phosphocreatine and Hypoxia-Ischemia--Brain

It is difficult to predict the neurologic outcome of neonates with hypoxic-ischemic encephalopathy (HIE). Our goal was to investigate the prognostic values of magnetic resonance spectroscopy (MRS) in neonatal HIE. During this study, 46 neonates with HIE underwent magnetic resonance imaging (MRI) and proton MRS ((1)HMRS). The sample included 25 cases of mild HIE, 11 cases of moderate HIE, and 10 cases of severe HIE. Nine healthy neonates without asphyxia served as controls. (1)HMRS techniques included single-voxel MRS and 2-D-point-resolved spatially localized spectroscopy (PRESS) multivoxel chemical shift spectroscopy imaging. Then, 31 of 46 neonates with HIE were divided into 3 groups according to their prognosis: dead, abnormal, and normal outcome. Abnormal and normal outcome were defined by follow-up MRI. Metabolic changes were analyzed and compared with HIE grading and prognosis. As a result, the GLx-alpha peak was markedly increased in the moderate and severe HIE groups. The GLx-alpha/Cr ratio in the control, mild, moderate, and severe HIE groups was 0.18, 0.21, 0.64, 1.31, respectively. The Lac/Cr ratio was 0.12, 0.14, 0.19, and 0.26, respectively. A Spearman rank correlation test confirmed that the ratio of GLx-alpha/Cr and Lac/Cr had significant positive correlation with clinical grading of HIE (P < 0.01). The GLx-alpha/Cr ratio in the dead, abnormal, and normal outcome groups was 1.28, 0.82, and 0.25, respectively; the Lac/Cr ratio was 0.34, 0.19, and 0.14, respectively. An anaylsis of variance demonstrated that the differences were significant (both P < 0.01). A Spearman rank correlation test confirmed that the ratio of GLx-alpha/Cr and Lac/Cr had significant negative correlation with prognosis of HIE; GLx-alpha/Cr showed a much stronger correlation than the Lac/Cr ratio (P < 0.01). The formula of the relationship between the poor prognosis of HIE and the ratio of GLx-alpha/Cr in basal ganglia was established by the logistic regression model. In conclusion, (1)HMRS is a useful tool for evaluating the severity and prognosis of HIE. The higher ratio of GLx-alpha/Cr in the basal ganglia and thalamus may predict a poor outcome in neonates with HIE.

Topics: Asphyxia Neonatorum; Basal Ganglia; Choline; Creatine; Female; Follow-Up Studies; Glutamic Acid; Glutamine; Humans; Hypoxia-Ischemia, Brain; Infant, Newborn; Logistic Models; Magnetic Resonance Spectroscopy; Male; Phosphocreatine; Predictive Value of Tests; Prognosis; Protons; Severity of Illness Index; Thalamus

Hypoxia-ischemia (HI) results in increased activation of Ca2+/calmodulin kinase IV (CaM kinase IV) mediated by Src kinase. Therapeutic hypothermia ameliorates neuronal injury in the newborn.. Inhibition of Src kinase concurrently with hypothermia further attenuates the hypoxia-induced increased activation of CaM kinase IV compared with hypothermia alone.. Ventilated piglets were exposed to HI, received saline or a selective Src kinase inhibitor (PP2), and were cooled to 33°C. Neuropathology, adenosine triphosphate (ATP) and phosphocreatine (PCr) concentrations, and CaM kinase IV activity were determined.. The neuropathology mean score (mean ± SD) was 0.4 ± 0.43 in normoxia-normothermia (p < 0.05 vs. hypoxia-normothermia), 3.5 ± 0.89 in hypoxia-normothermia (p < 0.05 vs. normoxia-normothermia), 0.7 ± 0.73 in hypoxia-hypothermia (p < 0.05 vs. normoxia-normothermia), and 0.5 ± 0.70 in normoxia-hypothermia (p < 0.05 vs. hypoxia-normothermia). The CaM kinase IV activity in cerebral tissue (pmol Pi/mg protein/min; mean ± SD) was 2,002 ± 729 in normoxia-normothermia, 1,704 ± 18 in normoxia-hypothermia, 6,017 ± 2,510 in hypoxia-normothermia, 4,104 ± 542 in hypoxia-hypothermia (p < 0.05 vs. normoxia-hypothermia), and 2,165 ± 415 in hypoxia-hypothermia with PP2 (p < 0.05 vs. hypoxia-hypothermia). The hypoxic groups with and without hypothermia or Src kinase inhibitor were comparable in the levels of ATP and PCr, indicating that they were similar in their degree of energy failure prior to treatments. Hypothermia or Src kinase inhibitor (PP2) did not restore the ATP and PCr levels.. Hypothermia and Src kinase inhibition attenuated apoptotic cell death and improved neuropathology after hypoxia. The combination of short-duration hypothermia with Src kinase inhibition following hypoxia further attenuates the increased activation of CaM kinase IV compared to hypothermia alone in the newborn swine brain.

