GPx-1-encoded adenoviral vector attenuates dopaminergic impairments induced by methamphetamine in GPx-1 knockout mice through modulation of NF-κB transcription factor
- Authors
- Sharma, N.; Shin, E.-J.; Pham, D.T.; Sharma, G.; Dang, D.-K.; Duong, C.X.; Kang, S.W.; Nah, S.-Y.; Jang, C.-G.; Lei, X.G.; Nabeshima, T.; Bing, G.; Jeong, J.H.; Kim, H.-C.
- Issue Date
- Aug-2021
- Publisher
- Elsevier Ltd
- Keywords
- GPx-1 gene-encoded adenoviral vector; GPx-1 knockout mice; GPx-1 overexpressing transgenic mice; Methamphetamine-induced dopaminergic toxicity; NF-κB inhibitor; Striatum
- Citation
- Food and Chemical Toxicology, v.154
- Journal Title
- Food and Chemical Toxicology
- Volume
- 154
- URI
- https://scholarworks.bwise.kr/cau/handle/2019.sw.cau/54316
- DOI
- 10.1016/j.fct.2021.112313
- ISSN
- 0278-6915
1873-6351
- Abstract
- We suggested that selenium-dependent glutathione peroxidase (GPx) plays a protective role against methamphetamine (MA)-induced dopaminergic toxicity. We focused on GPx-1, a major selenium-dependent enzyme and constructed a GPx-1 gene-encoded adenoviral vector (Ad-GPx-1) to delineate the role of GPx-1 in MA-induced dopaminergic neurotoxicity. Exposure to Ad-GPx-1 significantly induced GPx activity and GPx-1 protein levels in GPx-1-knockout (GPx-1-KO) mice. MA-induced dopaminergic impairments [i.e., hyperthermia; increased nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) DNA-binding activity; and decreased dopamine levels, TH activity, and behavioral activity] were more pronounced in GPx-1-KO mice than in WT mice. In contrast, exposure to Ad-GPx-1 significantly attenuated MA-induced dopaminergic loss in GPx-1-KO mice. The protective effect exerted by Ad-GPx-1 was comparable to that exerted by pyrrolidine dithiocarbamate (PDTC), an NF-κB inhibitor against MA insult. Consistently, GPx-1 overexpression significantly attenuated MA dopaminergic toxicity in mice. PDTC did not significantly impact the protective effect of GPx-1 overexpression, suggesting that interaction between NF-κB and GPx-1 is critical for dopaminergic protection. Thus, NF-κB is a potential therapeutic target for GPx-1-mediated dopaminergic protective activity. This study for the first time demonstrated that Ad-GPx-1 rescued dopaminergic toxicity in vivo following MA insult. Furthermore, GPx-1-associated therapeutic interventions may be important against dopaminergic toxicity. © 2021 Elsevier Ltd
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