Trace Elements in Healthy and Diseased Elderly (FOR 2558), Berlin, Germany
| | - Tanja Schwerdtle
- Institute of Nutritional Science, University of Potsdam, Arthur-Scheunert-Allee 114-116, 14558 Nuthetal, Germany; TraceAge - DFG Research Unit on Interactions of Essential Trace Elements in Healthy and Diseased Elderly (FOR 2558), Berlin, Germany; German Federal Institute for Risk Assessment (BfR), Max-Dohrn-Strasse 8-10, 10589 Berlin, Germany.
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Sun X, Zhang X, Yan H, Wu H, Cao S, Zhao W, Dong T, Zhou A. Protective effect of curcumin on hepatolenticular degeneration through copper excretion and inhibition of ferroptosis. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2023; 113:154539. [PMID: 36898256 DOI: 10.1016/j.phymed.2022.154539] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Revised: 10/05/2022] [Accepted: 11/01/2022] [Indexed: 06/18/2023]
Abstract
BACKGROUND Hepatolenticular degeneration (HLD) is an autosomal recessive disorder concerning copper metabolism. Copper overload is also accompanied by iron overload in HLD patients, which can lead to ferroptosis. Curcumin, the active component in turmeric, has the potential to inhibit ferroptosis. PURPOSE The current study proposed a systematic investigation of the protective effects of curcumin against HLD and the underlying mechanisms. METHODS The protective effect of curcumin on toxic milk (TX) mice was studied. Liver tissue was observed via hematoxylin-eosin (H&E) staining and the ultrastructure of the liver tissue was observed through transmission electron microscopy. Copper levels in the tissues, serum, and metabolites were measured by atomic absorption spectrometry (AAS). In addition, serum and liver indicators were evaluated. In cellular experiments, the effect of curcumin on the viability of rat normal liver cells (BRL-3A) was determined via the 3-[4,5-dimethylthiazol-2-yl)]-2,5-diphenyltetrazolium bromide (MTT) assay. Cell and mitochondrial morphology were observed in curcumin-mediated HLD model cells. The intracellular copper ion fluorescence intensity was observed via fluorescence microscopy, and intracellular copper iron content was detected using AAS. Further, oxidative stress indicators were evaluated. Cellular reactive oxygen species (ROS) and cellular mitochondrial membrane potential were examined via flow cytometry. Furthermore, the expression levels of nuclear factor erythroid-2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and glutathione peroxidase 4 (GPX4) were determined via western blotting (WB). RESULTS The histopathology of the liver confirmed the hepatoprotective effects of curcumin. Curcumin improved copper metabolism in TX mice. Both serum liver enzyme markers and antioxidant enzyme levels indicated the protective effect of curcumin against HLD-related liver injury. The MTT assay results showed that curcumin was protective against excess copper-induced injury. Curcumin improved the morphology of HLD model cells and their mitochondrial morphology. The Cu2+ fluorescent probe and the AAS results indicated that curcumin reduced Cu2+ content in HLD hepatocytes. In addition, curcumin improved oxidative stress levels and prevented the decline of mitochondrial membrane potential in HLD model cells. The ferroptosis inducer Erastin reversed these effects of curcumin. WB revealed that curcumin promoted Nrf2, HO-1, and GPX4 protein expression in HLD model cells, and the Nrf2 inhibitor ML385 reversed the effects of curcumin. CONCLUSION Curcumin demonstrates a protective role by expelling copper and inhibiting ferroptosis, activating the Nrf2/HO-1/GPX4 signaling pathway in HLD.
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Affiliation(s)
- Xun Sun
- The Experimental Research Center, Anhui University of Chinese Medicine, Hefei, 230038, China
| | - Xinyu Zhang
- The Experimental Research Center, Anhui University of Chinese Medicine, Hefei, 230038, China
| | - Hui Yan
- The Experimental Research Center, Anhui University of Chinese Medicine, Hefei, 230038, China
| | - Hongfei Wu
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei, 230038, China; Anhui Province Key Laboratory of Research and Development of Chinese Medicine, Anhui Province Key Laboratory of Chinese Medicinal Formula, Hefei, 230038, China.
| | - Shijian Cao
- The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, 230031, China
| | - Wenchen Zhao
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh 15219, United States
| | - Ting Dong
- The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, 230031, China
| | - An Zhou
- The Experimental Research Center, Anhui University of Chinese Medicine, Hefei, 230038, China; Anhui Province Key Laboratory of Research and Development of Chinese Medicine, Anhui Province Key Laboratory of Chinese Medicinal Formula, Hefei, 230038, China.
