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

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.

• Authors: Sonal Agrawal, Anubhuti Dixit, Ashish Singh, Pratibha Tripathi, Dhirendra Singh, Devendra Kumar Patel, Mahendra Pratap Singh
• Journal: Molecular neurobiology (Mol Neurobiol) Vol. 52 Issue 3 Pg. 1619-1628 (Dec 2015) ISSN: 1559-1182 [Electronic] United States
• PMID: 25370934 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Metalloporphyrins
• Mn(III) 5,10,15,20-tetrakis(N-methylpyridinium-2-yl)porphyrin
• Pyrethrins
• alpha-Synuclein
• cypermethrin
• Cyclosporine

Topics

• Animals
• Corpus Striatum (metabolism)
• Cyclosporine (pharmacology)
• Dopaminergic Neurons (drug effects)
• Metalloporphyrins (pharmacology)
• Mitochondria (metabolism)
• Oxidative Stress (physiology)
• Parkinson Disease (drug therapy, metabolism)
• Parkinsonian Disorders (drug therapy, metabolism)
• Pyrethrins (pharmacology)
• Rats, Wistar
• Substantia Nigra (drug effects)
• alpha-Synuclein (drug effects, metabolism)