Topics: Adenosine Triphosphate; Animals; Animals, Newborn; Brain; Calcium-Calmodulin-Dependent Protein Kinase Type 4; Hypothermia, Induced; Hypoxia-Ischemia, Brain; Hypoxia, Brain; Male; Neurons; Phosphocreatine; src-Family Kinases; Swine

Near-infrared spectroscopy (NIRS) offers the ability to assess brain function at the bedside of critically ill neonates. Our group previously demonstrated a persistent reduction in the cerebral metabolic rate of oxygen (CMRO(2)) after hypoxia-ischemia (HI) in newborn piglets. The purpose of this current study was to determine the causes of this reduction by combining NIRS with magnetic resonance spectroscopy (MRS) to measure high-energy metabolites and diffusion-weighted imaging to measure cellular edema. Nine piglets were exposed to 30 min of HI and nine piglets served as controls. Proton and phosphorous MRS spectra, apparent diffusion coefficient (ADC) maps, and CMRO(2) measurements were collected periodically before and for 5.5 h after HI. A significant decrease in CMRO(2) (26 +/- 7%) was observed after HI. Incomplete recovery of nucleotide triphosphate concentration (8 +/- 3%

Topics: Animals; Animals, Newborn; Brain; Brain Edema; Diffusion Magnetic Resonance Imaging; Disease Models, Animal; Energy Metabolism; Hypoxia-Ischemia, Brain; Lactic Acid; Magnetic Resonance Spectroscopy; Mitochondria; Oxygen Consumption; Phosphates; Phosphocreatine; Recovery of Function; Spectroscopy, Near-Infrared; Swine; Time Factors

The aim of this study was to evaluate the hypothesis that cerebral hemoglobin (Hb) oxygenation is related to phosphorylation potential during primary and secondary cerebral energy failure in newborn infants who have experienced birth asphyxia. We subjected newborn piglets to severe transient cerebral hypoxic-ischemia followed by resuscitation and examined cerebral energy metabolism by 31P-magnetic resonance spectroscopy and evaluated changes in cerebral Hb oxygen saturation (ScO2) using full-spectrum near-infrared spectroscopy before, during, and up to 54 h after the hypoxic-ischemic insult. ScO2 was significantly decreased during the hypoxic-ischemic insult compared with baseline values. During secondary energy failure, piglets were separated based on the relationship between the ratio of phosphocreatine to inorganic phosphate and ScO2; those with a negative correlation were less injured than those with a positive correlation. These results indicate that changes in ScO2 as measured by near-infrared spectroscopy are related to phosphorylation potential during secondary energy failure in asphyxiated infants.

Topics: Animals; Animals, Newborn; Energy Metabolism; Hemoglobins; Hypoxia-Ischemia, Brain; Magnetic Resonance Spectroscopy; Oxygen; Phosphocreatine; Phosphorylation; Spectroscopy, Near-Infrared

Phosphorus magnetic resonance spectroscopy ((31)P MRS) often reveals apparently normal brain metabolism in the first hours after intrapartum hypoxia-ischemia (HI) at a time when conventional clinical assessment of injury severity is problematic. We aimed to elucidate very-early, injury-severity biomarkers. Twenty-seven newborn piglets underwent cerebral HI: (31)P-MRS measures approximately 2 h after HI were compared between injury groups defined by secondary-energy-failure severity as quantified by the minimum nucleotide triphosphate (NTP) observed after 6 h. For severe and moderate injury versus baseline, [Pi]/[total exchangeable high-energy phosphate pool (EPP)] was increased (p < 0.001 and < 0.02, respectively), and [NTP]/[EPP] decreased (p < 0.03 and < 0.006, respectively): severe-injury [Pi]/[EPP] was also increased versus mild injury (p < 0.04). Mild-injury [phosphocreatine]/[EPP] was increased (p < 0.004). Severe-injury intracellular pH was alkaline versus baseline (p < 0.002). For severe and moderate injury [total Mg]/[ATP] (p < 0.0002 and < 0.02, respectively) and [free Mg] (p < 0.0001 and < 0.02, respectively) were increased versus baseline. [Pi]/[EPP], [phosphocreatine]/[Pi] and [NTP]/[EPP] correlated linearly with injury severity (p < 0.005, < 0.005 and < 0.02, respectively). Increased [Pi]/[EPP], intracellular pH and intracellular Mg approximately 2 h after intrapartum HI may prognosticate severe injury, whereas increased [phosphocreatine]/[EPP] may suggest mild damage. In vivo(31)P MRS may have potential to provide very-early prognosis in neonatal encephalopathy.

