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Insulin Receptor Substrate-1 Activation Mediated p53 Downregulation Protects Against Hypoxic-Ischemia in the Neonatal Brain

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Abstract

This study determined if dietary restriction (DR) protects against hypoxic-ischemia (HI) in the neonatal brain via insulin receptor substrate-1 (IRS-1)/Akt pathway-mediated downregulation of p53 in the neurovascular unit. On postnatal (P) day 7, HI was induced in rat pups grouped from P1 into normal litter size (NL, 12 pups/dam) and increased litter size (DR, 18 pups/dam). In vivo IRS-1 anti-sense oligonucleotide and IRS-1 overexpressed recombinant adenovirus were given, and neurovascular damage was assessed. In vitro models of oxygen-glucose deprivation (OGD) examined the inhibition and overexpression of IRS-1 on p53 and cell death in neurons and endothelial cells. Compared to NL pups, DR pups had significantly higher IRS-1, p-IRS-1, and pAkt levels, decreased p53, more tight junction proteins, reduced blood-brain barrier (BBB) damage after HI, and less infarct volumes at P21. Immunofluorescence revealed that IRS-1 was upregulated in the endothelial cells and neurons of DR pups. IRS-1 downregulation in DR pups reduced p-Akt, increased p53, worsened BBB damage, and increased brain injury, whereas IRS-1 overexpression in NL pups upregulated p-Akt, decreased p53, attenuated BBB damage, and decreased brain injury. In vitro, IRS-1 downregulation aggravated cell death in neurons and endothelial cells and is associated with decreased p-Akt and increased p53. In contrast, IRS-1 overexpression reduced cell death in endothelial cells with increased p-Akt and decreased p53. In conclusion, DR reduces neurovascular damage after HI in the neonatal brain through an IRS-1/Akt-mediated p53 downregulation, suggesting that IRS-1 signaling is a therapeutic target for hypoxic brain injury in neonates.

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Acknowledgments

This study was supported by grants from the Taiwan Ministry of Science and Technology (NSC100-2314-B-006-042-MY3, NSC101-2314-B-006-034-MY3, MOST 103-2314-B-006-017-MY3).

Conflicts of Interest

The authors declare that they have no competing interests.

Research Involving Animals

This study was approved by National Cheng Kung University’s Animal Care Committee

Informed Consent

Not indicated

Author information

Authors and Affiliations

  1. Department of Pediatrics, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan

    Yi-Fang Tu, Chao-Ching Huang, Chien-Jung Ho & Ya-Ping Chou

  2. National Laboratory Animal Center, National Applied Research Laboratories, Taipei, Taiwan

    Si-Tse Jiang

  3. National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Zhunan Town, Miaoli County, Taiwan

    Yen-Hung Chow

  4. Department of Pediatrics, Wan-Fang Hospital, Taipei Medical University, Taipei, Taiwan

    Chao-Ching Huang

  5. Department of Pediatrics, College of Medicine, Taipei Medical University, #250, Wu-Hsing Street, Taipei City, 11031, Taiwan

    Chao-Ching Huang

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  1. Yi-Fang Tu
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  2. Si-Tse Jiang
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  3. Yen-Hung Chow
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  4. Chao-Ching Huang
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  5. Chien-Jung Ho
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  6. Ya-Ping Chou
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Corresponding author

Correspondence to Chao-Ching Huang.

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Fig. 1S

A representative picture showed the dark stained 5′ biotinylated-oligonucleotide introcerebroventricularly delivered into the ipsilateral cortex, hippocampus and striatum. (GIF 209 kb)

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Tu, YF., Jiang, ST., Chow, YH. et al. Insulin Receptor Substrate-1 Activation Mediated p53 Downregulation Protects Against Hypoxic-Ischemia in the Neonatal Brain. Mol Neurobiol 53, 3658–3669 (2016). https://doi.org/10.1007/s12035-015-9300-5

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  • DOI: https://doi.org/10.1007/s12035-015-9300-5

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