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Increased Oxidative Damage and Decreased Antioxidant Function in Aging Human Substantia Nigra Compared to Striatum: Implications for Parkinson’s Disease

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Abstract

Parkinson’s disease (PD) is characterized by selective degeneration and loss of dopaminergic neurons in the substantia nigra (SN) of the ventral mid brain leading to dopamine depletion in the striatum. Oxidative stress and mitochondrial damage have been implicated in the death of SN neurons during the evolution of PD. In our previous study on human PD brains, we observed that compared to SN, striatum was significantly protected against oxidative damage and mitochondrial dysfunction. To understand whether brain aging contributes to the vulnerability of midbrain to neurodegeneration in PD compared to striatum, we assessed the status of oxidant and antioxidant markers, glutathione metabolic enzymes, glial fibrillary acidic protein (GFAP) expression and mitochondrial complex I(CI) activity in SN (n = 23) and caudate nucleus (n = 24) during physiological aging in human brains. We observed a significant increase in protein oxidation (P < 0.001), loss of CI activity (P = 0.04) and increased astrocytic proliferation indicated by GFAP expression (P < 0.001) in SN compared to CD with increasing age. These changes were attributed to significant decrease in antioxidant function represented by superoxide dismutase (SOD) (P = 0.03), glutathione (GSH) peroxidase (GPx) (P = 0.02) and GSH reductase (GR) (P = 0.03) and a decreasing trend in total GSH and catalase with increasing age. However, these parameters were relatively unaltered in CD. We propose that SN undergoes extensive oxidative damage, loss of antioxidant and mitochondrial function and increased GFAP expression during physiological aging which might make it more vulnerable to neurotoxic insults thus contributing to selective degeneration during evolution of PD.

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Abbreviations

PD:

Parkinson’s disease

SN:

Substantia nigra

CI:

Mitochondrial complex I

GSH:

Glutathione reduced

PMI:

Postmortem interval

CD:

Caudate nucleus

3-NT:

3-Nitrotyrosine

GFAP:

Glial fibrillary acidic protein

SOD:

Superoxide dismutase

GST:

Glutathione-s-transferase

GR:

Glutathione reductase

GPx:

Glutathione peroxidase

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Acknowledgments

This work was financially supported by a research grant from the Indian Council of Medical Research (ICMR IRIS ID No. 2009-07710), India, to MMSB. GH is a senior research fellow of ICMR, India. RM was supported by a senior research fellowship (extended) from Council of Scientific and Industrial Research (CSIR), India. VC gratefully acknowledges the financial support from Sri Siddhartha Medical College, Tumkur, Karnataka, India. We thank all the donors and their relatives for donating human brain tissue samples for this study. Human brain tissues for the study were sourced from Human Brain Tissue Repository for Neurobiological Studies (A National Research Facility), Department of Neuropathology, NIMHANS, Bangalore—560 029.

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  1. Departments of Neurochemistry, National Institute of Mental Health and Neurosciences (NIMHANS), No. 2900, Hosur Road, Bangalore, Karnataka, 560029, India

    C. Venkateshappa, G. Harish, Rajeswara Babu Mythri & M. M. Srinivas Bharath

  2. Departments of Neuropathology, National Institute of Mental Health and Neurosciences (NIMHANS), No. 2900, Hosur Road, Bangalore, Karnataka, 560029, India

    Anita Mahadevan & S. K. Shankar

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  1. C. Venkateshappa
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Correspondence to M. M. Srinivas Bharath.

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Venkateshappa, C., Harish, G., Mythri, R.B. et al. Increased Oxidative Damage and Decreased Antioxidant Function in Aging Human Substantia Nigra Compared to Striatum: Implications for Parkinson’s Disease. Neurochem Res 37, 358–369 (2012). https://doi.org/10.1007/s11064-011-0619-7

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