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Memory and Learning Dysfunction Following Copper Toxicity: Biochemical and Immunohistochemical Basis

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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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Abbreviations

Cu:

Copper

GSH:

Glutathione

TAC:

Total antioxidant capacity

MDA:

Malondialdehyde

LPO:

Lipid peroxidation

kgBWt:

kg body weight

WD:

Wilson disease

NMDA:

N-methyl-d-aspartate

GFAP:

Glial fibrillary acidic protein

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Author notes

  1. J Kalita and V Kumar contributed equally in this work.

Authors and Affiliations

  1. Department of Neurology, Sanjay Gandhi Post Graduate Medical Sciences, Raebareli Road, Lucknow, 226014, India

    Jayantee Kalita, Vijay Kumar & Usha K. Misra

  2. National Laboratory Animal Centre, CSIR-Central Drug Research Institute, Lucknow, India

    Himangsu K. Bora

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  1. Jayantee Kalita
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  2. Vijay Kumar
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  3. Usha K. Misra
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  4. Himangsu K. Bora
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Correspondence to Jayantee Kalita.

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The authors declare that they have no conflicts of interest.

Ethics Approval

This research was approved by the Animal Ethics Committee of the CSIR-Central Drug Research Institute, Lucknow, India (IACE/2012/29).

Funding

Mr. Vijay Kumar received scholarship from Indian Council of Medical Research, Government of India (ICMR-JRF, 3/1/3/JRF-2009/MPD 31381).

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Kalita, J., Kumar, V., Misra, U.K. et al. Memory and Learning Dysfunction Following Copper Toxicity: Biochemical and Immunohistochemical Basis. Mol Neurobiol 55, 3800–3811 (2018). https://doi.org/10.1007/s12035-017-0619-y

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