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Published on: November 20, 2015
Insulin Receptor Substrate-1 Activation Mediated p53 Downregulation Protects Against Hypoxic-Ischemia in the Neonatal
Yi-Fang Tu1, Si-Tse Jiang2, Yen-Hung Chow3
1Department of Pediatrics, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Insights
Dietary restriction (DR) protects neonatal brains from hypoxic-ischemia (HI) by activating the insulin receptor substrate-1 (IRS-1)/Akt pathway, which downregulates p53 and reduces brain damage. This suggests IRS-1 signaling is a potential therapeutic target for neonatal hypoxic brain injury.
Area of Science:
- Neuroscience
- Developmental Biology
- Metabolic Research
Background:
- Neonatal hypoxic-ischemia (HI) is a major cause of brain injury.
- The insulin receptor substrate-1 (IRS-1)/Akt pathway and p53 are implicated in cellular response to injury.
- Dietary restriction (DR) is known to affect metabolic pathways and cellular stress responses.
Purpose of the Study:
- To investigate whether dietary restriction (DR) protects the neonatal brain against hypoxic-ischemia (HI).
- To determine the role of the insulin receptor substrate-1 (IRS-1)/Akt pathway and p53 in mediating the neuroprotective effects of DR.
- To explore IRS-1 signaling as a potential therapeutic target for neonatal brain injury.
Main Methods:
- Neonatal rat pups were subjected to HI under conditions of normal litter size (NL) or increased litter size (DR) to induce dietary restriction.
- In vivo and in vitro experiments utilized IRS-1 antisense oligonucleotides and recombinant adenovirus for IRS-1 inhibition or overexpression.
- Neurovascular damage, blood-brain barrier integrity, infarct volume, and protein levels (IRS-1, p-IRS-1, pAkt, p53) were assessed.
Main Results:
- DR pups exhibited significantly reduced neurovascular damage, improved blood-brain barrier (BBB) integrity, and smaller infarct volumes compared to NL pups after HI.
- DR was associated with increased IRS-1, p-IRS-1, and pAkt levels, and decreased p53 levels in the neurovascular unit.
- Modulating IRS-1 levels directly affected p53 levels, Akt phosphorylation, and neuronal/endothelial cell death, confirming its role in mediating DR's protective effects.
Conclusions:
- Dietary restriction confers significant neuroprotection against HI in the neonatal brain.
- The protective mechanism involves the IRS-1/Akt pathway, leading to the downregulation of p53.
- IRS-1 signaling represents a promising therapeutic target for mitigating neonatal hypoxic-ischemic brain injury.
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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