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Chen K, Wu L, Liu Q, Tan F, Wang L, Zhao D, Fang X, Liu X, Liu J, Han H. Glutathione improves testicular spermatogenesis through inhibiting oxidative stress, mitochondrial damage, and apoptosis induced by copper deposition in mice with Wilson disease. Biomed Pharmacother 2023; 158:114107. [PMID: 36502753 DOI: 10.1016/j.biopha.2022.114107] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Revised: 12/02/2022] [Accepted: 12/05/2022] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND AND OBJECTIVE There are considerable evidence of reproductive impairment in male organisms with Wilson disease (WD). The purpose of this study was to observe spermatogenesis, mitochondrial damage, apoptosis, and the level of oxidative stress in the testes of Wilson disease model TX mice, and to observe the effect and mechanism of glutathione on testicular spermatogenesis. METHODS Mice were divided into a normal control group (control group), Wilson disease model TX mice group (WD group), penicillamine-treated TX mice group (penicillamine group) and glutathione-treated TX mice group (glutathione group). Testicular coefficient, histomorphology of testis and epididymis, number of spermatozoa, apoptosis of spermatogenic cells and expression of apoptosis-related proteins were observed. Ultrastructural analysis of mitochondria and mitochondrial membrane potential (MMP) monitored using JC-1 dye were used to detect mitochondrial damage. The levels of malondialdehyde (MDA), glutathione (GSH), catalase (CAT), and reactive oxygen species (ROS) in testicular cells were measured to assess oxidative stress. RESULTS Testicular coefficient did not change in mice with Wilson disease. However, the tissue structure of the testicular seminiferous tubules was damaged, and the number of spermatozoa in the epididymal lumen was significantly reduced in WD group. The apoptosis rate in the testes was significantly increased. The protein expression of the pro-apoptotic proteins Bax and Caspase-3 significantly increased, and the expressions of the anti-apoptotic protein Bcl-2 significantly decreased. The levels of ROS and MDA significantly increased, and the levels of CAT and GSH significantly decreased. Mitochondria with abnormal ultrastructure and the rate of JC-1 positive cells were significantly increased in the WD group. After copper chelation by penicillamine, the structure of the testicular seminiferous tubules and the number of spermatozoa in the epididymal lumen were significantly improved. The number of apoptotic cells was significantly reduced. The levels of Bax and Caspase-3 decreased, and the expression of Bcl-2 increased. The contents of CAT and GSH increased, and the levels of ROS and MDA decreased significantly. The abnormal mitochondria and JC-1 positive cells was significantly decreased. The histomorphology of seminiferous tubules, spermatogenic function, apoptosis rate, apoptosis-related proteins, mitochondrial damage, and oxidative stress in Wilson disease TX mice significantly improved after glutathione treatment. CONCLUSION Copper deposition in Wilson disease can lead to oxidative stress injury, mitochondrial damage, and apoptosis in the testis, leading to the impairment of spermatogenesis. Glutathione may improve testicular spermatogenesis in male Wilson disease TX mice by inhibiting copper deposition-induced oxidative stress, mitochondrial damage, and apoptosis.
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Affiliation(s)
- Kuiyu Chen
- Department of Neurology, The First Affiliated Hospital of Anhui University of Traditional Chinese Medicine, Hefei 230031, China
| | - Limin Wu
- Reproductive and genetic branch, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China.
| | - Qianzhuo Liu
- Department of Neurology, The First Affiliated Hospital of Anhui University of Traditional Chinese Medicine, Hefei 230031, China
| | - Fang Tan
- Department of Neurology, The First Affiliated Hospital of Anhui University of Traditional Chinese Medicine, Hefei 230031, China
| | - Luyao Wang
- Department of Neurology, The First Affiliated Hospital of Anhui University of Traditional Chinese Medicine, Hefei 230031, China
| | - Dan Zhao
- Department of Neurology, The First Affiliated Hospital of Anhui University of Traditional Chinese Medicine, Hefei 230031, China
| | - Xinru Fang
- Department of Neurology, The First Affiliated Hospital of Anhui University of Traditional Chinese Medicine, Hefei 230031, China
| | - Xiang Liu
- Department of Neurology, The First Affiliated Hospital of Anhui University of Traditional Chinese Medicine, Hefei 230031, China
| | - Jiabo Liu
- Department of Neurology, The First Affiliated Hospital of Anhui University of Traditional Chinese Medicine, Hefei 230031, China
| | - Hui Han
- Department of Neurology, The First Affiliated Hospital of Anhui University of Traditional Chinese Medicine, Hefei 230031, China.
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Dev S, Muchenditsi A, Gottlieb A, Deme P, Murphy S, Gabrielson KL, Dong Y, Hughes R, Haughey NJ, Hamilton JP, Lutsenko S. Oxysterol misbalance critically contributes to Wilson disease pathogenesis. SCIENCE ADVANCES 2022; 8:eadc9022. [PMID: 36260680 PMCID: PMC9581482 DOI: 10.1126/sciadv.adc9022] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 05/14/2023]
Abstract
Wilson disease (WD) is a metabolic disorder caused by inactivation of the copper-transporting ATPase 2 (ATP7B) and copper (Cu) overload in tissues. Excess Cu causes oxidative stress and pathologic changes with poorly understood mechanistic connections. In Atp7b-/- mice with established liver disease, Cu overload activates the stress-sensitive transcription factor Nrf2 (nuclear factor erythroid-derived 2-like 2). Nrf2 targets, especially sulfotransferase 1e1 (Sult1e1), are strongly induced and cause elevation of sulfated sterols, whereas oxysterols are decreased. This sterol misbalance results in inhibition of the liver X receptor (LXR) and up-regulation of LXR targets associated with inflammatory responses. Pharmacological inhibition of Sult1e1 partially reverses oxysterol misbalance and LXR inhibition. Contribution of this pathway to advanced hepatic WD was demonstrated by treating mice with an LXR agonist. Treatment decreased inflammation by reducing expression of proinflammatory molecules, diminished fibrosis by down-regulating the noncanonical transforming growth factor-β signaling pathway, and improved liver morphology and function. Thus, the identified pathway is an important driver of WD.
