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Glutamoyl diester of the dietary polyphenol curcumin offers improved protection against peroxynitrite-mediated nitrosative stress and damage of brain mitochondria in vitro: implications for Parkinson’s disease

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Abstract

Oxidative/nitrosative stress plays a crucial role in Parkinson’s disease (PD) by triggering mitochondrial dysfunction. Nitrosative stress is mediated by reactive species such as peroxynitrite (PN) which could damage biomolecules thereby impinging on the cellular machinery. We observed that PN (0–1000 μM) inhibited brain mitochondrial complex I (CI) activity in a dose-dependent manner with concomitant tyrosine nitration of proteins. We also observed that exposure to PN at low concentrations (62.5–125 μM) significantly decreased the mitochondrial membrane potential and affected the mitochondrial integrity at higher doses (500–750 μM) as indicated by the mitochondrial swelling experiment. Therefore, it could be surmised that compounds that prevent such mitochondrial damage might have therapeutic value in neurological conditions such as PD. We previously showed that curcumin could detoxify PN and protect against CI inhibition and protein nitration. However, the therapeutic potential of curcumin is constrained by limited bioavailability. To address this issue and obtain improved antioxidants, three bioconjugates of curcumin (Di-demethylenated piperoyl, di-valinoyl and di-glutamoyl esters) were generated and tested against PN-mediated nitrosative stress and mitochondrial damage. We found that among the bioconjugates, the glutamoyl diester of curcumin showed improved protection against PN-dependent CI inhibition and protein nitration compared to other conjugates. Di-glutamoyl curcumin protected dopaminergic neurons against 1-methyl-4-phenylpyridinium (MPP+)-mediated neuronal death. These effects were improved compared to curcumin alone suggesting that di-glutamoyl curcumin could be a better neuroprotective agent in neurodegenerative diseases such as PD.

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Abbreviations

PD:

Parkinson’s disease

SN:

Substantia nigra

NO:

Nitric oxide

PN:

Peroxynitrite

CI:

Mitochondrial complex I

3-NT:

3-nitrotyrosine

RNS:

Reactive nitrogen species

GSH:

Glutathione

PTP:

Permeability transition pore

∆Ψm :

Mitochondrial membrane potential

JC-1:

5,5′,6,6′-Tetrachloro-1,1′3,3′-tetra ethyl benzimidazolyl carbocyanine iodide

D1:

Di-demethylenated piperoyl curcumin

D2:

Di-valinoyl curcumin

D3:

Di-glutamoyl curcumin

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Acknowledgments

This study was supported by a fast-track grant to M.M.S.B. from the Department of Science and Technology, India. RBM is a senior research fellow of Council for Scientific and Industrial Research, India. GH is a junior research fellow of Indian Council for Medical Research, India.

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Author notes

  1. Shiv Kumar Dubey

    Present address: Division of Hematology & Oncology, University of Michigan Cancer Center, Ann Arbor, MI, 48109, USA

Authors and Affiliations

  1. Department of Neurochemistry, National Institute of Mental Health and Neurosciences, # 2900, Hosur Road, Bangalore, 560029, India

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

  2. Center for Biotechnology, University of Allahabad, Allahabad, India

    Shiv Kumar Dubey

  3. Indo-Russian Center for Biotechnology, Indian Institute of Information Technology-Allahabad, Jhalwa Campus, Allahabad, 211002, India

    Krishna Misra

Authors
  1. Rajeswara Babu Mythri
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  2. G. Harish
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  5. M. M. Srinivas Bharath
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Correspondence to M. M. Srinivas Bharath.

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Mythri, R.B., Harish, G., Dubey, S.K. et al. Glutamoyl diester of the dietary polyphenol curcumin offers improved protection against peroxynitrite-mediated nitrosative stress and damage of brain mitochondria in vitro: implications for Parkinson’s disease. Mol Cell Biochem 347, 135–143 (2011). https://doi.org/10.1007/s11010-010-0621-4

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  • DOI: https://doi.org/10.1007/s11010-010-0621-4

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