Glutathione peroxidase-1 overexpressing transgenic mice are protected from neurotoxicity induced by microcystin-leucine-arginine
- Authors
- Shin, Eun-Joo; Hwang, Yeong Gwang; Duc Toan Pham; Lee, Ji Won; Lee, Yu Jeung; Pyo, Dongjin; Jeong, Ji Hoon; Lei, Xin Gen; Kim, Hyoung-Chun
- Issue Date
- Oct-2018
- Publisher
- WILEY
- Keywords
- GPx-1 overexpressing transgenic mice; hippocampus; intracerebroventricular infusion; microcystin-leucine-arginine; neurotoxicity; NFB
- Citation
- ENVIRONMENTAL TOXICOLOGY, v.33, no.10, pp 1019 - 1028
- Pages
- 10
- Journal Title
- ENVIRONMENTAL TOXICOLOGY
- Volume
- 33
- Number
- 10
- Start Page
- 1019
- End Page
- 1028
- URI
- https://scholarworks.bwise.kr/cau/handle/2019.sw.cau/694
- DOI
- 10.1002/tox.22580
- ISSN
- 1520-4081
1522-7278
- Abstract
- Although it has been well-recognized that microcystin-leucine-arginine (MCLR), the most common form of microcystins, induces neurotoxicity, little is currently known about the underlying mechanism for this neurotoxicity. Here, we found that MCLR (10 ng/L/mouse, i.c.v.) induces significant neuronal loss in the hippocampus of mice. MCLR-induced neurotoxicity was accompanied by oxidative stress, as shown by a significant increase in the level of 4-hydroxynonenal, protein carbonyl, and reactive oxygen species (ROS). Superoxide dismutase-1 (SOD-1) activity was significantly increased, but glutathione peroxidase (GPx) level was significantly decreased following MCLR insult. In addition, MCLR significantly inhibited GSH/GSSG ratio, and significantly induced NFB DNA binding activity. Because reduced activity of GPx appeared to be critical for the imbalance between activities of SODs and GPx, we utilized GPx-1 overexpressing transgenic mice to ascertain the role of GPx-1 in this neurotoxicity. Genetic overexpression of GPx-1 or NFB inhibitor pyrrolidine dithiocarbamate (PDTC) significantly attenuated MCLR-induced hippocampal neuronal loss in mice. However, PDTC did not exert any additive effect on neuroprotection mediated by GPx-1 overexpression, indicating that NFB is a neurotoxic target of MCLR. Combined, these results suggest that MCLR-induced neurotoxicity requires oxidative stress associated with failure in compensatory induction of GPx, possibly through activation of the transcription factor NFB.
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