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Affiliation(s)
- Som Dev
- Department of Physiology, Johns Hopkins University, School of Medicine, 725 North Wolfe St, Baltimore, MD 21205, USA
| | - Abigael Muchenditsi
- Department of Physiology, Johns Hopkins University, School of Medicine, 725 North Wolfe St, Baltimore, MD 21205, USA
| | - Aline Gottlieb
- Department of Physiology, Johns Hopkins University, School of Medicine, 725 North Wolfe St, Baltimore, MD 21205, USA
| | - Pragney Deme
- Department of Neurology, Johns Hopkins University, School of Medicine, 600 North Wolfe St, Baltimore, MD 21287, USA
| | - Sean Murphy
- Department of Biomedical Engineering, Johns Hopkins University, School of Medicine, 720 Rutland Ave, Baltimore, MD 21205, USA
| | - Kathleen L. Gabrielson
- Department of Molecular and Comparative Pathobiology, Johns Hopkins University, School of Medicine, 733 North Broadway, Baltimore, MD 21205, USA
| | - Yixuan Dong
- Department of Physiology, Johns Hopkins University, School of Medicine, 725 North Wolfe St, Baltimore, MD 21205, USA
| | - Robert Hughes
- Department of Medicine, Johns Hopkins University, School of Medicine, 733 North Broadway, Baltimore, MD 21205, USA
| | - Norman J. Haughey
- Department of Neurology, Johns Hopkins University, School of Medicine, 600 North Wolfe St, Baltimore, MD 21287, USA
| | - James P. Hamilton
- Department of Medicine, Johns Hopkins University, School of Medicine, 733 North Broadway, Baltimore, MD 21205, USA
- Corresponding author. (S.L.); (J.P.H.)
| | - Svetlana Lutsenko
- Department of Physiology, Johns Hopkins University, School of Medicine, 725 North Wolfe St, Baltimore, MD 21205, USA
- Department of Medicine, Johns Hopkins University, School of Medicine, 733 North Broadway, Baltimore, MD 21205, USA
- Corresponding author. (S.L.); (J.P.H.)
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Tang S, Bai L, Hou W, Hu Z, Chen X, Zhao J, Liang C, Zhang W, Duan Z, Zheng S. Comparison of the Effectiveness and Safety of d-Penicillamine and Zinc Salt Treatment for Symptomatic Wilson Disease: A Systematic Review and Meta-Analysis. Front Pharmacol 2022; 13:847436. [PMID: 35370752 PMCID: PMC8975209 DOI: 10.3389/fphar.2022.847436] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2022] [Accepted: 01/31/2022] [Indexed: 12/21/2022] Open
Abstract
Background: Pharmacological therapy is currently the main treatment method for patients with Wilson disease (WD). We aimed to evaluate the efficacy and safety of the common treatment regimens in these patients. Methods: We conducted a systemic review and meta-analysis by searching multiple databases for studies from inception to October 2021. Outcomes of interest were the improved rate and safety of d-penicillamine and zinc salts treatment in WD patients. Two independent reviewers performed the study selection and data extraction. Results: Sixteen studies were included in this meta-analysis. The pooled improved rate for all included symptomatic WD patients was 78.0% (95% CI: 70.8%-85.2%). In symptomatic hepatic WD patients, there is no difference in the treatment efficiency of d-penicillamine and zinc salts (RR: 0.98, 95% CI: 0.86%-1.12%; p = 0.765). In neurological WD patients, the pooled improved rate of those who received d-penicillamine and zinc salts was 56.3% (95% CI: 37.5%-75.1%) and 80.2% (95% CI: 67.2%-93.2%), respectively. The incidence of adverse effects (RR: 2.42, 95% CI: 1.20%-4.88%; p = 0.014) and neurological deterioration (RR: 1.96, 95% CI: 1.31%-2.93%; p = 0.001) in all symptomatic WD patients treated with d-penicillamine was both higher than that of patients treated with zinc salts. Conclusion: Our analysis suggests that symptomatic WD patients treated with d-penicillamine have higher incidence of adverse effects and neurological deterioration than that of zinc salts. The therapeutic effectiveness of these two regimens does not seem to be significantly different, and these results must be interpreted with caution. Systematic Review Registration: PROSPERO registration, identifier CRD 42021287126.
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Affiliation(s)
- Shan Tang
- The First Unit, Department of Hepatology, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - Li Bai
- The Fourth Unit, Department of Hepatology, Beijing YouAn Hospital, Capital Medical University, Beijing, China
- Beijing Key Laboratory of Liver Failure and Artificial Liver Treatment Research, Beijing, China
| | - Wei Hou
- The First Unit, Department of Hepatology, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - Zhongjie Hu
- The First Unit, Department of Hepatology, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - Xinyue Chen
- The First Unit, Department of Hepatology, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - Jing Zhao
- The First Unit, Department of Hepatology, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - Chen Liang
- The First Unit, Department of Hepatology, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - Wei Zhang
- The First Unit, Department of Hepatology, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - Zhongping Duan
- The Fourth Unit, Department of Hepatology, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - Sujun Zheng
- The First Unit, Department of Hepatology, Beijing YouAn Hospital, Capital Medical University, Beijing, China
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Thankappan B, Bhattacharya K. Wilson's disease update: An Indian perspective. Ann Indian Acad Neurol 2022; 25:43-53. [PMID: 35342245 PMCID: PMC8954307 DOI: 10.4103/aian.aian_1070_21] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Accepted: 01/22/2022] [Indexed: 11/10/2022] Open
Abstract
Wilson's disease (WD) is an autosomal recessive disorder due to ATP7B gene mutation, resulting in defective copper metabolism, with liver and brain being primarily affected. Being a treatable disorder, early diagnosis and proper management of WD may result in near complete recovery. It has received significant attention over the past 50 years, with several Indian contributions. This study collates published Indian studies on WD in Pubmed and Embase databases and puts them in perspective. Several Indian case series suggest that WD may be more prevalent than thought. Commonly detected ATP7B mutation in India is p.C271X. Although initial Indian series reported significant osseomuscular presentation, neuropsychiatric and hepatic manifestations dominated the later reports. A significant male predominance is observed in Indian series. Pure hepatic presentation starts earlier than neurological or osseomuscular WD. A positive family history may be seen in nearly 50% of Indian WD cases with a high rate of consanguinity. Up to two-third of Indian cases may be initially misdiagnosed, with a mean diagnostic delay of up to 2 years. Abnormalities in serum ceruloplasmin and 24-hour urinary copper has been reported in more than four-fifth cases. Brain MRI is abnormal in nearly all neurological WD cases. Copper chelation remains the mainstay of therapy, with D-penicillamine being the most widely used chelator in India. Global Assessment Scale for WD is a comprehensive tool for clinical monitoring. Hepatic presentation carries a five-time higher mortality risk than neurological, with up to 90% Indian neurological WD cases recovering to pre-morbid functionality with adequate therapy.
