TY - JOUR
T1 - GPx-1-encoded adenoviral vector attenuates dopaminergic impairments induced by methamphetamine in GPx-1 knockout mice through modulation of NF-κB transcription factor
AU - Sharma, Naveen
AU - Shin, Eun Joo
AU - Pham, Duc Toan
AU - Sharma, Garima
AU - Dang, Duy Khanh
AU - Duong, Chu Xuan
AU - Kang, Sang Won
AU - Nah, Seung Yeol
AU - Jang, Choon Gon
AU - Lei, Xin Gen
AU - Nabeshima, Toshitaka
AU - Bing, Guoying
AU - Jeong, Ji Hoon
AU - Kim, Hyoung Chun
N1 - Publisher Copyright:
© 2021 Elsevier Ltd
PY - 2021/8
Y1 - 2021/8
N2 - 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.
AB - 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.
KW - GPx-1 gene-encoded adenoviral vector
KW - GPx-1 knockout mice
KW - GPx-1 overexpressing transgenic mice
KW - Methamphetamine-induced dopaminergic toxicity
KW - NF-κB inhibitor
KW - Striatum
UR - http://www.scopus.com/inward/record.url?scp=85107540969&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85107540969&partnerID=8YFLogxK
U2 - 10.1016/j.fct.2021.112313
DO - 10.1016/j.fct.2021.112313
M3 - Article
C2 - 34082047
AN - SCOPUS:85107540969
SN - 0278-6915
VL - 154
JO - Food and Chemical Toxicology
JF - Food and Chemical Toxicology
M1 - 112313
ER -