scholarly journals Hypothermia Suppresses Uncoupling of Oxidative- Phosphorylation after Neonatal Cerebral Hypoxia-Ischemia

2021 ◽  
Author(s):  
Naidi Sun ◽  
Yu-Yo Sun ◽  
Rui Cao ◽  
Hong-Ru Chen ◽  
Yiming Wang ◽  
...  
Keyword(s):  
Oxidative Phosphorylation ◽  
Optical Measurement ◽  
Oxygen Extraction Fraction ◽  
Energy Output ◽  
Photoacoustic Microscopy ◽  
Artery Ligation ◽  
Mitochondrial Oxygen Consumption ◽  
Carotid Artery Ligation ◽  
Hypoxia Ischemia ◽  
Uncoupling Of Oxidative Phosphorylation

Hypothermia is the best available therapy for neonatal hypoxia ischemia (HI) brain injury, but its primary mechanisms remain uncertain. We hypothesize that HI induces, whereas hypothermia represses, uncoupling of oxidative phosphorylation (OXPHOS), an increase of the cerebral metabolic rate of oxygen (CMRO2) despite reduction of the mitochondrial energy output. We used a multiparametric photoacoustic microscopy (PAM) system to compare the effects of HI and post HI hypothermic treatment on CMRO2 in awake 10 day old (P10) mice. Here we show that hypoxia (10% O2) elevated CMRO2, but the addition of unilateral carotid artery ligation suppressed CMRO2 and sparked a rapid overshoot of post HI CMRO2 in the ipsilateral cerebral cortex for at least 2 hours. The post HI surge of CMRO2 was linked to an increase of mitochondrial oxygen consumption and superoxide outburst, despite reduction of the mitochondrial membrane potential. Notably, post HI hypothermia blocked the surge of superoxide and CMRO2, primarily by limiting oxygen extraction fraction (OEF), leading to better preservation of adenosine triphosphate (ATP), creatine (Cr) and N acetylaspartate (NAA) after HI. Mice that did not receive hypothermia exhibited ~80% reduction of CMRO2 at 24 h post HI, coupled to a large cortical infarction. These results suggest that mitigation of post HI uncoupling of OXPHOS is an early and/or pivotal effect of hypothermia. Further, optical measurement of CMRO2 may be a sensitive and noninvasive method to monitor brain damage in hypoxic ischemic encephalopathy (HIE).

scholarly journals Global Gene Expression in the Immature Brain after Hypoxia-Ischemia

2004 ◽  
Vol 24 (12) ◽  
pp. 1317-1332 ◽  
Author(s):  
Hedtjärn Maj ◽  
Carina Mallard ◽  
Saskia Eklind ◽  
Katarina Gustafson-Brywe ◽  
Henrik Hagberg
Keyword(s):  
Global Gene Expression ◽  
Differentially Expressed ◽  
Global Changes ◽  
Artery Ligation ◽  
Oligonucleotide Arrays ◽  
Genomic Changes ◽  
Neonatal Hypoxia ◽  
Carotid Artery Ligation ◽  
New Genes ◽  
Hypoxia Ischemia

Ischemia induces a complex response of differentially expressed genes in the brain. In order to understand the specific mechanisms of injury in the developing brain, it is important to obtain information on global changes in the transcriptome after neonatal hypoxia-ischemia. In this study, oligonucleotide arrays were used to investigate genomic changes at 2, 8, 24, and 72 hours after neonatal hypoxia-ischemia, which was induced in 9-day-old mice by left carotid artery ligation followed by hypoxia (10% O2). In total, 343 genes were differentially expressed in cortex, hippocampus, thalamus, and striatum 2 to 72 hours after hypoxia-ischemia, when comparing ipsilateral with contralateral hemispheres and with controls, using the significance analysis for microarrays. A total of 283 genes were upregulated and 60 were downregulated, and 94% of the genes had not previously been shown after neonatal hypoxia-ischemia. Genes related to transcription factors and metabolism had mostly upregulated transcripts, whereas most downregulated genes belonged to the categories of ion and vesicular transport and signal transduction. Genes involved in transcription, stress, and apoptosis were induced early after the insult, and many new genes that may play important roles in the pathophysiology of neonatal hypoxiaischemia were identified.