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Borchard S, Raschke S, Zak KM, Eberhagen C, Einer C, Weber E, Müller SM, Michalke B, Lichtmannegger J, Wieser A, Rieder T, Popowicz GM, Adamski J, Klingenspor M, Coles AH, Viana R, Vendelbo MH, Sandahl TD, Schwerdtle T, Plitz T, Zischka H. Bis-choline tetrathiomolybdate prevents copper-induced blood-brain barrier damage. Life Sci Alliance 2021; 5:5/3/e202101164. [PMID: 34857647 PMCID: PMC8675913 DOI: 10.26508/lsa.202101164] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Revised: 11/16/2021] [Accepted: 11/17/2021] [Indexed: 11/24/2022] Open
Abstract
The blood–brain barrier endothelial cell monolayer becomes permeable to elevated copper loosely bound to albumin, which can be avoided by a high-affinity copper chelator but not by D-penicillamine. In Wilson disease, excessive copper accumulates in patients’ livers and may, upon serum leakage, severely affect the brain according to current viewpoints. Present remedies aim at avoiding copper toxicity by chelation, for example, by D-penicillamine (DPA) or bis-choline tetrathiomolybdate (ALXN1840), the latter with a very high copper affinity. Hence, ALXN1840 may potentially avoid neurological deterioration that frequently occurs upon DPA treatment. As the etiology of such worsening is unclear, we reasoned that copper loosely bound to albumin, that is, mimicking a potential liver copper leakage into blood, may damage cells that constitute the blood-brain barrier, which was found to be the case in an in vitro model using primary porcine brain capillary endothelial cells. Such blood–brain barrier damage was avoided by ALXN1840, plausibly due to firm protein embedding of the chelator bound copper, but not by DPA. Mitochondrial protection was observed, a prerequisite for blood–brain barrier integrity. Thus, high-affinity copper chelators may minimize such deterioration in the treatment of neurologic Wilson disease.
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Affiliation(s)
- Sabine Borchard
- Institute of Molecular Toxicology and Pharmacology, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany
| | - Stefanie Raschke
- Institute of Nutritional Science, University of Potsdam, Nuthetal, Germany.,TraceAge-Deutsche Forschungsgemeinschaft Research Unit on Interactions of Essential Trace Elements in Healthy and Diseased Elderly (Forschungsgruppe 2558), Berlin-Potsdam-Jena-Wuppertal, Germany
| | - Krzysztof M Zak
- Institute of Structural Biology, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany
| | - Carola Eberhagen
- Institute of Molecular Toxicology and Pharmacology, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany
| | - Claudia Einer
- Institute of Molecular Toxicology and Pharmacology, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany
| | - Elisabeth Weber
- Institute of Molecular Toxicology and Pharmacology, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany
| | - Sandra M Müller
- Institute of Nutritional Science, University of Potsdam, Nuthetal, Germany
| | - Bernhard Michalke
- Research Unit Analytical BioGeoChemistry, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany
| | - Josef Lichtmannegger
- Institute of Molecular Toxicology and Pharmacology, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany
| | - Albrecht Wieser
- Institute of Radiation Medicine, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany
| | - Tamara Rieder
- Technical University Munich, School of Medicine, Institute of Toxicology and Environmental Hygiene, Munich, Germany
| | - Grzegorz M Popowicz
- Institute of Structural Biology, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany
| | - Jerzy Adamski
- Research Unit Molecular Endocrinology and Metabolism, Genome Analysis Center, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.,Lehrstuhl für Experimentelle Genetik, Technical University Munich, Freising-Weihenstephan, Germany.,Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Martin Klingenspor
- Chair of Molecular Nutritional Medicine, Technical University of Munich, School of Life Sciences Weihenstephan, Freising, Germany.,Else-Kröner Fresenius Center for Nutritional Medicine, Technical University of Munich, Freising, Germany
| | | | - Ruth Viana
- Alexion AstraZeneca Rare Disease, Boston, MA, USA
| | - Mikkel H Vendelbo
- Department of Nuclear Medicine and Positron Emission Tomography Centre, Aarhus University Hospital, Aarhus, Denmark.,Department of Biomedicine, Aarhus University, Aarhus C, Denmark
| | - Thomas D Sandahl
- Medical Department Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | - Tanja Schwerdtle
- Institute of Nutritional Science, University of Potsdam, Nuthetal, Germany.,TraceAge-Deutsche Forschungsgemeinschaft Research Unit on Interactions of Essential Trace Elements in Healthy and Diseased Elderly (Forschungsgruppe 2558), Berlin-Potsdam-Jena-Wuppertal, Germany
| | | | - Hans Zischka
- Institute of Molecular Toxicology and Pharmacology, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany .,Technical University Munich, School of Medicine, Institute of Toxicology and Environmental Hygiene, Munich, Germany
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Seetharaman J, Sarma MS. Chelation therapy in liver diseases of childhood: Current status and response. World J Hepatol 2021; 13:1552-1567. [PMID: 34904029 PMCID: PMC8637676 DOI: 10.4254/wjh.v13.i11.1552] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Revised: 05/07/2021] [Accepted: 08/20/2021] [Indexed: 02/06/2023] Open
Abstract
Chelation is the mainstay of therapy in certain pediatric liver diseases. Copper and iron related disorders require chelation. Wilson’s disease (WD), one of the common causes of cirrhosis in children is treated primarily with copper chelating agents like D-penicillamine and trientine. D-Penicillamine though widely used due its high efficacy in hepatic WD is fraught with frequent adverse effects resulting discontinuation. Trientine, an alternative drug has comparable efficacy in hepatic WD but has lower frequency of adverse effects. The role of ammonium tetra-thiomolybdate is presently experimental in hepatic WD. Indian childhood cirrhosis is related to excessive copper ingestion, rarely seen in present era. D-Penicillamine is effective in the early part of this disease with reversal of clinical status. Iron chelators are commonly used in secondary hemochromatosis of liver in hemolytic anemias. There are strict chelation protocols during bone marrow transplant. The role of iron chelation in neonatal hemochromatosis is presently not in vogue due to its poor efficacy and availability of other modalities of therapy. Hereditary hemochromatosis is rare in children and the use of iron chelators in this condition is limited.
