The melatonin and enriched environment ameliorated Low protein-induced intrauterine growth retardation by IGF-1 and mTOR signaling pathway and autophagy inhibition in rats

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Author(s): Dan Wang*, Xiao Wu, Dan Lu, Yan Li, Peng Zhang

Journal Name: Current Molecular Medicine

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Aim: The present study investigated whether melatonin (MEL) and enriched environment (EE) might protect against intrauterine growth retardation (IUGR) rats.

Methods: Sprague-Dawley rats were randomly allocated to 3 groups: control (C), model (M) and EE+MEL group. Animals were housed in enriched environment (EE+MEL group) or remained in a standard environment (C group, M group). IUGR rat model was built by feeding a low protein diet during pregnancy. MEL was administered by gavaging. At day 1 post-birth, the baseline characteristics and serum biochemical parameters, morphology of liver and small intestine, enzyme activities, and mRNA expressions level of fetal rats were determined. The autophagy marker LC3 and Beclin1 were determined by western blot analysis.

Results: EE+MEL markedly improved the baseline characteristics, hepatic and intestinal morphology of IUGR fetuses. In addition, the lactase activities in fetal intestine were markedly increased by the EE+MEL. The level of serum somatostatin (SST), Growth hormone (GH), GH releasing hormone (GHRH), Insulin-like Growth Factor 1 (IGF-1), triiodothyronine (T3), tetraiodothyronine (T4) were recovered by EE+MEL, In addition, the EE+MEL significantly ameliorated the mRNA expression of SST, GHRH, GHRH receptor (GHRHR), GH, GHR, IGF-1, IGF-1 receptor (IGF1R), IGF binding protein-1 (IGFBP1), mammaliantarget of rapamycin (mTOR), S6 kinase 1 (S6K1) and eukaryotic initiation factor 4E (eIF4E)-binding protein 1 (4EBP1) in fetuses. In IUGR fetal livers, LC3 and Beclin1 were increased at birth, while LC3 and Beclin1 were significantly decreased in the EE+MEL group.

Conclusion: EE+MEL could improve fetal rats baseline characteristics, serum biochemical parameters, birth weight, intestinal and hepatic morphology and enzyme activities. These effects could be explained by the activation of the IGF1/IGFBP1 and IGF-1/mTOR/S6K1/4EBP1 signaling pathway, autophagy inhibition.

Keywords: melatonin, enriched environment, Intrauterine growth restriction, insulin-like growth factor-1, mTOR, Autophagy

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(E-pub Ahead of Print)
DOI: 10.2174/1566524020666200726221735
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