scholarly journals Alteration in Downstream Hypoxia Gene Signaling in Neonatal Glutathione Peroxidase Overexpressing Mouse Brain after Hypoxia-Ischemia

2015 ◽  
Vol 37 (4-5) ◽  
pp. 398-406 ◽  
Author(s):  
R. Ann Sheldon ◽  
Raha Sadjadi ◽  
Matthew Lam ◽  
Russell Fitzgerald ◽  
Donna M. Ferriero
Keyword(s):  
Cell Death ◽  
Brain Injury ◽  
Glutathione Peroxidase ◽  
Apoptotic Cell ◽  
Hypoxia Inducible Factor ◽  
Artery Ligation ◽  
Epo Receptor ◽  
Carotid Artery Ligation ◽  
Mouse Cortex ◽  
Hypoxia Ischemia

We have previously shown that glutathione peroxidase (GPx) overexpressing mice (hGPx-tg) have reduced brain injury after neonatal hypoxia-ischemia (HI) as a consequence of reduced hydrogen peroxide accumulation. However, this protection is reversed with hypoxia preconditioning, raising the question of the roles of the genes regulated by hypoxia-inducible factor-1α (HIF-1α) and their transcription products, such as erythropoietin (EPO), in both the initial protection and subsequent reversal of protection. hGPx-tg and their wild-type (WT) littermates underwent the Vannucci procedure of HI brain injury at postnatal day 9 - left carotid artery ligation followed by exposure to 10% oxygen for 50 min. Brain cortices and hippocampi were subsequently collected 0.5, 4 and 24 h later for the determination of protein expression by Western blot for GPx, HIF-1α, HIF-2α, EPO, EPO receptor, ERK1/2, phospho-ERK1/2, spectrin 145/150 (as a marker of calpain-specific necrotic cell death), and spectrin 120 (as a marker of apoptotic cell death mediated via caspase-3). As expected, the GPx overexpressing mouse cortex had approximately 3 times the GPx expression as WT naïve. Also, GPx expression remained higher in the GPx overexpressing brain than WT at all time points after HI (0.5, 4, 24 h). HIF-1α was not significantly changed in hGPx-tg as a consequence of HI but decreased in the WT cortex 4 h after HI. HIF-2α decreased in the WT hippocampus after HI. EPO was higher in the GPx overexpressing cortex and hippocampus 30 min after HI compared to WT, but the EPO receptor was unchanged by HI. ERK1/2 phosphorylation increased in the hippocampus at 4 h after HI and in the cortex at 24 h after HI in both WT and hGPx-tg. Spectrin 145/150 was increased in the WT cortex at 4 and 24 h after HI, and spectrin 120 increased 24 h after HI, perhaps reflecting greater injury in the WT brain, especially at 24 h when brain injury is more evident. The effect of GPx overexpression does not appear to upregulate the HIF pathway, yet EPO was upregulated, perhaps via ERK. This might explain, in part, why cell death takes a necrotic or apoptotic path. This may also be an explanation for why the GPx overexpressing brain cannot be preconditioned. This information may prove valuable in the development of therapies for neonatal HI brain injury.

scholarly journals Hypoxia—Ischemia Induces a Rapid Elevation of Ubiquitin Conjugate Levels and Ubiquitin Immunoreactivity in the Immature Rat Brain

1998 ◽  
Vol 18 (4) ◽  
pp. 376-385 ◽  
Author(s):  
Susan J. Vannucci ◽  
Rosemary Mummery ◽  
Richard B. Hawkes ◽  
Christopher C. Rider ◽  
Philip W. Beesley
Keyword(s):  
Rat Brain ◽  
Control Level ◽  
Artery Ligation ◽  
Western Blots ◽  
Immature Rat ◽  
Carotid Artery Ligation ◽  
Hypoxia Ischemia ◽  
The Right ◽  
Ubiquitin Conjugate ◽  
Postnatal Rats