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Affiliation(s)
- Jayendra Seetharaman
- Department of Pediatric Gastroenterology, Sanjay Gandhi Post-graduate Institute of Medical Sciences, Lucknow 226014, Uttar Pradesh, India
| | - Moinak Sen Sarma
- Department of Pediatric Gastroenterology, Sanjay Gandhi Post-graduate Institute of Medical Sciences, Lucknow 226014, Uttar Pradesh, India
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Zhou ZH, Wu YF, Yan Y, Liu AQ, Yu QY, Peng ZX, Wang GQ, Hong MF. Persistence with medical treatment for Wilson disease in China based on a single center's survey research. Brain Behav 2021; 11:e02168. [PMID: 33949793 PMCID: PMC8213922 DOI: 10.1002/brb3.2168] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Revised: 03/08/2021] [Accepted: 04/17/2021] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Wilson's disease (WD) is one of the few hereditary diseases that can be successfully treated with medicines. We conduct this survey research to assess treatment persistence among patients with WD and try to identify what factors affect the treatment persistence. METHODS We employed WeChat which is the most popular social software in China to carry out this anonymous questionnaire research. The questionnaire included medication adherence scale. We also collected available medical records related to demographic and clinical characteristics. All the patients were divided into group of persistence with drug treatment (PDT) and nonpersistence with drug treatment (n-PDT). RESULTS We collected 242 qualified questionnaires. Only 66.5% of patients were PDT during the mean 12.6 years of follow-up. In PDT group, better outcomes were observed: improvement (78.3%) and no change (16.1%) versus those in n-PDT (55.6%; and 28.4%, respectively). In PDT group, only nine patients deteriorated (6.8%) in comparison with 13 patients in n-PDT (16.0%). The adverse events (AEs) in PDT group were significantly less than those in n-PDT group. There were no significant differences in clinical type, gender, age, education level, and family knowledge about WD between the two groups. There were significant differences in AEs and family position toward treatment. CONCLUSION Medication Adherence of Chinese WD patients was low. One third of the patients (33.5%) were unable to PDT, and it had an important negative effect on clinical outcome. AEs and family support had an important impact on treatment persistence.
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Affiliation(s)
- Zhi-Hua Zhou
- Department of Neurology, The first affiliated hospital, School of Clinical Medicine of Guangdong Pharmaceutical University, Guangzhou, China
| | - Yun-Fan Wu
- The Second School of Clinical Medicine, Southern Medical University, Guangdong Second Provincial General Hospital, Guangzhou, China
| | - Yan Yan
- Wilson Disease Centre, Hospital Affiliated to Institute of Neurology, Anhui University of Chinese Traditional Medicine, Hefei, China
| | - Ai-Qun Liu
- Department of Neurology, The first affiliated hospital, School of Clinical Medicine of Guangdong Pharmaceutical University, Guangzhou, China
| | - Qing-Yun Yu
- Department of Neurology, The first affiliated hospital, School of Clinical Medicine of Guangdong Pharmaceutical University, Guangzhou, China
| | - Zhong-Xing Peng
- Department of Neurology, The first affiliated hospital, School of Clinical Medicine of Guangdong Pharmaceutical University, Guangzhou, China
| | - Gong-Qiang Wang
- Wilson Disease Centre, Hospital Affiliated to Institute of Neurology, Anhui University of Chinese Traditional Medicine, Hefei, China
| | - Ming-Fan Hong
- Department of Neurology, The first affiliated hospital, School of Clinical Medicine of Guangdong Pharmaceutical University, Guangzhou, China
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Movement Disorder in Wilson Disease: Correlation with MRI and Biomarkers of Cell Injury. J Mol Neurosci 2020; 71:338-346. [DOI: 10.1007/s12031-020-01654-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Accepted: 06/30/2020] [Indexed: 02/07/2023]
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Kalita J, Kumar V, Misra UK, Bora HK. Movement Disorder in Copper Toxicity Rat Model: Role of Inflammation and Apoptosis in the Corpus Striatum. Neurotox Res 2019; 37:904-912. [PMID: 31811585 DOI: 10.1007/s12640-019-00140-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2019] [Revised: 10/31/2019] [Accepted: 11/08/2019] [Indexed: 12/14/2022]
Abstract
The pattern of copper (Cu) toxicity in humans is similar to Wilson disease, and they have movement disorders and frequent involvement of corpus striatum. The extent of cell deaths in corpus striatum may be the basis of movement disorder and may be confirmed in the experimental study. To evaluate the extent of apoptosis and glial activation in corpus striatum following Cu toxicity in a rat model, and correlate these with spontaneous locomotor activity (SLA), six male Wistar rats were fed normal saline (group I) and another six were fed copper sulfate 100 mg/kgBWt/daily orally (group II). At 1 month, neurobehavioral studies including SLA, rotarod, and grip strength were done. Corpus striatum was removed and was subjected to glial fibrillary acidic protein (GFAP) and caspase-3 immunohistochemistry. The concentration of tissue Cu, total antioxidant capacity (TAC), glutathione (GSH), malondialdehyde (MDA), and glutamate were measured. Group II rats had higher expression of caspase-3 (Mean ± SEM 32.67 ± 1.46 vs 4.47 ± 1.08; p < 0.01) and GFAP (41.81 ± 1.68 vs 31.82 ± 1.27; p < 0.01) compared with group I. Neurobehavioral studies revealed reduced total distance traveled, time moving, the number of rearing, latency to fall on the rotarod, grip strength, and increased resting time compared with group I. The expression of GFAP and caspase-3 correlated with SLA parameters, tissue Cu, GSH, MDA, TAC, and glutamate levels. The impaired locomotor activity in Cu toxicity rats is due to apoptotic and inflammatory-mediated cell death in the corpus striatum because of Cu-mediated oxidative stress and excitotoxicity.
