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

1990 ◽  
Vol 10 (2) ◽  
pp. 227-235 ◽  
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.

scholarly journals Cerebral Glucose and Energy Utilization during the Evolution of Hypoxic—Ischemic Brain Damage in the Immature Rat

1994 ◽  
Vol 14 (2) ◽  
pp. 279-288 ◽  
Author(s):  
Robert C. Vannucci ◽  
Jermone Y. Yager ◽  
Susan J. Vannucci
Keyword(s):  
Carotid Artery ◽  
Brain Damage ◽  
Cerebral Hemisphere ◽  
Energy Utilization ◽  
Contralateral Hemisphere ◽  
Early Recovery ◽  
Ischemic Brain Damage ◽  
Ipsilateral Hemisphere ◽  
Ischemic Brain ◽  
Hypoxia Ischemia

The cerebral metabolic rate for glucose (CMRg1) and cerebral energy utilization (CEU) were assessed in immature rats during recovery from cerebral hypoxia–ischemia. CMRg1 was determined using a modification of the Sokoloff technique with 2-deoxy-[14C]glucose (2-DG) as the radioactive tracer. CEU was determined using the Lowry decapitation technique. Seven-day postnatal rats underwent unilateral common carotid artery ligation, followed 4 h thereafter by exposure to 8% oxygen at 37°C for 3 h. At 1, 4, or 24 h of recovery, the rat pups underwent those procedures necessary for the measurement of either CMRg1 or CEU. At 1 h of recovery, the CMRg1 of the cerebral hemisphere ipsilateral to the carotid artery occlusion was 97% of the control rate (8.7 μmol 100 g−1 min−1) but was only 48% of the control in the contralateral hemisphere. At 4 h of recovery, the CMRg1 was increased 49% above baseline in the ipsilateral hemisphere, decreasing thereafter to 84% of the control at 24 h. The CMRg1 of the contralateral hemisphere normalized by 4 h of recovery. An inverse correlation between endogenous concentrations of ATP or phosphocreatine and CMRg1 in the ipsilateral hemisphere was apparent at 4 h of recovery. CEU in the ipsilateral cerebral hemisphere was 64 and 46% of the control (3.47 mmol ∼P/kg/min) at 1 and 24 h, respectively (p < 0.05) and 77% of the control at 4 h of recovery. CEU in the contralateral hemisphere was unchanged from the control at all measured intervals. Correlation of the alterations in CMRg1 with those in CEU at the same intervals indicated that substrate supply exceeds energy utilization during early recovery from hypoxia-ischemia. The discrepancy combined with a persistent disruption of the cerebral energy state implies the existence of an uncoupling of mitochondrial oxidative phosphorylation as one mechanism for the occurrence of perinatal hypoxic-ischemic brain damage.

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

1992 ◽  
Vol 262 (3) ◽  
pp. H672-H677 ◽  
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.

scholarly journals Calcium Accumulation during the Evolution of Hypoxic—Ischemic Brain Damage in the Immature Rat

1988 ◽  
Vol 8 (6) ◽  
pp. 834-842 ◽  
Author(s):  
Dagmar T. Stein ◽  
Robert C. Vannucci
Keyword(s):  
Brain Damage ◽  
Cerebral Hemisphere ◽  
Ischemic Injury ◽  
Calcium Flux ◽  
Variable Degree ◽  
Ischemic Brain Damage ◽  
Ischemic Brain ◽  
Calcium Accumulation ◽  
Hypoxia Ischemia ◽  
Hypoxic Ischemic Injury

An excessive accumulation of calcium in neuronal and other tissues has been postulated to represent a “final common pathway” for cell death arising from hypoxia-ischemia. To clarify the role of altered calcium flux into and distribution within the perinatal brain undergoing hypoxic-ischemic injury, 7-day postnatal rats underwent unilateral common carotid artery ligation followed by 3 h of hypoxia with 8% oxygen. This insult is known to produce brain damage confined to the cerebral hemisphere ipsilateral to the arterial occlusion in >90% of the animals. Either before or after hypoxia-ischemia, the animals received a subcutaneous injection of [45Ca]Cl2, and their brains were subjected to 45Ca autoradiography at 0–1, 5, 24, and 72 h, 7 or 15 days thereafter. During hypoxia-ischemia, calcium flux into the ipsilateral cerebral hemisphere was prominent in 13 of 14 rat pups, especially in neocortex, hippocampus, striatum, and thalamus. Calcium accumulation also occurred to a variable degree (6 of 14 animals) in the contralateral cerebral hemisphere. During recovery, radioactivity in the contralateral cerebral hemisphere was no longer apparent, whereas in the ipsilateral hemisphere, the extent of calcium accumulation was mild in four of six at 1 h, moderate in three of six at 5 h, moderate to intense in six of seven and six of seven at 24 and 72 h, respectively, and intense in three of three and two of two animals at 7 and 15 days, respectively. As during hypoxia-ischemia, the distribution of the radioactivity was most prominent in those structures that are known to be vulnerable to hypoxic-ischemic injury. Thus, hypoxia-ischemia is associated with enhanced calcium uptake into the immature brain, which does not dissipate but rather progressively accumulates for up to 15 days of recovery. The findings implicate a disruption of intracellular calcium homeostasis as a major factor in the evolution of perinatal hypoxic-ischemic brain damage.

