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Cyclosporine A and MnTMPyP Alleviate α-Synuclein Expression and Aggregation in Cypermethrin-Induced Parkinsonism

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Abstract

Cypermethrin induces the mitochondrial dysfunction and oxidative damage to the nigrostriatal dopaminergic neurons leading to Parkinsonism in rats. Despite α-synuclein aggregation is reported to be critical in Parkinson’s disease, its role and alliance with the mitochondrial dysfunction and oxidative damage leading to cypermethrin-induced Parkinsonism have not yet been deciphered. The present study aimed to examine the effect of cypermethrin on the expression and aggregation of α-synuclein and its subsequent connection with oxidative damage and mitochondrial dysfunction leading to the nigrostriatal dopaminergic neurodegeneration in the presence or absence of a mitochondrial membrane transition pore opening inhibitor, cyclosporine A and a superoxide dismutase/catalase mimetic, manganese (III) tetrakis (1-methyl-4-pyridyl) porphyrin pentachloride (MnTMPyP). The expression of α-synuclein, 3-nitrotyrosine (3-NT), 4-hydroxynonenal (4-HNE)-modified proteins, mitochondrial dysfunction-dependent apoptotic proteins, nitrite content, lipid peroxidation (LPO) and number of tyrosine hydroxylase (TH)-positive neurons were estimated in the substantia nigra and dopamine content in the striatum of control and treated rats employing standard procedures. Cypermethrin augmented the expression of α-synuclein, 3-NT, 4-HNE-modified proteins, caspase-3, mitochondrial Bax and cytosolic cytochrome-c along with nitrite and LPO and reduced the expression of cytosolic Bax, mitochondrial cytochrome-c, dopamine and number of TH-positive neurons. Cyclosporine A or MnTMPyP alleviated the expression and aggregation of α-synuclein along with indicators of the mitochondrial dysfunction, oxidative damage and dopaminergic neurodegeneration. The results demonstrate that cypermethrin induces α-synuclein expression and aggregation while cyclosporine A or MnTMPyP rescues from α-synuclein over-expression and aggregation along with the mitochondrial dysfunction and oxidative damage leading to Parkinsonism in rats.

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Acknowledgments

The authors are grateful to the Council of Scientific and Industrial Research (CSIR), New Delhi, India, for providing research fellowship to Sonal Agrawal. Furthermore, the Department of Biotechnology, New Delhi, India, and CSIR, New Delhi, India are gratefully acknowledged for the financial support (BT/PR14382/MED/12/474/2010 and miND/BSC0115) to the study. The CSIR-IITR communication number of this article is 3245.

Conflict of Interest

The authors declare that they do not have any conflicts of interest.

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Authors and Affiliations

  1. CSIR-Indian Institute of Toxicology Research, Mahatma Gandhi Marg, Post Box No. 80, Lucknow, 226001, Uttar Pradesh, India

    Sonal Agrawal, Anubhuti Dixit, Ashish Singh, Pratibha Tripathi, Dhirendra Singh, Devendra Kumar Patel & Mahendra Pratap Singh

  2. Academy of Scientific and Innovative Research, New Delhi, 110025, India

    Sonal Agrawal & Mahendra Pratap Singh

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  1. Sonal Agrawal
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  2. Anubhuti Dixit
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  3. Ashish Singh
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Correspondence to Mahendra Pratap Singh.

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Agrawal, S., Dixit, A., Singh, A. et al. Cyclosporine A and MnTMPyP Alleviate α-Synuclein Expression and Aggregation in Cypermethrin-Induced Parkinsonism. Mol Neurobiol 52, 1619–1628 (2015). https://doi.org/10.1007/s12035-014-8954-8

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