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Affiliation(s)
- Jayantee Kalita
- Department of Neurology, Sanjay Gandhi Post Graduate Medical Sciences, Raebareily Road, Lucknow, 226014, India.
| | - Vijay Kumar
- Department of Biotechnology, Yeungnam University, Gyeongsan, Gyeongbuk, 38541, Republic of Korea
| | - Usha K Misra
- Department of Neurology, Sanjay Gandhi Post Graduate Medical Sciences, Raebareily Road, Lucknow, 226014, India
| | - Himangsu K Bora
- National Laboratory Animal Centre, CSIR-Central Drug Research Institute, Lucknow, India
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Kalita J, Kumar V, Misra UK, Parashar V, Ranjan A. Adjunctive Antioxidant Therapy in Neurologic Wilson’s Disease Improves the Outcomes. J Mol Neurosci 2019; 70:378-385. [DOI: 10.1007/s12031-019-01423-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2019] [Accepted: 10/18/2019] [Indexed: 12/21/2022]
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Predictors of seizure in Wilson disease: A clinico-radiological and biomarkers study. Neurotoxicology 2018; 71:87-92. [PMID: 30583001 DOI: 10.1016/j.neuro.2018.12.005] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2018] [Revised: 10/12/2018] [Accepted: 12/20/2018] [Indexed: 12/24/2022]
Abstract
BACKGROUND There is paucity of studies on predictors of seizures in Wilson disease with neurological manifestation (WDNM), and none has evaluated the role of copper (Cu) induced oxidative stress, proinflammatory and excitotoxicity in the genesis of seizure. OBJECTIVES To report frequency, refractoriness, and outcome of seizure in WDNM. We also evaluate role of Cu induced oxidative stress, excitotoxicity and cytokines in predicting seizures. METHODS The diagnosis of WDNM was based on clinical, MRI, KF ring and 24 h urinary Cu. Detailed clinical examination including severity of WD, occurrence of seizure, seizure semiology, antiepileptic drug (AED) and breakthrough seizures were noted. Cranial MRI and electroencephalography findings were noted. Serum free-Cu, oxidative stress markers (glutathione, total antioxidant capacity, malondialdehyde), glutamate and cytokines (interleukin 6, 8 and 10 and tumour necrosis factor α) were measured by atomic absorption spectrophotometer, spectrophotometer, fluorometer and flow cytometer respectively, and correlated with seizures. Patients were treated with zinc with or without penicillamine, and those with epilepsy received second-generation antiepileptic drugs (AEDs). RESULTS Out of 110 patients with WDNM, 16(14.5%) had seizures; focal in 11(68.7%) and generalized in 5(31.3%). Patients with seizure had higher serum free-Cu (35.87 ± 1.34 vs 31.72 ± 0.68; P = 0.02), severe dystonia (P = 0.04), and more frequent cortical (100% vs 6.4%; P < 0.01) and subcortical (81.3% vs 20.2%; P < 0.01) lesions on MRI compared to those without seizure. Oxidative stress markers (glutathione, total antioxidant capacity, malondialdehyde), cytokines and glutamate were elevated in WDNM compared to controls. On multivariate logistic regression analysis, cortical involvement (OR = 105.49; 95%CI = 8.74-1272.39; P < 0.01) and number of MRI lesions (OR = 1.99; 95% CI = 1.11-3.57; P = 0.02) were independent predictors of seizure. The seizures were controlled with single and dual AEDs in seven patients each, and two patients needed three AEDs. All the patients had seizure remission for a median follow up of 66(24-180) months. CONCLUSION About one-sixth WDNM patients have seizures especially in those with cortical and extensive MRI lesions. Seizures are easily controlled by AEDs.