Topics: Adenosine Triphosphate; Animals; Animals, Newborn; Disease Models, Animal; Female; Hypoxia-Ischemia, Brain; Magnetic Resonance Spectroscopy; Male; Phosphocreatine; Phosphorus; Spectrum Analysis; Swine; Time Factors

Previous studies have shown contradictory results regarding magnesium-mediated neuroprotection in animal models of perinatal asphyxia. The aim of this study is to investigate the effects of MgSO(4) postasphyxial treatment on hypoxia-ischemia (HI)-induced brain injury in neonatal rats and the possibility that this effect is related to the severity of brain damage. Seven-day-old rats underwent unilateral carotid artery ligation followed by 1 or 2 hours of hypoxia (8% O(2)) and MgSO(4) administration. Adenosine triphosphate/phosphocreatine and glutamate/glutamine measurements and neuropathological evaluation of the hippocampus were used to assess the effects of HI and MgSO(4). HI caused time-dependent changes in energy stores, amino acid concentrations, and brain damage. Administration of MgSO(4) after 1 hour but not after 2 hours of hypoxia resulted in significant prevention of HI-induced brain injury. MgSO(4) administration results in a significant protection against moderate HI-induced brain damage, whereas it fails to offer a similar effect against severe brain damage.

Topics: Adenosine Triphosphate; Age Factors; Amino Acids; Animals; Animals, Newborn; Female; Hippocampus; Hypoxia-Ischemia, Brain; Hypoxia, Brain; Magnesium Sulfate; Male; Neuroprotective Agents; Phosphocreatine; Random Allocation; Rats; Rats, Wistar

Results from cerebral proton (1)H-MR spectroscopy studies of neonates with perinatal hypoxic-ischemic injury have generally been presented as metabolite peak-area ratios, which are T1- and T2-weighted, rather than absolute metabolite concentrations. We hypothesized that compared with (1)H-MR spectroscopy peak-area ratios, calculation of absolute metabolite concentrations and relaxation times measured within the first 4 days after birth (1) would improve prognostic accuracy and (2) enhance the understanding of underlying neurochemical changes in neonates with neonatal encephalopathy.. Seventeen term infants with neonatal encephalopathy and 10 healthy controls were studied at 2.4T at 1 (1-3) and 2 (2-4) (median [interquartile range]) days after birth, respectively. Infants with neonatal encephalopathy were classified into 2 outcome groups (normal/mild and severe/fatal), according to neurodevelopmental assessments at 1 year. The MR spectroscopy peak-area ratios, relaxation times, absolute concentrations, and concentration ratios of lactate (Lac), creatine plus phosphocreatine (Cr), N-acetylaspartate (NAA), and choline-containing compounds (Cho) from a voxel centered on the thalami were analyzed according to outcome group.. Comparing the severe/fatal group with the controls (significance assumed with P < 0.05), we found that Lac/NAA, Lac/Cho, and Lac/Cr peak-area ratios increased and NAA/Cr and NAA/Cho decreased; Lac, NAA, and Cr T2s were increased; [Lac] was increased and [Cho], [Cr], and [NAA] decreased; and among the concentration ratios, only [Lac]/[NAA] was increased. Comparison of the normal/mild group with controls revealed no differences in peak-area ratios, relaxation times, or concentration ratios but decreased [NAA], [Cho], and [Cr] were observed in the infants with normal/mild outcome. Comparison of the normal/mild and severe/fatal groups showed increased Lac/NAA and Lac/Cho and decreased NAA/Cr and NAA/Cho peak-area ratios, reduced [NAA], and increased Lac T2 in the infants with the worse outcome.. Metabolite concentrations, in particular [NAA], enhance the prognostic accuracy of cerebral (1)H-MR spectroscopy-[NAA] was the only measurable to discriminate among all (control, normal/mild, and severe/fatal outcome) groups. However, peak-area ratios are more useful prognostic indicators than concentration ratios because they depend on metabolite concentrations and T2s, both of which are pathologically modulated. Concentration ratios depend only on the concentrations of the constituent metabolites. Increased Cr T2 may provide an indirect marker of impaired cellular energetics, and similarly, NAA T2 may constitute an index of exclusively neuronal energy status. Our recommendation is to collect data that enable calculation of brain metabolite concentrations. However, if time constraints make this impossible, metabolite peak-area ratios provide the next best method of assigning early prognosis in neonatal encephalopathy.

