NADPH protects against kainic acid-induced excitotoxicity via autophagy-lysosome pathway in rat striatum and primary cortical neurons.
Toxicology
; 435: 152408, 2020 04 15.
Article
en En
| MEDLINE
| ID: mdl-32057834
PURPOSE: To investigate the effects and mechanisms of NADPH on Kainic acid (KA)-induced excitotoxicity. METHODS: KA, a non-N-methyl-d-aspartate glutamate receptor agonist, was exposed to adult SD rats via intrastriatal injection and rat primary cortical neurons to establish excitotoxic models in vivo and in vitro, respectively. To determine the effects of NADPH on KA-induced excitotoxicity, neuronal survival, neurologically behavioral score and oxidative stress were evaluated. To explore the mechanisms of neuroprotective effects of NADPH, the autophagy-lysosome pathway related proteins were detected. RESULTS: In vivo, NADPH (1 mg/kg or 2 mg/kg) diminished KA (2.5 nmol)-induced enlargement of lesion size in striatum, improved KA-induced dyskinesia and reversed KA-induced activation of glial cells. Nevertheless, the neuroprotective effect of NADPH was not significant under the condition of autophagy activation. NADPH (2 mg/kg) inhibited KA (2.5 nmol)-induced down-regulation of TP-53 induced glycolysis and apoptosis regulator (TIGAR) and p62, and up-regulation of the protein levels of LC3-II/LC3-I, Beclin-1 and Atg5. In vitro, the excitotoxic neuronal injury was induced after KA (50 µM, 100 µM or 200 µM) treatment as demonstrated by decreased cell viability. Moreover, KA (100 µM) increased the intracellular levels of calcium and reactive oxygen species (ROS) and declined the levels of the reduced form of glutathione (GSH). Pretreatment of NADPH (10 µM) effectively reversed these changes. Meanwhile NADPH (10 µM) inhibited KA (100 µM)-induced down-regulation of TIGAR and p62, and up-regulation of the ratio of LC3-II/LC3-I, Beclin-1, Atg5, active-cathepsin B and active-cathepsin D. CONCLUSIONS: Our data provide a possible mechanism that NADPH ameliorates KA-induced excitotoxicity by blocking the autophagy-lysosome pathway and up-regulating TIGAR along with its antioxidant properties.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Autofagia
/
Corteza Cerebral
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Fármacos Neuroprotectores
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Agonistas de Aminoácidos Excitadores
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Cuerpo Estriado
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Ácido Kaínico
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Lisosomas
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NADP
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Neuronas
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
Toxicology
Año:
2020
Tipo del documento:
Article
País de afiliación:
China
Pais de publicación:
Irlanda