GPx-1-encoded adenoviral vector attenuates dopaminergic impairments induced by methamphetamine in GPx-1 knockout mice through modulation of NF-κB transcription factor

Naveen Sharma, Eun Joo Shin, Duc Toan Pham, Garima Sharma, Duy Khanh Dang, Chu Xuan Duong, Sang Won Kang, Seung Yeol Nah, Choon Gon Jang, Xin Gen Lei, Toshitaka Nabeshima, Guoying Bing, Ji Hoon Jeong, Hyoung Chun Kim

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

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.

Original languageEnglish
Article number112313
JournalFood and Chemical Toxicology
Volume154
DOIs
StatePublished - Aug 2021

Keywords

  • GPx-1 gene-encoded adenoviral vector
  • GPx-1 knockout mice
  • GPx-1 overexpressing transgenic mice
  • Methamphetamine-induced dopaminergic toxicity
  • NF-κB inhibitor
  • Striatum

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