Postnatal rats at 7 and 21 days of age were subjected to unilateral hypoxia—ischemia (H/I) by right carotid artery ligation followed by 1.5 to 2 hours of hypoxia (8% oxygen). Brains were frozen at specific intervals of recovery from 0 to 24 hours. Western blots of samples of right and left forebrain were immunodeveloped with a monoclonal antibody specific for ubiquitin, RHUb 1. An elevation of ubiquitin conjugate levels in the right compared with the left forebrain of 7-day-old animals was detectable immediately following H/I and increased by close to 60% of control level within 1 hour of recovery. The conjugate immunoreactivity remained at this level for 6 hours but had declined to control levels by 24 hours of recovery. No such increase was observed in response to hypoxia alone. Similar changes were observed in samples from the 21-day-old rat brain. However, the elevation of ubiquitin conjugate levels was of slower onset and persisted longer than observed for the 7-day-old animals. Immunocytochemical studies of brain fixed by immersion in formaldehyde/acetone/methanol showed that ubiquitin-like immunoreactivity was increased in the right, but not left, cerebral cortex and hippocampus of animals subjected to H/I. The data suggest that elevated ubiquitination may represent a neuroprotective response to H/I.

scholarly journals Knockdown of IL-6 Plays a Crucial Role in Protection of Hypoxia-Ischemia in Neonatal Rats via Inhibiting Casp3 and BAX Signaling Pathway

2021 ◽  
Author(s):  
Ting-Hua Wang ◽  
Xue Bai ◽  
Liu-Lin Xiong ◽  
Ting-Ting Li ◽  
Chang-Le Fang ◽  
...  
Keyword(s):  
Cortical Neurons ◽  
Neonatal Rat ◽  
Regulation Mechanism ◽  
Sprague Dawley ◽  
Artery Ligation ◽  
Carotid Artery Ligation ◽  
Hypoxia Ischemia ◽  
Neurologic Function ◽  
Underlying Mechanisms ◽  
The Right

Abstract Background: The effect of interleukin-6 (IL-6) knockdown on hypoxia-ischemia (HI) of neonatal rat models was investigated to explore the underlying molecular regulation mechanism. Methods: To establish the HI model, we treated 7days postnatal Sprague-Dawley (SD) rats with the right carotid artery ligation and had them exposed to the environment of 8% oxygen and 92% nitrogen for 2 h, respectively. Then, the neurologic function and morphology changes were assessed. Subsequently, IL-6 siRNA lentivirus was injected into cerebral cortex motor area 2 days before HI; meanwhile, the interference efficiency was detected by quantitative real-time polymerase chain reaction (QRT-PCR) and Western blot. Immunofluorescence staining of Glial fibrillary acidic protein (GFAP), Hexaribonucleotide Binding Protein-3 (NeuN) and IL-6 were used to identify the location and interference effect of IL-6. In order to further research the underlying mechanisms, the expressions of downstream molecular including Bcl-2-associated X protein (BAX) and Casp3 were examined following IL-6 up-regulation by QRT-PCR.Results: It was found that both the growth of cortical neurons and the length of axon were promoted after IL-6 interference, and the cell apoptosis was decreased. In addition, the expression of BAX and Casp3 were closely associated with IL-6. Conclusions: The present findings confirmed that the decreased IL-6 improves the deficiencies in neurologic function and morphology induced by HI, and the potential mechanism may be closely related with the regulation of Casp3 and BAX.