scholarly journals Focal Cerebral Ischemia in the Cat: Pretreatment with a Competitive NMDA Receptor Antagonist, D-CPP-ene

1990 ◽  
Vol 10 (5) ◽  
pp. 668-674 ◽  
Author(s):  
Ross Bullock ◽  
David I. Graham ◽  
Min-Hsiung Chen ◽  
David Lowe ◽  
James McCulloch
Keyword(s):  
Cerebral Ischemia ◽  
Nmda Receptor ◽  
Receptor Antagonist ◽  
Brain Damage ◽  
Cerebral Hemisphere ◽  
Focal Cerebral Ischemia ◽  
Nmda Receptor Antagonist ◽  
Ischemic Brain Damage ◽  
Ischemic Brain ◽  
Permanent Occlusion

The effects of the competitive N-methyl-D-aspartate (NMDA) receptor antagonist D-( E)-4-(3-phosphonoprop-2-enyl)piperazine-2-carboxylic acid (D-CPP-ene; SDZ EAA 494) upon ischemic brain damage have been examined in anesthetized cats. Focal cerebral ischemia was produced by permanent occlusion of the middle cerebral artery (MCA) and the animals were killed 6 h later. The amount of early ischemic brain damage was assessed in coronal sections at 16 predetermined stereotaxic planes. Pretreatment with D-CPP-ene (15 mg/kg i.v. followed by continuous infusion at 0.17 mg/kg/min until death), 15 min prior to MCA occlusion, significantly reduced the volume of ischemic brain damage (from 20.6 ± 9.9% of the cerebral hemisphere in vehicle-treated cats to 7.2 ± 4.4% in drug-treated cats; p < 0.01). The competitive NMDA receptor antagonist D-CPP-ene is as effective as noncompetitive NMDA antagonists in reducing the amount of ischemic brain damage in this model of focal cerebral ischemia in a gyrencephalic species.

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

2019 ◽  
Vol 244 (12) ◽  
pp. 1017-1027 ◽  
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.

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

2004 ◽  
Vol 24 (10) ◽  
pp. 1090-1097 ◽  
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.

scholarly journals TP53-induced glycolysis and apoptosis regulator alleviates hypoxia/ischemia-induced microglial pyroptosis and ischemic brain damage

2021 ◽  
Vol 16 (6) ◽  
pp. 1037
Author(s):  
Zu-Bin Zhang ◽  
Xing Feng ◽  
Mei Li ◽  
Lan-Lan Tan ◽  
Xiao-Lu Jiang ◽  
...  
Keyword(s):  
Brain Damage ◽  
Ischemic Brain Damage ◽  
Ischemic Brain ◽  
Hypoxia Ischemia

scholarly journals Ischemic Brain Damage Induced by Repeated Brief Occlusions of Bilateral Common Carotid Artery in Rats.

1994 ◽  
Vol 172 (3) ◽  
pp. 253-262 ◽  
Author(s):  
TAKESHI NAGAHORI ◽  
MICHIHARU NISHIJIMA ◽  
SHUNRO ENDO ◽  
AKIRA TAKAKU ◽  
YUZO IWASAKI
Keyword(s):  
Carotid Artery ◽  
Brain Damage ◽  
Common Carotid Artery ◽  
Ischemic Brain Damage ◽  
Ischemic Brain ◽  
Bilateral Common Carotid Artery

Effect of Unilateral Perinatal Hypoxic-Ischemic Brain Damage on the Gross Development of Opposite Cerebral Hemisphere

Neonatology ◽  
1994 ◽  
Vol 65 (2) ◽  
pp. 108-118 ◽  
Author(s):  
Javad Towfighi ◽  
Cathy Housman ◽  
Robert C. Vannucci ◽  
Daniel F. Heitjan
Keyword(s):  
Brain Damage ◽  
Cerebral Hemisphere ◽  
Ischemic Brain Damage ◽  
Ischemic Brain
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