Topics: Aspartic Acid; Birth Injuries; Body Water; Brain; Brain Chemistry; Child Development; Choline; Creatine; Follow-Up Studies; Gestational Age; Humans; Hydrogen; Hypoxia-Ischemia, Brain; Infant, Newborn; Lactic Acid; Magnetic Resonance Spectroscopy; Phosphocreatine; Prognosis; Protons; Thalamus

The aim of this study was to determine the validity of the hypothesis that excitatory amino acids are related to phosphorylation potential during primary and secondary cerebral energy failure observed in asphyxiated infants. We report here the results of experiments using newborn piglets subjected to severe transient cerebral hypoxia-ischemia followed by resuscitation. We examined cerebral energy metabolism by phosphorus nuclear magnetic resonance spectroscopy and changes in levels of amino acid neurotransmitters in the cortex by microdialysis before, during, and up to 24 h after the hypoxic-ischemic insult. The concentrations of aspartate, glutamate, taurine, and gamma-aminobutyric acid were significantly elevated during the hypoxic-ischemic insult compared with prebaseline values. Shortly after resuscitation, glutamate, taurine, and gamma-aminobutyric acid concentrations decreased but then began to increase again. These secondary elevations were greater than the primary elevations. A negative linear correlation was found between primary interstitial levels of glutamate and taurine and minimum values of phosphocreatine/inorganic phosphate during the secondary energy failure. The cerebral energy state depended on the time course of changes in excitatory amino acids, suggesting that amino acids play distinct roles during the early and delayed phases of injury.

Topics: Amino Acids; Animals; Animals, Newborn; Brain; Energy Metabolism; Extracellular Fluid; Hypoxia-Ischemia, Brain; Magnetic Resonance Spectroscopy; Phosphates; Phosphocreatine; Phosphorus Isotopes; Phosphorylation; Swine

Early detection of delayed cerebral energy failure may be important in the prevention of reperfusion injury of the brain after severe perinatal hypoxia-ischaemia (HI). This study investigated whether monitoring of the redox state of cytochrome aa(3) (Cytaa(3)) with near infrared spectroscopy (NIRS) after severe perinatal asphyxia may allow us to detect early a compromised energy metabolism of the developing brain. We therefore correlated serial Cytaa(3) measurements (to estimate mitochondrial oxygenation) simultaneously with the (31)phosphorous-magnetic resonance spectroscopy ((31)P-MRS)-measured phosphocreatin/inorganic phosphate (PCr/Pi) ratio (to estimate cerebral energy reserve) in newborn piglets before and after severe hypoxia-ischaemia. The animals were treated upon reperfusion with either allopurinol, deferoxamine, or 2-iminobiotin or with a vehicle to reduce post-HI reperfusion injury of the brain. Four sham-operated piglets served as controls. Before HI, the individual Cytaa(3) values ranged between -0.02 and 0.71 micromol/L (mean value: -0.07) relative to baseline. The pattern over post-HI time of the vehicle-treated animals was remarkably different from the other groups in as far Cytaa(3) became more oxidised from 3 h after start of HI onwards (increase of Cytaa(3) as compared with baseline), whereas the other groups showed a significant reduction over time (decrease of Cytaa(3) as compared with baseline: allopurinol and deferoxamine) or hardly any change (2-iminobiotin and sham-operated piglets). Vehicle-treated piglets showed a significant reduction in PCr/Pi at 24 h after start of HI, but the cerebral energy state was preserved in 2-iminobiotin-, allopurinol- and deferoxamine-treated piglets. With severe reduction in PCr/Pi-ratio, major changes in the redox-state of Cytaa(3) also occurred: Cytaa(3) was mostly either in a reduced state (down to -6.45 micromol/L) or in an oxidised state (up to 6.84 micromol/L) at these low PCr/Pi ratios. The positive predictive value (PPV) of Cytaa(3) to predict severe reduction of the PCr/Pi ratio was 42%; the negative PPV was 87%. A similar relation was found for Cytaa(3) with histologically determined loss of neurons.