Carbon Dioxide Protects the Perinatal Brain From Hypoxic-Ischemic Damage: An Experimental Study in the Immature Rat

PEDIATRICS ◽  
1995 ◽  
Vol 95 (6) ◽  
pp. 868-874 ◽  
Author(s):  
Robert C. Vannucci ◽  
Javad Towfighi ◽  
Daniel F. Heitjan ◽  
Robert M. Brucklacher
Keyword(s):  
Carbon Dioxide ◽  
Carotid Artery ◽  
Brain Damage ◽  
Artery Ligation ◽  
Immature Rat ◽  
Rat Pups ◽  
Carotid Artery Ligation ◽  
Respiratory Management ◽  
Systemic Hypoxia ◽  
Hypoxia Ischemia

Background and Objective. Clinical investigations suggest that premature infants who require mechanical ventilation from respiratory distress syndrome are at increased risk for periventricular leukomalacia if hypocapnia occurs during respiratory management. The question remains as to the contribution of hypocapnia to hypoxic-ischemic brain damage and whether or not hypercapnia is neuroprotective. Methods. Seven-day postnatal rats underwent unilateral common carotid artery ligation followed thereafter by exposure to systemic hypoxia with 8% oxygen (O2) combined with either 0, 3, 6, or 9% carbon dioxide (CO2) for 2.5 hours at 37°C. Survivors underwent neuropathologic examination at 30 days of postnatal age, and their brains were categorized as follows: 0 = normal; 1 = mild atrophy; 2 = moderate atrophy; 3 = atrophy with cystic cavitation <3 mm; 4 = cystic cavitation >3 mm of the cerebral hemisphere ipsilateral to the carotid artery ligation. The width of the ipsilateral hemisphere also was determined on a posterior coronal section and compared with that of the contralateral hemisphere to ascertain the severity of cerebral atrophy/cavitation. Data were analyzed by linear models. Results. CO2 tensions averaged 26, 42, 54, and 71 mm Hg in the 0, 3, 6, and 9% CO2 exposed animals, respectively, during systemic hypoxia. Blood O2 tensions during hypoxia were not different among the four groups and averaged 34.7 mm Hg. Neuropathologic results showed that 30/38 (79%) rats exposed to 3% CO2 showed either no or mild brain damage compared with 13/33 (39%) controls (0% CO2). Cystic cavitation occurred in only four CO2 exposed rat pups compared with 14 controls (P = .001). At 6% CO2 exposure, all of 20 rat pups showed either no damage or mild atrophy compared with controls (P < .001); and at 9% CO2 exposure, 19/23 (83%) rat pups showed no or mild damage compared with controls (P < .001). The data also showed that the greatest reduction in brain damage occurred in immature rats exposed to 6% CO2 with slightly less protection at 9% CO2 (P = .012), the latter comparable with the severity of brain damage sustained by animals inhaling 3% CO2. Analyses of coronal width ratios at each CO2 exposure provided results comparable with those of the gross neuropathology scores. Conclusions. The results indicate that in an immature rat model normocapnic cerebral hypoxia-ischemia is associated with less severe brain damage than in hypocapnic hypoxia-ischemia and that mild hypercapnia is more protective than normocapnia. The findings in an experimental model merit further animal investigations as well as a clinical reappraisal of the ventilatory management of sick newborn human infants.

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 Inflammatory Gene Profiling in the Developing Mouse Brain after Hypoxia-Ischemia

2004 ◽  
Vol 24 (12) ◽  
pp. 1333-1351 ◽  
Author(s):  
Hedtjärn Maj ◽  
Carina Mallard ◽  
Henrik Hagberg
Keyword(s):  
Nuclear Factor Κb ◽  
Adult Brain ◽  
Gene Profiling ◽  
Artery Ligation ◽  
Oligonucleotide Arrays ◽  
Inflammatory Genes ◽  
Inflammatory Gene ◽  
Carotid Artery Ligation ◽  
Hypoxia Ischemia ◽  
Developing Mouse Brain