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Zein-polysaccharide nanoparticles as matrices for antioxidant compounds: A strategy for prevention of chronic degenerative diseases. Food Res Int 2018; 111:451-471. [DOI: 10.1016/j.foodres.2018.05.036] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2017] [Revised: 05/14/2018] [Accepted: 05/18/2018] [Indexed: 02/07/2023]
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Bhattacharjee A, Chakraborty K, Shukla A. Cellular copper homeostasis: current concepts on its interplay with glutathione homeostasis and its implication in physiology and human diseases. Metallomics 2018; 9:1376-1388. [PMID: 28675215 DOI: 10.1039/c7mt00066a] [Citation(s) in RCA: 76] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Copper is a trace element essential for almost all living organisms. But the level of intracellular copper needs to be tightly regulated. Dysregulation of cellular copper homeostasis leading to various diseases demonstrates the importance of this tight regulation. Copper homeostasis is regulated not only within the cell but also within individual intracellular compartments. Inactivation of export machinery results in excess copper being redistributed into various intracellular organelles. Recent evidence suggests the involvement of glutathione in playing an important role in regulating copper entry and intracellular copper homeostasis. Therefore interplay of both homeostases might play an important role within the cell. Similar to copper, glutathione balance is tightly regulated within individual cellular compartments. This review explores the existing literature on the role of glutathione in regulating cellular copper homeostasis. On the one hand, interplay of glutathione and copper homeostasis performs an important role in normal physiological processes, for example neuronal differentiation. On the other hand, perturbation of the interplay might play a key role in the pathogenesis of copper homeostasis disorders.
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Kalita J, Naik S, Bhoi SK, Misra UK, Ranjan A, Kumar S. Pontomesencephalic Atrophy and Postural Instability in Wilson Disease. AJNR Am J Neuroradiol 2017; 38:1343-1347. [PMID: 28495941 DOI: 10.3174/ajnr.a5207] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2016] [Accepted: 02/21/2017] [Indexed: 12/28/2022]
Abstract
BACKGROUND AND PURPOSE The MR Parkinsonism index helps in differentiating progressive supranuclear palsy from Parkinson disease and multisystem atrophy. Pontomesencephalic involvement is common in neurologic Wilson disease, but there is no prior study evaluating the MR Parkinsonism index and its indices in Wilson disease. We report the MR Parkinsonism index and its indices in Wilson disease and correlate these changes with clinical severity and postural reflex. MATERIALS AND METHODS Thirteen individuals with neurologic Wilson disease were included, and their clinical details, including neurologic severity, postural reflex abnormality, and location of signal changes on MR imaging, were noted. The 3D BRAVO T1 sequence was used for measurement of the MR Parkinsonism index and its indices. The MR Parkinsonism index and its indices were also obtained in 6 age- and sex-matched controls. The morphometric parameters in Wilson disease were compared with those in with healthy controls and among the patients with and without abnormal postural reflex. RESULTS The midbrain area was reduced in patients with Wilson disease compared with controls (112.08 ± 27.94 versus 171.95 ± 23.66 mm2, P = .002). The patients with an abnormal postural reflex had an increased MR Parkinsonism index and pons-to-midbrain ratio compared with controls, whereas these parameters were equivalent in patients with normal postural reflex and controls. The patients with abnormal postural reflex had more severe illness, evidenced by higher Burke-Fahn-Marsden scores (51.0 ± 32.27 versus 13.75 ± 12.37, P = .04) and neurologic severity grades (2.57 ± 0.53 versus 1.67 ± 0.82, P = .04). CONCLUSIONS An increase in the MR Parkinsonism index in Wilson disease is mainly due to midbrain atrophy and it correlates with neurologic severity and abnormal postural reflex.
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Affiliation(s)
- J Kalita
- From the Departments of Neurology (J.K., S.K.B., U.K.M., A.R.)
| | - S Naik
- Radiology (S.N., S.K.), Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India
| | - S K Bhoi
- From the Departments of Neurology (J.K., S.K.B., U.K.M., A.R.)
| | - U K Misra
- From the Departments of Neurology (J.K., S.K.B., U.K.M., A.R.)
| | - A Ranjan
- From the Departments of Neurology (J.K., S.K.B., U.K.M., A.R.)
| | - S Kumar
- Radiology (S.N., S.K.), Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India
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Memory and Learning Dysfunction Following Copper Toxicity: Biochemical and Immunohistochemical Basis. Mol Neurobiol 2017; 55:3800-3811. [PMID: 28536976 DOI: 10.1007/s12035-017-0619-y] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2017] [Accepted: 05/12/2017] [Indexed: 12/21/2022]
Abstract
The prototype disease of Cu toxicity in human is Wilson disease, and cognitive impairment is the presenting symptom of it. There is no study correlating Cu-induced excitotoxicity, apoptosis, and astrocytic reaction with memory dysfunction. We report excitotoxicity, apoptosis, and astrocytic reaction of the hippocampus and frontal cortex with memory dysfunction in rat model of Cu toxicity. Thirty-six rats were divided into group I (control) and group II (100 mg/kgBwt/day CuSO4 orally). Y-maze was performed for memory and learning at 0, 30, 60, and 90 days. Frontal and hippocampal free Cu concentration, oxidative stress markers [glutathione (GSH), total antioxidant toxicity (TAC), and malondialdehyde (MDA)], and glutamate were measured by atomic absorption spectroscopy, spectrophotometry, and ELISA, respectively. N-methyl-D-aspartate receptors (NMDARs) NR1, NR2A, and NR2B were done by real-time polymerase chain reaction. Immunohistochemistry for caspase-3 and glial fibrillary acidic protein (GFAP) were done and quantified using the ImageJ software. The glutamate level in hippocampus was increased, and NMDAR expression was decreased at 30, 60, and 90 days in group II compared to group I. In the frontal cortex, glutamate was increased at 90 days, but NMDARs were not significantly different in group II compared to group I. Caspase-3 and GFAP expressions were also higher in group II compared to group I, and these changes were more marked in hippocampus than frontal cortex. These changes correlated with respective free tissue Cu, oxidative stress, and Y-maze attention score. Cu toxicity induces apoptosis and astrocytosis of the hippocampus and frontal cortex through direct or glutamate and oxidative stress pathways, and results in impaired memory and learning.
