title: Moderate dietary restriction reduces p53-mediated neurovascular damage and microglia activation after hypoxic ischemia in neonatal brain.
abstract: OBJECTIVE
  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.
authors.affiliation: Institute of Clinical Medicine, National Cheng Kung University, Medical College and Hospital, Tainan, Taiwan.
authors.forename: Yi-Fang
authors.initials: YF
authors.lastname: Tu
authors.forename: Pei-Jung
authors.initials: PJ
authors.lastname: Lu
authors.forename: Chao-Ching
authors.initials: CC
authors.lastname: Huang
authors.forename: Chien-Jung
authors.initials: CJ
authors.lastname: Ho
authors.forename: Ya-Ping
authors.initials: YP
authors.lastname: Chou
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000502:physiology; D052160:Benzothiazoles / Q000494:pharmacology; D001812:Blood-Brain Barrier / Q000502:physiology; D015153:Blotting, Western; D001835:Body Weight; D001921:Brain / Q000473:pathology; D002545:Brain Ischemia / Q000150:complications / Q000178:diet therapy* / Q000473:pathology; D031204:Caloric Restriction; D002544:Cerebral Infarction / Q000473:pathology; D005455:Fluorescent Antibody Technique; D020925:Hypoxia-Ischemia, Brain / Q000178:diet therapy* / Q000209:etiology / Q000473:pathology; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008262:Macrophage Activation / Q000502:physiology*; D018782:Maze Learning; D017628:Microglia / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014050:Toluene / Q000031:analogs & derivatives / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000502:physiology*
chemical_list: D052160:Benzothiazoles; D016159:Tumor Suppressor Protein p53; D014050:Toluene; C121565:pifithrin