Brain ischemia triggers an inflammatory reaction that progresses for days to weeks and seems to have a role in secondary progression of injury. Inflammation induces a complex pattern of signaling molecules with partly contradictory actions, and the responses may be different in the immature and adult brain. The authors characterized the global inflammatory gene expression in the developing brain as a first step toward understanding the protective and deleterious effects of inflammation after hypoxia-ischemia. Oligonucleotide arrays were used to investigate inflammatory genes in cortex, hippocampus, thalamus, and striatum at 2, 8, 24, and 72 hours after hypoxia-ischemia, which was induced in 9-day-old mice by left carotid artery ligation followed by hypoxia. After hypoxia-ischemia, 148 inflammatory genes were differentially expressed. More than 97% of the genes were upregulated and 93% had not previously been reported after hypoxia-ischemia in the immature brain. The results indicate that microglia/macrophages, T-and B-cells, NK-cells, mast cells, dendritic cells, and polymorphonuclear leukocytes may participate in the response to hypoxia-ischemia. In addition, novel cytokines/chemokines, complement-related, interferon-regulated, components of the TIR/nuclear factor-κB pathway, and a number of immunomodulatory genes were induced. Several of these genes may be of pathophysiologic significance after neonatal hypoxia-ischemia.

scholarly journals Columnar Alterations of NADH Fluorescence during Hypoxia-Ischemia in Immature Rat Brain

1982 ◽  
Vol 2 (2) ◽  
pp. 221-228 ◽  
Author(s):  
Frank A. Welsh ◽  
Robert C. Vannucci ◽  
James B. Brierley
Keyword(s):  
Recovery Period ◽  
High Energy ◽  
High Energy Phosphates ◽  
Contralateral Hemisphere ◽  
Artery Ligation ◽  
Ipsilateral Hemisphere ◽  
Carotid Artery Ligation ◽  
Systemic Hypoxia ◽  
Nadh Fluorescence ◽  
Hypoxia Ischemia

Cerebral hypoxia-ischemia was produced in 7-day postnatal rats by unilateral carotid artery ligation combined with systemic hypoxia (8% O2). Levels of high energy phosphates, which were only slightly altered in the contralateral hemisphere, were nearly depleted in the ipsilateral hemisphere during the 3-h hypoxic insult. With hypoxia of between 1 and 3 hours' duration, columnar alterations of cortical NADH fluorescence occurred in the same location and regional pattern as did histologic damage demonstrated previously (Rice et al., 1981). In regions exhibiting columns of NADH fluorescence, there was no evidence of a columnar reduction of high energy phosphates as levels of ATP and phosphocreatine were nearly zero. Recovery from 3 h of hypoxia was accompanied by partial and regionally heterogeneous restoration of ATP within the ipsilateral hemisphere. Columnar variations of NADH fluorescence were not detected in the recovery period; rather, regions with impaired restitution of high energy phosphates exhibited NADH fluorescence that was diminished diffusely compared to the contralateral hemisphere. The correlation between depressed NADH fluorescence and depleted ATP, present as cortical columns during hypoxia and as larger regions during recovery, suggests that decreased formation of NADH may be limiting the resynthesis of high energy phosphates.

scholarly journals Temporal Changes of Regional Glucose Use, Blood Flow, and Microtubule-Associated Protein 2 Immunostaining after Hypoxia—Ischemia in the Immature Rat Brain

1998 ◽  
Vol 18 (2) ◽  
pp. 222-228 ◽  
Author(s):  
Eric Gilland ◽  
Elsa Bona ◽  
Henrik Hagber
Keyword(s):  
Secondary Phase ◽  
Contralateral Side ◽  
Energy Utilization ◽  
Artery Ligation ◽  
Early Reperfusion ◽  
Immature Rat ◽  
Ipsilateral Hemisphere ◽  
Carotid Artery Ligation ◽  
Hypoxia Ischemia ◽  
Old Rats

