Measuring the Accentuation of the Brain Damage That Arises from Perinatal Cerebral Hypoxia-Ischemia

The major pathway of brain cholesterol turnover relies on its hydroxylation into 24S-hydroxycholesterol (24S-HC) using brain-specific cytochrome P450 46A1 (CYP46A1). 24S-HC produced exclusively in the brain normally traverses the blood-brain barrier to enter the circulation to the liver for excretion; therefore, the serum 24S-HC level is an indication of cholesterol metabolism in the brain. We recently reported an upregulation of CYP46A1 following hypoxia-ischemia (HI) in the neonatal mouse brain and a correlation between serum 24S-HC levels and acute brain damage. Here, we performed a longitudinal study to investigate whether the serum 24S-HC concentrations predict long-term brain structural and functional outcomes. In postnatal day 9 mice subjected to HI, the serum 24S-HC levels increased at 6 h and 24 h after HI and correlated with the infarct volumes measured histologically or by T2-weighted MRI. The 24 h levels were associated with white matter volume loss quantified by MBP immunostaining and luxol fast blue staining. The animals with higher serum 24S-HC at 6 h and 24 h corresponded to those with more severe motor and cognitive deficits at 35-40 days after HI. These data suggest that 24S-HC could be a novel and early blood biomarker for severity of neonatal HI brain damage and associated functional impairments.

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Experimental Biology of Cerebral Hypoxia-Ischemia: Relation to Perinatal Brain Damage

Pediatric Research ◽

10.1203/00006450-199004000-00001 ◽

1990 ◽

Vol 27 (4) ◽

pp. 317-326 ◽

Cited By ~ 309

Author(s):

Robert C Vannucci

Keyword(s):

Brain Damage ◽

Experimental Biology ◽

Cerebral Hypoxia ◽

Perinatal Brain Damage ◽

Hypoxia Ischemia

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Failure of Iron Chelators to Protect Against Cerebral Infarction in Hypoxia-Ischemia

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques ◽

10.1017/s0317167100047387 ◽

1993 ◽

Vol 20 (1) ◽

pp. 41-43 ◽

Cited By ~ 11

Author(s):

V. MacMillan ◽

I. Fridovich ◽

J. Davis

Keyword(s):

Carbon Monoxide ◽

Cerebral Infarction ◽

Brain Damage ◽

Histological Examination ◽

Iron Chelators ◽

Ischemic Brain ◽

Hypoxia Ischemia ◽

The Mean ◽

Preliminary Study ◽

The Brain

ABSTRACT:In this study the ability of iron chelators to attenuate hypoxic-ischemic brain damage was assessed in hyperglycemic rats that were exposed to 1% carbon monoxide and right carotid occlusion. The animals received deferoxamine (50 mg/kg), manganese-deferoxamine (50 mg/kg) or vehicle i.p. 0.5 h prior to hypoxemic-ischemic exposure and at 0.5, 3 and 24 h post-exposure; with subsequent histological examination of the brain at 7 days recovery. The area of cerebral infarction was measured at three levels using video imaging methods. The mean percentage of total hemisphere that was infarcted in the three groups was: vehicle — 28.5 ± 5.0; deferoxamine — 31.7 ± 12.1; and manganese deferoxamine — 30.6 ± 6.8 (p - n.s.). The results as obtained in this preliminary study indicate that aggressive pre- and post-treatment with iron chelators has no ability to attenuate cerebral infarction in this model.

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Carbohydrate and Energy Metabolism during the Evolution of Hypoxic-Ischemic Brain Damage in the Immature Rat

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.1990.39 ◽

1990 ◽

Vol 10 (2) ◽

pp. 227-235 ◽

Cited By ~ 73

Author(s):

Charles Palmer ◽

Robert M. Brucklacher ◽

Melanie A. Christensen ◽

Robert C. Vannucci

Keyword(s):

