Perinatal nicotine exposure alters Akt/GSK-3ß/mTOR/autophagy signaling, leading to development of hypoxic-ischemic-sensitive phenotype in rat neonatal brain.
Am J Physiol Regul Integr Comp Physiol
; 317(6): R803-R813, 2019 12 01.
Article
em En
| MEDLINE
| ID: mdl-31553625
ABSTRACT
Maternal cigarette smoking is a major perinatal insult that contributes to an increased risk of cardiovascular and neurodevelopmental diseases in offspring. Our previous studies revealed that perinatal nicotine exposure reprograms a sensitive phenotype in neonatal hypoxic-ischemic encephalopathy (HIE), yet the underlying molecular mechanisms remain largely elusive. The present study tested the hypothesis that perinatal nicotine exposure impacts autophagy signaling in the developing brain, resulting in enhanced susceptibility to neonatal HIE. Nicotine was administered to pregnant rats via subcutaneous osmotic minipumps. Neonatal HIE was conducted in 9-day-old male rat pups. Protein kinase B/glycogen synthase kinase-3ß/mammalian target of rapamycin (Akt/GSK-3ß/mTOR) signaling and key autophagy markers were determined by Western blotting analysis. Rapamycin and MK2206 were administered via intracerebroventricular injection. Nicotine exposure significantly inhibited autophagy activities in neonatal brain tissues, characterized by an increased ratio of phosphoylated (p-) to total mTOR protein expression but reduced levels of autophagy-related 5, Beclin 1, and LC3ßI/II. Treatment with mTOR inhibitor rapamycin effectively blocked nicotine-mediated autophagy deficiency and, more importantly, reversed the nicotine-induced increase in HI brain infarction. In addition, nicotine exposure significantly upregulated p-Akt and p-GSK-3ß. Treatment with the Akt selective inhibitor MK2206 reversed the enhanced p-Akt and p-GSK-3ß, restored basal autophagic flux, and abolished nicotine-mediated HI brain injury. These findings suggest that perinatal nicotine-mediated alteration of Akt/GSK-3ß/mTOR signaling plays a key role in downregulation of autophagic flux, which contributes to the development of hypoxia/ischemia-sensitive phenotype in the neonatal brain.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Autofagia
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Hipóxia-Isquemia Encefálica
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Proteínas Proto-Oncogênicas c-akt
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Serina-Treonina Quinases TOR
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Glicogênio Sintase Quinase 3 beta
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Nicotina
Tipo de estudo:
Diagnostic_studies
Limite:
Animals
/
Pregnancy
Idioma:
En
Revista:
Am J Physiol Regul Integr Comp Physiol
Assunto da revista:
FISIOLOGIA
Ano de publicação:
2019
Tipo de documento:
Article