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Biochemical, Histological, and Memory Impairment Effects of Chronic Copper Toxicity: A Model for Non-Wilsonian Brain Copper Toxicosis in Wistar Rat

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Abstract

Animal models of copper toxicosis rarely exhibit neurological impairments and increased brain copper accumulation impeding the development of novel therapeutic approaches to treat neurodegenerative diseases having high brain Cu content. The aim of this study was to investigate the effects of intraperitoneally injected copper lactate (0.15 mg Cu/100 g body weight) daily for 90 days on copper and zinc levels in the liver and hippocampus, on biochemical parameters, and on neurobehavioral functions (by Morris water maze) of male Wistar rats. Copper-administered animals exhibited significantly decreased serum acetylcholinesterase (AChE) activity and impaired neuromuscular coordination and spatial memory compared to control rats. Copper-intoxicated rats showed significant increase in liver and hippocampus copper content (99.1 and 73 % increase, respectively), 40.7 % reduction in hepatic zinc content, and interestingly, 77.1 % increase in hippocampus zinc content with concomitant increase in copper and zinc levels in serum and urine compared to control rats. Massive grade 4 copper depositions and grade 1 copper-associated protein in hepatocytes of copper-intoxicated rats were substantiated by rhodanine and orcein stains, respectively. Copper-intoxicated rats demonstrated swelling and increase in the number of astrocytes and copper deposition in the choroid plexus, with degenerated neurons showing pyknotic nuclei and dense eosinophilic cytoplasm. In conclusion, the present study shows the first evidence in vivo that chronic copper toxicity causes impaired spatial memory and neuromuscular coordination, swelling of astrocytes, decreased serum AChE activity, copper deposition in the choroid plexus, neuronal degeneration, and augmented levels of copper and zinc in the hippocampus of male Wistar rats.

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Acknowledgments

The authors acknowledge the financial support provided by the Indian Council of Medical Research (I.C.M.R., New Delhi) as JRF/SRF to Mr. Amit Pal. The authors are thankful to Professor K.D. Gill for the guidance in carrying out the neurobehavioral studies and Dr. Jayagandhan J. for the suggestions and revision of the manuscript. The authors also acknowledge the support of Mr. Charan Singh (for the staining studies), Mr. Rakesh Mohindra (for the statistics), and Mrs. Minni (for the metal analysis).

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The authors declare no conflict of interest.

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Authors and Affiliations

  1. Department of Biochemistry, PGIMER, Chandigarh, India, 160012

    Amit Pal & Rajendra Prasad

  2. Department of Histopathology, PGIMER, Chandigarh, India

    Rama Kumari Badyal & Rakesh Kumar Vasishta

  3. APC Department, PGIMER, Chandigarh, India

    Savita Verma Attri

  4. Department of Gastroenterology, PGIMER, Chandigarh, India

    Babu Ram Thapa

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  1. Amit Pal
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Correspondence to Rajendra Prasad.

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Pal, A., Badyal, R.K., Vasishta, R.K. et al. Biochemical, Histological, and Memory Impairment Effects of Chronic Copper Toxicity: A Model for Non-Wilsonian Brain Copper Toxicosis in Wistar Rat. Biol Trace Elem Res 153, 257–268 (2013). https://doi.org/10.1007/s12011-013-9665-0

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