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Development-dependent regulation of molecular chaperones after hypoxia-ischemia.

ABSTRACT: Cellular stress response after hypoxia-Ischemia (HI) may be substantially different between immature and mature brains. To study this phenomenon, postnatal day 7 (P7) and P26 rats were subjected to HI followed by different periods of recovery. Nuclear accumulation of heat-shock transcription factor-1 (HSF1) and expression of molecular chaperone proteins and mRNAs were analyzed by in situ hybridization, Western blotting and confocal microscopy. Nuclear accumulation of HSF1 protein and induction of hsp70 mRNA occurred dramatically in P26 neurons, but minimally in P7 neurons and moderately in microglial cells after HI. Consistently, the level of HSF1 was significantly higher in P26 brain samples, compared with that in P7 brain. Translation of hsp70 mRNA into proteins in P26 mature neurons was seen at 4h and peaked at 24h, when some neurons had already died after HI. Induction of ER glucose-regulated protein-78 (grp78) and mitochondrial hsp60 mRNAs and proteins was moderate and occurred also only in P26 mature brain after HI. These results suggest that the cellular stress response after HI is development-dependent, being pronounced in mature but virtually negligible in neonatal neurons. Therefore, the effectiveness of therapeutic strategies targeting the stress pathway against HI may be significantly different between immature and mature brains. The delayed induction of molecular chaperones in mature brain may be somewhat late for protecting HI neurons from acute HI injury.

SUBMITTER: Sun X

PROVIDER: S-EPMC4641006 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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Development-dependent regulation of molecular chaperones after hypoxia-ischemia.

Sun Xin X Crawford Robert R Liu Chunli C Luo Tianfei T Hu Bingren B

Neurobiology of disease 20150609

Cellular stress response after hypoxia-Ischemia (HI) may be substantially different between immature and mature brains. To study this phenomenon, postnatal day 7 (P7) and P26 rats were subjected to HI followed by different periods of recovery. Nuclear accumulation of heat-shock transcription factor-1 (HSF1) and expression of molecular chaperone proteins and mRNAs were analyzed by in situ hybridization, Western blotting and confocal microscopy. Nuclear accumulation of HSF1 protein and induction o ...[more]

PMID: 26070787

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Project description:Human brain lesions in the perinatal period result in life-long neuro-disabilities impairing sensory-motor, cognitive, and behavior functions for years. Topographical aspects of brain lesions depend on gestational age at the time of insult in preterm or term infants and impaired subsequent steps of brain development and maturation. In mice, the Rice-Vannucci procedure of neonate hypoxia-ischemia (HI) was used at 5 days (P5) or P10, mimicking the development of 30 week-gestation fetus/preterm newborn, or full-term infant, respectively. Transcription response to HI was assessed at 3, 6, 12, and 24 h after insult, using micro-array technology. Statistical Pathway and Gene Ontology terms enrichments were investigated using DAVID®, Revigo® and Ingenuity Pathway Analysis (IPA®) to identify a core of transcription response to HI, age-specific regulations, and interactions with spontaneous development. Investigations were based on direction, amplitude, and duration of responses, basal expression, and annotation. Five major points deserve attention; (i) inductions exceeded repressions (60/40%) at both ages, (ii) only 20.3% (393/1938 records) were common to P5 and P10 mice, (iii) at P5, HI effects occurred early and decreased 24 h after insult whereas they were delayed at P10 and increased 24 h after insult, (iv) common responses at P5 and P10 involved inflammation, immunity, apoptosis, and angiogenesis. (v) age-specific effects occurred with higher statistical significance at P5 than at P10. Transient repression of 12 genes encoding cholesterol biosynthesis enzymes was transiently observed 12 h after HI at P5. Synaptogenesis appeared inhibited at P5 while induced at P10, showing reciprocal effects on glutamate receptors. Specific involvement of Il-1 (interleukin-1) implicated in the firing of inflammation was observed at P10. This study pointed out age-differences in HI responses kinetics, e.g., a long-lasting inflammatory response at P10 compared to P5. Whether the specific strong depression of cholesterol biosynthesis genes that could account for white matter-specific vulnerability at P5 or prevent delayed inflammation needs further investigation. Determination of putative involvement of Il-1 and the identification of upstream regulators involved in the delayed inflammation firing at P10 appears promising routes of research in the understandings of age-dependent vulnerabilities in the neonatal brain.

Project description:Injuries to the developing brain due to hypoxia-ischemia (HI) are common causes of neurological disabilities in preterm babies. HI, with oxygen deprivation to the brain or reduced cerebral blood perfusion due to birth asphyxia, often leads to severe brain damage and sequelae. Injury mechanisms include glutamate excitotoxicity, oxidative stress, blood-brain barrier dysfunction, and exacerbated inflammation. Nutritional intervention is emerging as a therapeutic alternative to prevent and rescue brain from HI injury. Lactoferrin (Lf) is an iron-binding protein present in saliva, tears, and breast milk, which has been shown to have antioxidant, anti-inflammatory and anti-apoptotic properties when administered to mothers as a dietary supplement during pregnancy and/or lactation in preclinical studies of developmental brain injuries. However, despite Lf's promising neuroprotective effects, there is no established dose. Here, we tested three different doses of dietary maternal Lf supplementation using the postnatal day 3 HI model and evaluated the acute neurochemical damage profile using 1H Magnetic Resonance Spectroscopy (MRS) and long-term microstructure alterations using advanced diffusion imaging (DTI/NODDI) allied to protein expression and histological analysis. Pregnant Wistar rats were fed either control diet or bovine Lf supplemented chow at 0.1, 1, or 10 g/kg/body weight concentration from the last day of pregnancy (embryonic day 21-E21) to weaning. At postnatal day 3 (P3), pups from both sexes had their right common carotid artery permanently occluded and were exposed to 6% oxygen for 30 min. Sham rats had the incision but neither surgery nor hypoxia episode. At P4, MRS was performed on a 9.4 T scanner to obtain the neurochemical profile in the cortex. At P4 and P25, histological analysis and protein expression were assessed in the cortex and hippocampus. Brain volumes and ex vivo microstructural analysis using DTI/NODDI parameters were performed at P25. Acute metabolic disturbance induced in cortical tissue by HIP3 was reversed with all three doses of Lf. However, data obtained from MRS show that Lf neuroprotective effects were modulated by the dose. Through western blotting analysis, we observed that HI pups supplemented with Lf at 0.1 and 1 g/kg were able to counteract glutamatergic excitotoxicity and prevent metabolic failure. When 10 g/kg was administered, we observed reduced brain volumes, increased astrogliosis, and hypomyelination, pointing to detrimental effects of high Lf dose. In conclusion, Lf supplementation attenuates, in a dose-dependent manner, the acute and long-term cerebral injury caused by HI. Lf reached its optimal effects at a dose of 1 g/kg, which pinpoints the need to better understand effects of Lf, the pathways involved and possible harmful effects. These new data reinforce our knowledge regarding neuroprotection in developmental brain injury using Lf through lactation and provide new insights into lactoferrin's neuroprotection capacities and limitation for immature brains.

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Development-dependent regulation of molecular chaperones after hypoxia-ischemia.

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Development-dependent regulation of molecular chaperones after hypoxia-ischemia.

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