Moderate dietary restriction reduces p53-mediated neurovascular damage and microglia activation after hypoxic ischemia in neonatal brain

Yi Fang Tu, Pei Jung Lu, Chao Ching Huang, Chien Jung Ho, Ya Ping Chou

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

Background and Purpose-: Neurovascular damage, including neuronal apoptosis and blood-brain barrier (BBB) damage, and microglia activation account for the hypoxic-ischemia (HI) susceptibility in neonatal brain. The p53 upregulation is involved in apoptosis, endothelial cell damage, and microglia activation. We hypothesized that underweight induced by dietary restriction (DR) protects against HI in rat pups by attenuating p53-mediated neurovascular damage. Methods-: Male rat pups were grouped as normal litter (NL) size (12 pups/dam), DR (18 pups/dam), and extreme DR (24 pups/dam) from postnatal day 1 and subjected to HI on postnatal day 7. Immunohistochemistry and immunoblotting were used to determine p53, phospho-murine double minute-2, caspases, BBB damage and microglia activation, and immunofluorescence to determine the cellular distribution of p53. Pharmacological approaches were used to regulate p53. Results-: The NL, DR, and extreme DR pups had similar TUNEL-positive cells and caspases on postnatal day 7 and comparable learning performance at adulthood. After HI, the DR-HI, but not extreme DR-HI, pups had significantly lower p53, higher phospho-murine double minute-2, lower cleaved caspases, less BBB damage and microglia activation, and less brain volume loss than NL-HI pups. In NL-HI pups, p53 expression was located mainly in the neurons, endothelial cells, and microglia. The p53 blockage by pifithrin-α in NL-HI pups decreased apoptosis, BBB damage, and microglia activation, and was neuroprotective. In contrast, upregulating p53 by nutlin-3 in DR-HI pups increased apoptosis, BBB damage, and microglia activation, and worsened brain damage. Conclusions-: Moderate DR, but not extreme DR, reduces p53-mediated neurovascular damage after HI and confers long-term protection in neonatal brain.

Original languageEnglish
Pages (from-to)491-498
Number of pages8
JournalStroke
Volume43
Issue number2
DOIs
Publication statusPublished - Feb 2012
Externally publishedYes

Fingerprint

Microglia
Ischemia
Brain
Blood-Brain Barrier
Apoptosis
Caspases
Endothelial Cells
Caspase 2
Litter Size
Thinness
In Situ Nick-End Labeling
Immunoblotting
Fluorescent Antibody Technique
Up-Regulation
Immunohistochemistry
Learning
Pharmacology
Neurons

Keywords

  • dietary restriction
  • hypoxic-ischemia
  • neonatal brain
  • underweight

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Clinical Neurology
  • Advanced and Specialised Nursing

Cite this

Moderate dietary restriction reduces p53-mediated neurovascular damage and microglia activation after hypoxic ischemia in neonatal brain. / Tu, Yi Fang; Lu, Pei Jung; Huang, Chao Ching; Ho, Chien Jung; Chou, Ya Ping.

In: Stroke, Vol. 43, No. 2, 02.2012, p. 491-498.

Research output: Contribution to journalArticle

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AU - Chou, Ya Ping

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AB - Background and Purpose-: Neurovascular damage, including neuronal apoptosis and blood-brain barrier (BBB) damage, and microglia activation account for the hypoxic-ischemia (HI) susceptibility in neonatal brain. The p53 upregulation is involved in apoptosis, endothelial cell damage, and microglia activation. We hypothesized that underweight induced by dietary restriction (DR) protects against HI in rat pups by attenuating p53-mediated neurovascular damage. Methods-: Male rat pups were grouped as normal litter (NL) size (12 pups/dam), DR (18 pups/dam), and extreme DR (24 pups/dam) from postnatal day 1 and subjected to HI on postnatal day 7. Immunohistochemistry and immunoblotting were used to determine p53, phospho-murine double minute-2, caspases, BBB damage and microglia activation, and immunofluorescence to determine the cellular distribution of p53. Pharmacological approaches were used to regulate p53. Results-: The NL, DR, and extreme DR pups had similar TUNEL-positive cells and caspases on postnatal day 7 and comparable learning performance at adulthood. After HI, the DR-HI, but not extreme DR-HI, pups had significantly lower p53, higher phospho-murine double minute-2, lower cleaved caspases, less BBB damage and microglia activation, and less brain volume loss than NL-HI pups. In NL-HI pups, p53 expression was located mainly in the neurons, endothelial cells, and microglia. The p53 blockage by pifithrin-α in NL-HI pups decreased apoptosis, BBB damage, and microglia activation, and was neuroprotective. In contrast, upregulating p53 by nutlin-3 in DR-HI pups increased apoptosis, BBB damage, and microglia activation, and worsened brain damage. Conclusions-: Moderate DR, but not extreme DR, reduces p53-mediated neurovascular damage after HI and confers long-term protection in neonatal brain.

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