Topics: Allopurinol; Animals; Animals, Newborn; Biotin; Brain; Cell Survival; Deferoxamine; Disease Models, Animal; Disease Progression; Electron Transport Complex IV; Energy Metabolism; Free Radical Scavengers; Hypoxia-Ischemia, Brain; Iron Chelating Agents; Magnetic Resonance Spectroscopy; Neurons; Neuroprotective Agents; Oxidation-Reduction; Phosphates; Phosphocreatine; Predictive Value of Tests; Spectroscopy, Near-Infrared; Swine

Cerebral hypoxia-ischemia (HI) is an important cause of perinatal brain damage in the term newborn. The areas most affected are the parasagittal regions of the cerebral cortex and, in severe situations, the basal ganglia. The aim of this study was to show that the newborn piglet model can be used to produce neuropathology resulting from moderate HI insult and to monitor damage for 7 days. Two acute cerebral HI were induced in newborn Large White piglets by reducing the inspired oxygen fraction to 4% and occluding the carotid arteries. Newborn piglets were resuscitated, extubated and monitored for 7 days. (31)P magnetic resonance spectroscopy (MRS) offers the ability to monitor the severity of the HI insults. Lactate (Lac) was detected in the HI group at 2 h, 3 days and 5 days after insult by (1)H MRS. Lac/n-acetylaspartate and Lac/choline and Lac/creatine ratios increased significantly (p < 0.01) in the HI group 2 h after HI insults and remained high over 7 days. For the HI group, mean T(2) values increased significantly in the parietal white matter (subcortical) for 5 days after HI insult [117.5 (+/-7.4) to 158.5 (+/-19.2) at T+3 days, 167.7 (+/-15.4) at T+5 days and 160.9 (+/-10.1) at T+7 days (p < 0.01)]. This newborn piglet model of moderate HI brain injury with reproducible cerebral damage could be use as reference for the study of neuroprotective strategy for a period of 7 days.

Topics: Animals; Animals, Newborn; Aspartic Acid; Basal Ganglia; Cerebral Cortex; Cerebrovascular Circulation; Disease Models, Animal; Energy Metabolism; Hydrogen; Hydrogen-Ion Concentration; Hypoxia-Ischemia, Brain; Ischemic Attack, Transient; Lactic Acid; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Phosphocreatine; Phosphorus Isotopes; Radiopharmaceuticals; Severity of Illness Index; Stroke; Swine

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.

Topics: Adenosine Triphosphate; Age Factors; Animals; Biomarkers; Brain; Creatine; Energy Metabolism; Female; Hypoxia-Ischemia, Brain; Phosphocreatine; Pregnancy; Rats; Rats, Wistar