Carotid Artery ◽

Brain Damage ◽

Cerebral Hemisphere ◽

Tissue Injury ◽

Adenine Nucleotides ◽

High Energy ◽

Cerebral Hypoxia ◽

Ischemic Brain Damage ◽

Ischemic Brain ◽

Hypoxia Ischemia

The brain damage that evolves from perinatal cerebral hypoxia-ischemia may involve lingering disturbances in metabolic activity that proceed into the recovery period. To clarify this issue, we determined the carbohydrate and energy status of cerebral tissue using enzymatic, fluorometric techniques in an experimental model of perinatal hypoxic-ischemic brain damage. Seven-day postnatal rats were subjected to unilateral common carotid artery ligation followed by 3 h of hypoxia with 8% oxygen at 37°C. This insult is known to produce tissue injury (selective neuronal necrosis or infarction) predominantly in the cerebral hemisphere ipsilateral to the carotid artery occlusion in 92% of the animals. Rat pups were quick-frozen in liquid nitrogen at 0, 1, 4, 12, 24, or 72 h of recovery; littermate controls underwent neither ligation nor hypoxia. Glucose in both cerebral hemispheres was nearly completely exhausted during hypoxia-ischemia, with concurrent increases in lactate to 10 mmol/kg. During recovery, glucose promptly increased above control values, suggesting an inhibition of glycolytic flux, as documented in the ipsilateral cerebral hemisphere by measurement of glucose utilization (CMRglc) at 24 h. Tissue lactate declined rapidly during recovery but remained slightly elevated in the ipsilateral hemisphere for 12 h. Phosphocreatine (P∼Cr) and ATP in the ipsilateral cerebral hemisphere were 14 and 26% of control (p < 0.001) at the end of hypoxia-ischemia; total adenine nucleotides (ATP + ADP + AMP) also were partially depleted (–46%). During the first hour of recovery, mean P∼Cr was replenished to within 90% of baseline, whereas mean ATP was incompletely restored to 68–81% of control (p < 0.05). Individual ATP and total adenine nucleotide values were >2 SD below control levels in 17/24 (71%) brains at all intervals of recovery. Both ATP and total adenine nucleotides were inversely correlated with tissue water content, reflecting the extent of cerebral edema. No major alterations in the high-energy phosphate reserves occurred in the contralateral cerebral hemisphere either during or following hypoxia-ischemia. Thus, following perinatal cerebral hypoxia-ischemia, ATP and total adenine nucleotides never recover completely in brains undergoing damage but rather are permanently depleted to levels that reflect the severity of tissue injury. Recovery of P∼Cr to near normal levels can occur despite evolving brain damage. The findings have relevance to the assessment of asphyxiated newborn humans using magnetic resonance spectroscopy.

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Hydrogen inhalation protects hypoxic–ischemic brain damage by attenuating inflammation and apoptosis in neonatal rats

Experimental Biology and Medicine ◽

10.1177/1535370219855399 ◽

2019 ◽

Vol 244 (12) ◽

pp. 1017-1027 ◽

Cited By ~ 2

Author(s):

Guojiao Wu ◽

Zhiheng Chen ◽

Peipei Wang ◽

Mingyi Zhao ◽

Masayuki Fujino ◽

...

Keyword(s):

Brain Injury ◽

Inflammatory Response ◽

Spatial Memory ◽

Brain Damage ◽

Morris Water Maze Test ◽

Ischemic Brain Damage ◽

Ischemic Brain ◽

Hypoxia Ischemia ◽

The Brain

Hypoxic–ischemic brain damage (HIBD) is one of the leading causes of brain injury in infant with high risk of mortality and disability; therefore, it is important to explore more feasible and effective treatment strategies. Here, we assessed the neuroprotective effects of different hydrogen inhalation times for the treatment of HIBD. We induced hypoxia–ischemia in Sprague–Dawley rats (postnatal day 7, both sexes), followed by treatment with hydrogen inhalation for 30, 60, or 90 min. Morphological brain injury was assessed by Nissl and TUNEL staining. Acute inflammation was evaluated by examining the expression of interleukin-1β (IL-1β) and NF-κB p65, as well as Iba-1 immunofluorescence in the brain. Neural apoptosis was evaluated by examining the expression of P-JNK and p53 as well as NeuN immunofluorescence. Neurobehavioral function of rats was evaluated by Morris water maze test at 36 days after surgery. The results showed that hypoxia–ischemia injury induced the inflammatory response of microglia; however, these changes were inhibited by hydrogen inhalation. The inhibitory effects became more apparent as the treatment duration increased ( P < 0.05). Furthermore, hypoxia–ischemia induced neuronal damage and increased the expression of the apoptotic factors, P-JNK, and p53, which were attenuated by hydrogen inhalation ( P < 0.05). Hypoxia–ischemia caused long-term spatial memory deficits during brain maturation, which were ameliorated by hydrogen inhalation ( P < 0.01). In conclusion, hypoxia–ischemia induced severe long-term damage to the brain, which could be alleviated by hydrogen inhalation in a time-dependent manner. Impact statement Oxidative stress is known to be involved in the main pathological progression of neonatal hypoxic–ischemic brain damage (HIBD). Hydrogen (H2) is an antioxidant that can be used to treat HIBD; however, the mechanism by which hydrogen may be used as a promising treatment for neonates with HIBD is not very clear. This study demonstrated that inhaled H2 is neuroprotective against HIBD in SpragueDawley rats by inhibiting the brain’s inflammatory response and neuronal apoptosis or damage and protecting against spatial memory decline. Further, this study showed that inhaled H2 has potential as a therapeutic approach for HIBD. This is relevant to clinical treatment protocols when hypoxia–ischemia is suspected in neonates.