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Kumar V, Kalita J, Bora HK, Misra UK. Temporal kinetics of organ damage in copper toxicity: A histopathological correlation in rat model. Regul Toxicol Pharmacol 2016; 81:372-380. [DOI: 10.1016/j.yrtph.2016.09.025] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2016] [Revised: 08/25/2016] [Accepted: 09/20/2016] [Indexed: 01/17/2023]
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Relationship of antioxidant and oxidative stress markers in different organs following copper toxicity in a rat model. Toxicol Appl Pharmacol 2016; 293:37-43. [PMID: 26780401 DOI: 10.1016/j.taap.2016.01.007] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2015] [Revised: 01/07/2016] [Accepted: 01/08/2016] [Indexed: 11/23/2022]
Abstract
Copper (Cu) at a higher level becomes toxic and it can catalyze the formation of highly reactive hydroxyl radical. We report the vulnerability of liver, kidney and brain to different dose of copper sulfate (CuSO4) induced oxidative stress at different time duration. Fifty-four male Wistar rats (weight range=205±10g) were equally divided into three groups. CuSO4 was administered orally to the experimental groups (Group-II and III) up to 90 days in a dose of 100 and 200mg/Kg body weight per day. Saline water was given to the control group (Group-I). At the end of 30, 60 and 90 days of administration, neurobehavioral studies were done and six rats from each group were sacrificed. Their liver, kidney and brain tissues were subjected for Cu, glutathione (GSH), malondialdehyde (MDA) and total antioxidant capacity (TAC) assay. Blood urea nitrogen (BUN), serum creatinine, bilirubin and transaminases were measured. GSH, TAC and MDA levels were correlated with the markers of respective organ dysfunction. Administration of CuSO4 resulted in increased free Cu and MDA level, and decrease GSH and TAC levels in group-II and III compared with group-I. In experimental groups, the reduction in TAC and GSH levels was maximum in liver tissue followed by brain and kidney; whereas increase in MDA level was highest in liver followed by brain and kidney at 30, 60 and 90 days. TAC and GSH levels in the liver inversely correlated with serum transaminases and bilirubin, and tissue free Cu, and positively correlated with MDA levels. Free Cu level in kidney tissue and BUN inversely correlated with TAC and GSH, and positively with MDA level. Grip-strength, rotarod and Y-maze findings were inversely correlated with brain free Cu and MDA levels and positively with GSH and TAC levels. The oxidative stress was highest in liver followed by brain and kidney after oral CuSO4 exposure in a rat model. These levels correlated with the respective organ dysfunction and tissue free Cu concentration.
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Kalita J, Kumar V, Misra UK. A Study on Apoptosis and Anti-apoptotic Status in Wilson Disease. Mol Neurobiol 2015; 53:6659-6667. [PMID: 26646538 DOI: 10.1007/s12035-015-9570-y] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2015] [Accepted: 11/29/2015] [Indexed: 12/24/2022]
Abstract
Wilson disease (WD) is characterized by hepatolenticular degeneration, but there is no report on apoptosis and anti-apoptotic markers in WD patients with neurological manifestation (WDN). The aim of this study was to evaluate active caspase-3 and X-linked inhibitors of apoptosis protein (XIAP) level in WDN and correlate these with disease severity and markers of death (tumor necrosis factor-alpha (TNF-α), interleukin (IL)-8, malondialdehyde (MDA), and Cu) and survival signals (glutathione). Fifty-four patients with WDN and 36 healthy matched controls were included. Their severity, Burke-Fahn-Marsden (BFM) scores, blood counts, hemoglobin, serum chemistry, ceruloplasmin, and free copper and 24-h urinary copper were measured. Cranial MRI findings were noted. Serum active caspase-3, XIAP, TNF-α, IL-8, and plasma glutathione and MDA were measured using enzyme-linked immunosorbent assay (ELISA), flow cytometry, and spectrophotometer respectively. In the patients with WDN, active caspase-3 (0.55 ± 0.11 vs 0.38 ± 0.06 ng/ml), TNF-α (76.05 ± 29.01 vs 36.05 ± 21.01 pg/ml), IL-8 (590.19 ± 89.19 vs 193.43 ± 71.01 pg/ml), and MDA (4.92 ± 0.39 vs 3.43 ± 0.21 nmol/ml) levels were increased whereas XIAP (84.66 ± 10.39 vs 95.76 ± 10.11 ng/ml) and glutathione (GSH) (2.03 ± 0.29 vs 2.98 ± 0.27 mg/dl) levels were decreased compared to controls. Active caspase-3 was correlated with neurological severity (r = 0.48), BFM score (r = 0.37), ceruloplasmin (r = -0.39), hemoglobin (r = -0.34), and serum Cu (r = 0.39). XIAP levels were correlated with neurological severity (r = -0.40), BFM (r = -0.51), serum Cu (r = -0.42), and ceruloplasmin (r = 0.34). The XIAP level positively correlated with survival (GSH) and inversely with death signals (TNF-α, IL-8, MDA and free serum Cu) whereas active caspase-3 positively correlated with death (TNF-α, IL-8, serum Cu, MDA) and inversely with survival signal (GSH). Serum active caspase-3 level increased in WDN and positively correlated with the severity of disease, death signals (TNF, IL-8, MDA, and free Cu) and inversely with GSH and XIAP.
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Affiliation(s)
- J Kalita
- Department of Neurology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Raebareily Road, Lucknow, 226014, India.
| | - V Kumar
- Department of Neurology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Raebareily Road, Lucknow, 226014, India
| | - U K Misra
- Department of Neurology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Raebareily Road, Lucknow, 226014, India
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