Cypermethrin-induced nigrostriatal dopaminergic neurodegeneration alters the mitochondrial function: a proteomics study.
Cypermethrin induces the slow and progressive degeneration of the nigrostriatal dopaminergic neurons in rats. Postnatal preexposure with low doses of cypermethrin is known to enhance the susceptibility of animals upon adulthood reexposure. The study was undertaken to delineate the role of mitochondria in cypermethrin-induced neurodegeneration. Indexes of dopaminergic neurodegeneration, microglial activation, and mitochondrial dysfunction and its proteome profile were assessed in controls and cypermethrin-treated rats. Cypermethrin increased nigral dopaminergic neurodegeneration and microglial activation while reduced mitochondrial membrane potential and complex I activity. Cypermethrin attenuated striatal dopamine content and differentially regulated the expressions of the nine striatal and ten nigral proteins. Western blot analyses showed that cypermethrin also increased c-Jun N-terminal kinase (JNK), caspase-3, tumor suppressor protein (p53), tumor necrosis factor-α (TNF-α), p38 mitogen-activated protein kinase (p38 MAPK), and heme oxygenase-1 (HO-1) expressions and reduced B cell lymphoma-2 protein (Bcl-2) expression. Syndopa and minocycline rescued from cypermethrin induced augmentation in microglial activation and reductions in mitochondrial membrane potential and complex I activity, striatal dopamine content, and degeneration of nigral dopaminergic neurons. Syndopa and minocycline, respectively, modulated the expressions of four and six striatal and four and seven nigral proteins. Furthermore, they reinstated the expressions of JNK, caspase-3, Bcl-2, p53, p38 MAPK, TNF-α, and HO-1. The study demonstrates that cypermethrin induces mitochondrial dysfunction and alters mitochondrial proteome leading to oxidative stress and apoptosis, which regulate the nigrostriatal dopaminergic neurodegeneration.
CSIR-Indian Institute of Toxicology Research, Mahatma Gandhi Marg, Post Box-80, Lucknow, 226 001, Uttar Pradesh, India.
Sonal
S
Agrawal
Ashish
A
Singh
Pratibha
P
Tripathi
Manisha
M
Mishra
Pradhyumna Kumar
PK
Singh
Mahendra Pratap
MP
Singh
D000595:Amino Acid Sequence; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects* / Q000502:physiology; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007306:Insecticides / Q000633:toxicity; D008297:Male; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology; D024101:Mitochondrial Proteins / Q000096:biosynthesis / Q000235:genetics; D008969:Molecular Sequence Data; D019636:Neurodegenerative Diseases / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism; D040901:Proteomics / Q000379:methods*; D011722:Pyrethrins / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D013378:Substantia Nigra / Q000187:drug effects* / Q000502:physiology
D007306:Insecticides; D024101:Mitochondrial Proteins; D011722:Pyrethrins; C017160:cypermethrin