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Secondary Energy Failure after Cerebral Hypoxia–Ischemia in the Immature Rat

Journal of Cerebral Blood Flow & Metabolism ◽

10.1097/01.wcb.0000133250.03953.63 ◽

2004 ◽

Vol 24 (10) ◽

pp. 1090-1097 ◽

Cited By ~ 90

Author(s):

Robert C. Vannucci ◽

Javad Towfighi ◽

Susan J. Vannucci

Keyword(s):

Brain Damage ◽

Recovery Phase ◽

High Energy ◽

Cerebral Hypoxia ◽

Protein Markers ◽

Protein Marker ◽

Secondary Energy ◽

Hypoxia Ischemia ◽

Late Recovery ◽

Energy Failure

A delayed or secondary energy failure occurs during recovery from perinatal cerebral hypoxia–ischemia. The question remains as to whether the energy failure causes or accentuates the ultimate brain damage or is a consequence of cell death. To resolve the issue, 7-day postnatal rats underwent unilateral common carotid artery occlusion followed thereafter by systemic hypoxia with 8% oxygen for 2.5 hours. During recovery, the brains were quick frozen and individually processed for histology and the measurements of 1) high-energy phosphate reserves and 2) neuronal (MAP-2, SNAP-25) and glial (GFAP) proteins. Phosphocreatine (PCr) and ATP, initially depleted during hypoxia–ischemia, were partially restored during the first 18 hours of recovery, with secondary depletions at 24 and 48 hours. During the initial recovery phase (6 to 18 hours), there was a significant correlation between PCr and the histology score (0 to 3), but not for ATP. During the late recovery phase, there was a highly significant correlation between all measured metabolites and the damage score. Significant correlation also exhibited between the neuronal protein markers, MAP-2 and SNAP-25, and PCr as well as the sum of PCr and Cr at both phases of recovery. No correlation existed between the high-energy reserves and the glial protein marker, GFAP. The close correspondence of PCr to histologic brain damage and the loss of MAP-2 and SNAP-25 during both the early and late recovery intervals suggest evolving cellular destruction as the primary event, which precedes and leads to the secondary energy failure.

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Cerebral energy metabolism during hypoxia-ischemia and early recovery in immature rats

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1992.262.3.h672 ◽

1992 ◽

Vol 262 (3) ◽

pp. H672-H677 ◽

Cited By ~ 7

Author(s):

J. Y. Yager ◽

R. M. Brucklacher ◽

R. C. Vannucci

Keyword(s):

Carotid Artery ◽

Brain Damage ◽

Adenine Nucleotides ◽

High Energy ◽

Cerebral Hypoxia ◽

High Energy Phosphate ◽

Early Recovery ◽

Artery Ligation ◽

Carotid Artery Ligation ◽

Hypoxia Ischemia

Persistent alterations in cellular energy homeostasis may contribute to the brain damage that evolves from perinatal cerebral hypoxia-ischemia. Accordingly, the presence and extent of perturbations in high-energy phosphate reserves were analyzed during hypoxia-ischemia and the early recovery period in the immature rat. Seven-day postnatal rats were subjected to unilateral common carotid artery ligation and hypoxia with 8% oxygen at 37 degrees C for 3 h, an insult that produces damage (selective neuronal necrosis or infarction) of the cerebral hemisphere ipsilateral to the common carotid artery ligation in 92% of animals. Rat pups were quick frozen in liquid nitrogen during hypoxia-ischemia and at 10, 30, and 60 min and 4 and 24 h of recovery for enzymatic, fluorometric analysis of phosphocreatine (PCr), creatine, ATP, ADP, and AMP. During hypoxia-ischemia, PCr, ATP, and total adenine nucleotides were decreased by 87, 72, and 50% of control, respectively. During recovery, PCr, ATP, and total adenine nucleotides exhibited a rapid (within 10 min) although incomplete and heterogeneous recovery that persisted for at least 24 h. Mean values for PCr remained between 55 and 85% of control, whereas ATP values remained between 57 and 67% of control. Individual ATP values were inversely related to tissue water content at 10 min of recovery, indicating a close correlation between failure of energy restoration and the extent of cerebral edema as a reflection of brain damage. Thus high-energy phosphate reserves display lingering alterations during recovery from hypoxia-ischemia. The interanimal variability in energy restoration presumably reflects the spectrum of brain damage seen in this model of perinatal cerebral hypoxia-ischemia.

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