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Mai, Huynh Nhu,Nguyen, Lan Thuy Ty,Shin, Eun-Joo,Kim, Dae-Joong,Jeong, Ji Hoon,Chung, Yoon Hee,Lei, Xin Gen,Sharma, Naveen,Jang, Choon-Gon,Nabeshima, Toshitaka,Kim, Hyoung-Chun Elsevier 2019 FREE RADICAL BIOLOGY AND MEDICINE Vol.131 No.-
<P><B>Abstract</B></P> <P>Compelling evidence indicates that oxidative stress contributes to cocaine neurotoxicity. The present study was performed to elucidate the role of the glutathione peroxidase-1 (GPx-1) in cocaine-induced kindling (convulsive) behaviors in mice. Cocaine-induced convulsive behaviors significantly increased <U>GPx-1</U>, p-IkB, and p-JAK2/STAT3 expression, and oxidative burdens in the hippocampus of mice. There was no significant difference in cocaine-induced p-IkB expression between non-transgenic (non-TG) and GPx-1 overexpressing transgenic (GPx-1 TG) mice, but significant differences were observed in cocaine-induced p-JAK2/STAT3 expression and oxidative stress between non-TG and GPx-1 TG mice. Cocaine-induced glial fibrillary acidic protein (GFAP)-labeled astrocytic level was significantly higher in the hippocampus of GPx-1 TG mice. Triple-labeling immunocytochemistry indicated that GPx-1-, p-STAT3-, and GFAP-immunoreactivities were co-localized in the same cells. AG490, a JAK2/STAT3 inhibitor, but not pyrrolidone dithiocarbamate, an NFκB inhibitor, significantly counteracted GPx-1-mediated protective potentials (i.e., anticonvulsant-, antioxidant-, antiapoptotic-effects). Genetic overexpression of GPx-1 significantly attenuated proliferation of Iba-1-labeled microglia induced by cocaine in mice. However, AG490 or astrocytic inhibition (by GFAP antisense oligonucleotide and α-aminoadipate) significantly increased Iba-1-labeled microglial activity and M1 phenotype microglial mRNA levels, reflecting that proinflammatory potentials were mediated by AG490 or astrocytic inhibition. This microglial activation was less pronounced in GPx-1 TG than in non-TG mice. Furthermore, either AG490 or astrocytic inhibition significantly counteracted GPx-1-mediated protective potentials. Therefore, our results suggest that astrocytic modulation between GPx-1 and JAK2/STAT3 might be one of the underlying mechanisms for protecting against convulsive neurotoxicity induced by cocaine.</P> <P><B>Highlights</B></P> <P> <UL> <LI> GPx-1 overexpression protects against oxidative burdens induced by cocaine. </LI> <LI> Anti-convulsive potentials of GPx-1 require JAK2/STAT3/GFAP signaling process. </LI> <LI> The activation of GFAP requires GPx-1 overexpression gene. </LI> <LI> AG490 or astrocytic inhibition increased Iba-1-labeld microglial activity. </LI> <LI> AG490 or astrocytic inhibition counteracted GPx-1-mediated protective potentials. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>
신은주,Xuan-Khanh Thi Nguyen,Thuy-Ty Lan Nguyen,Diem-Thu Pham,김형춘 한국뇌신경과학회 2011 Experimental Neurobiology Vol.20 No.3
We previously demonstrated that repeated exposure to extremely low frequency magnetic fields (ELF-MF) increases locomotor activity via stimulation of dopaminergic D1 receptor (J. Pharmacol. Sci., 2007;105:367-371). Since it has been demonstrated that activator protein-1 (AP-1) transcription factors, especially 35-kDa fos-related antigen (FRA), play a key role in the neuronal and behavioral adaptation in response to various stimuli, we examined whether repeated ELF-MF exposure induces FRA-immunoreactivity (FRA-IR) in the striatum and nucleus accumbens (striatal complex) of the mice. Repeated exposure to ELF-MF (0.3 or 2.4 mT, 1 h/day, for consecutive fourteen days) significantly induced hyperlocomotor activity and FRA-IR in the striatal complex in a field intensity-dependent manner. ELF-MF-induced FRA-IR lasted for at least 1 year, while locomotor activity returned near control level 3 months after the final exposure to ELF-MF. Pretreatment with SCH23390, a dopaminergic D1 receptor antagonist, but not with sulpiride, a dopaminergic D2 receptor antagonist, significantly attenuated hyperlocomotor activity and FRA-IR induced by ELF-MF. Our results suggest that repeated exposure to ELF-MF leads to prolonged locomotor stimulation and long-term expression of FRA in the striatal complex of the mice via stimulation of dopaminergic D1 receptor.
Shin, Eun-Joo,Shin, Seung Woo,Nguyen, Thuy-Ty Lan,Park, Dae Hun,Wie, Myung-Bok,Jang, Choon-Gon,Nah, Seung-Yeol,Yang, Byung Wook,Ko, Sung Kwon,Nabeshima, Toshitaka,Kim, Hyoung-Chun Humana Press 2014 Molecular Neurobiology Vol.49 No.3
<P>Ginsenoside Re, one of the main constituents of Panax ginseng, possesses novel antioxidant and anti-inflammatory properties. However, the pharmacological mechanism of ginsenoside Re in dopaminergic degeneration remains elusive. We suggested that protein kinase C (PKC) δ mediates methamphetamine (MA)-induced dopaminergic toxicity. Treatment with ginsenoside Re significantly attenuated methamphetamine-induced dopaminergic degeneration in vivo by inhibiting impaired enzymatic antioxidant systems, mitochondrial oxidative stress, mitochondrial translocation of protein kinase Cδ, mitochondrial dysfunction, pro-inflammatory microglial activation, and apoptosis. These protective effects were comparable to those observed with genetic inhibition of PKCδ in PKCδ knockout (-/-) mice and with PKCδ antisense oligonucleotides, and ginsenoside Re did not provide any additional protective effects in the presence of PKCδ inhibition. Our results suggest that PKCδ is a critical target for ginsenoside Re-mediated protective activity in response to dopaminergic degeneration induced by MA.</P>