Perinatal hypoxia-ischemia (HI) is the most common precipitant of seizures in the first 24-48 h of a newborn's life. In a previous study, our laboratory developed a model of prolonged, continuous electrographic seizures in 10-day-old rat pups using kainic acid (KA) as a proconvulsant. Groups of animals included those receiving only KA, or HI for 15 or 30 min, followed by KA infusion. Our results showed that prolonged electrographic seizures following 30 min of HI resulted in a marked exacerbation of brain damage. We have undertaken studies to determine alterations in hippocampal high-energy phosphate reserves and the extracellular release of hippocampal amino acids in an attempt to ascertain the underlying mechanisms responsible for the damage promoted by the combination of HI and KA seizures.. All studies were performed on 10-day-old rats. Five groups were identified: (1) group I--KA alone, (2) group II--15 min of HI plus KA, (3) group III--15 min of HI alone, (4) group IV--30 min of HI plus KA, and (5) group VI--30 min of HI alone. HI was induced by right common carotid artery ligation and exposure to 8% oxygen/balance nitrogen. Glycolytic intermediates and high-energy phosphates were measured. Prior to treatment, at the end of HI (both 15 and 30 min), prior to KA injection, and at 1 (onset of seizures), 3, 5 (end of seizures), 7, 24 and 48 h, blood samples were taken for glucose, lactate and beta-hydroxybutyrate. At the same time points, animals were sacrificed by decapitation and brains were rapidly frozen for subsequent dissection of the hippocampus and measurement of glucose, lactate, beta-hydroxybutyrate, adenosine triphosphate (ATP) and phosphocreatine (PCr). In separate groups of rats as defined above, microdialysis probes (CMA) were stereotactically implanted into the CA2-3 region of the ipsilateral hippocampus for measurement of extracellular amino acid release. Dialysate was collected prior to any treatment, at the end of HI (15 and 30 min), prior to KA injection, and at 1 (onset of seizures), 3, 5 (end of seizures), 7 and 9 h. Determination of glutamate, serine, glutamine, glycine, taurine, alanine, and GABA was accomplished using high-performance liquid chromatography with EC detection.. Blood and hippocampal glucose concentrations in all groups receiving KA were significantly lower than control during seizures (p < 0.05). beta-Hydroxybutyrate values displayed the inverse, in that values were significantly higher (p < 0.01) in all KA groups compared with pretreatment controls during seizure activity. Values returned to control by 2 h following the cessation of seizures. Lactate concentrations in brain and blood mimicked those of beta-hydroxybutyrate. ATP values declined to 0.36 mmol/l in both the 15 and 30 min hypoxia groups compared with 1.85 mmol/l for controls (p < 0.01). During seizures, ATP and PCr values declined significantly below their homologous controls. Following seizures, ATP values only for those animals receiving KA plus HI for 30 min remained below their homologous controls for at least 24 h. Determination of amino acid release revealed elevations of glutamate, glycine, taurine, alanine and GABA above pretreatment control during HI, with a return to normal prior to KA injections. During seizures and for the 4 h of recovery monitored, only glutamate in the combined HI and KA group rose significantly above both the 15 min of HI plus KA and the KA alone group (p < 0.05).. Under circumstances in which there is a protracted depletion of high-energy phosphate reserves, as occurs with a combination of HI- and KA-induced seizures, excess amounts of glutamate become toxic to the brain. The latter may account for the exacerbation of damage to the newborn hippocampus, and serve as a target for future therapeutic intervention.

Topics: 3-Hydroxybutyric Acid; Adenosine Triphosphate; Animals; Animals, Newborn; Blood Glucose; Excitatory Amino Acid Agonists; Excitatory Amino Acids; Extracellular Space; Female; Glucose; Hippocampus; Hypoxia-Ischemia, Brain; Kainic Acid; Lactic Acid; Microdialysis; Phosphocreatine; Rats; Seizures; Telencephalon; Time Factors

Recent studies have shown a protection from cerebral hypoxic-ischemic (HI) brain damage in the immature rat following a prior systemic hypoxic exposure when compared with those not exposed previously. To investigate the mechanism(s) of hypoxic preconditioning, brain glycogen and high-energy phosphate reserves were measured in naïve and preconditioned rat pups subjected to HI. Groups in this study included untouched (naïve) controls, preconditioned controls (i.e., hypoxia only), preconditioned with HI insult, and naïve pups with HI insult. Hypoxic preconditioning was achieved in postnatal-day-6 rats subjected to 8% systemic hypoxia for 2.5 h at 37 degrees C. Twenty-four hours later, they were subjected to unilateral common carotid artery ligation and systemic hypoxia with 8% oxygen at 37 degrees C for 90 min. Animals were allowed to recover from HI for up to 24 h. At specific intervals, animals in each group were frozen in liquid nitrogen for determination of cerebral metabolites. Preconditioned animals showed a significant increase in brain glycogen 24 h following the initial hypoxic exposure, corresponding to the beginning of the HI insult. Measurement at the end of 90 min of HI showed a depletion of high-energy phosphates, ATP and phosphocreatine, in all animals although ATP remained significantly higher in the preconditioned animals. Thus, the energy from increased glycogen following preconditioning slowed high-energy phosphate depletion during HI, thereby allowing for long-term protection.

Topics: Adenosine Triphosphate; Animals; Brain; Energy Metabolism; Glucose; Glycogen; Hypoxia-Ischemia, Brain; Ischemic Preconditioning; Phosphocreatine; Rats; Rats, Wistar

Topics: Humans; Hydrogen-Ion Concentration; Hypoxia-Ischemia, Brain; Infant, Newborn; Lactic Acid; Magnetic Resonance Imaging; Phosphates; Phosphocreatine