Astrocytic mobilization of glutathione peroxidase-1 contributes to the protective potential against cocaine kindling behaviors in mice via activation of JAK2/STAT3 signaling.
Free Radic Biol Med
; 131: 408-431, 2019 02 01.
Article
en En
| MEDLINE
| ID: mdl-30592974
ABSTRACT
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 GPx-1, 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-1â¯TG) mice, but significant differences were observed in cocaine-induced p-JAK2/STAT3 expression and oxidative stress between non-TG and GPx-1â¯TG mice. Cocaine-induced glial fibrillary acidic protein (GFAP)-labeled astrocytic level was significantly higher in the hippocampus of GPx-1â¯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-1â¯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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Convulsiones
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Cocaína
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Factor de Transcripción STAT3
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Janus Quinasa 2
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Glutatión Peroxidasa
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Excitación Neurológica
Idioma:
En
Revista:
Free Radic Biol Med
Asunto de la revista:
BIOQUIMICA
/
MEDICINA
Año:
2019
Tipo del documento:
Article