In a situation with normal CBF and without increased energy utilization, increased glucose utilization (CMRglc) can be a sign of impaired mitochondrial metabolism, which may be an early step in the injury cascade during reperfusion after hypoxia–ischemia (HI). Seven-day-old rats underwent unilateral carotid artery ligation and 70 minutes of HI. At 3, 6, 12, 24, and 48 or 72 hours after the insult, the CMRglc was measured by the 2-deoxyglucose method, and CBF by the iodoantipyrine method. These were compared with hematoxylin-eosin staining and microtubule-associated protein 2 (MAP 2) immunostaining in adjacent sections. In the ipsilateral hemisphere, there appeared regions with increased CMRglc compared with the contralateral hemisphere 3 to 12 hours after HI that also showed partial loss of MAP 2 immunostaining and early ischemic changes. These areas receded, leaving central glucose hypoutilizing areas with complete loss of MAP 2 immunostaining and histologic infarction, surrounded by only a rim of tissue with increased CMRglc. At 24 and 72 hours after the insult, no regions with increased CMRglc remained. Despite loss of MAP 2 immunostaining and histologic signs of infarction at 24 hours, cortical CBF was not reduced until 48 hours after HI, whereas the CBF in the caudate-putamen already was decreased compared with the contralateral side at 3 hours after HI. In conclusion, early reperfusion is characterized by glucose hyperutilizing areas in the cerebral cortex, followed by a secondary phase with low CMRglc and infarction.

scholarly journals The Effect of Hyperglycemia on Cerebral Metabolism during Hypoxia-Ischemia in the Immature Rat

1996 ◽  
Vol 16 (5) ◽  
pp. 1026-1033 ◽  
Author(s):  
Robert C. Vannucci ◽  
Robert M. Brucklacher ◽  
Susan J. Vannucci
Keyword(s):  
Cerebral Metabolism ◽  
Glycolytic Flux ◽  
Artery Ligation ◽  
Immature Rat ◽  
Ischemic Brain ◽  
Glucose Levels ◽  
Rat Pups ◽  
Carotid Artery Ligation ◽  
Hypoxia Ischemia ◽  
Blood Glucose Concentrations

Unlike adults, hyperglycemia with circulating glucose concentrations of 25–35 m M/L protects the immature brain from hypoxic–ischemic damage. To ascertain the effect of hyperglycemia on cerebral oxidative metabolism during the course of hypoxia–ischemia, 7-day postnatal rats underwent unilateral common carotid artery ligation followed by exposure to 8% O2 for 2 h at 37°C. Experimental animals received 0.2 cc s.c. 50% glucose at the onset of hypoxia–ischemia, and 0.15 cc 25% glucose 1 h later to maintain blood glucose concentrations at 20–25 m ML for 2 h. Control rat pups received equivalent concentrations or volumes of either mannitol or 1 N saline at the same intervals. The cerebral metabolic rate for glucose (CMRglc.) increased from 7.1 (control) to 20.2 μmol 100 g−1 min−1 in hyperglycemic rats during the first hour of hypoxia–ischemia, 79 and 35% greater than the rates for saline- and mannitol-injected animals at the same interval, respectively ( p < 0.01). Brain intracellular glucose concentrations were 5.2 and 3.0 m M/kg in the hyperglycemic rat pups at 1 and 2 h of hypoxia–ischemia, respectively; glucose levels were near negligible in mannitol- and saline-treated animals at the same intervals. Brain intracellular lactate concentrations averaged 13.4 and 23.3 m M/kg in hyperglycemic animals at 1 and 2 h of hypoxia–ischemia, respectively, more than twice the concentrations estimated for the saline- and mannitol-treated littermates. Phosphocreatine (PCr) and ATP decreased in all three experimental groups, but were preserved to the greatest extent in hyperglycemic animals. Results indicate that anaerobic glycolytic flux is increased to a greater extent in hyperglycemic immature rats than in normoglycemic littermates subjected to cerebral hypoxia–ischemia, and that the enhanced glycolysis leads to greater intracellular lactate accumulation. Despite cerebral lactosis, energy reserves were better preserved in hyperglycemic animals than in saline-treated controls, thus accounting for the greater resistance of hyperglycemic animals to hypoxic–ischemic brain damage.

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