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Sample records for moderate brain hypoxia

  1. Brain dysfunction in mild to moderate hypoxia.

    Science.gov (United States)

    Gibson, G E; Pulsinelli, W; Blass, J P; Duffy, T E

    1981-06-01

    Hypoxia is commonly invoked to explain alterations in mental function, particularly in patients with cardiac pulmonary failure. The effects of acute graded hypoxia or higher integrative functions are well documented experimentally in man. Hypoxia in experimental animal models demonstrates that the pathophysiology is complex. In mild to moderate hypoxia, in contrast to severe hypoxia and to ischemia, the supply of energy for the brain is not impaired; cerebral levels of adenosine triphosphate (ATP) and adenylate energy charge are normal. In contrast, the turnover of several neurotransmitters is altered by mild hypoxia. For example, acetylcholine synthesis is reduced proportionally to the reduction in carbohydrate oxidation. This relationship holds in vitro and with several in vivo models of hypoxia. Pharmacologic and physiologic studies in man and experimental animals are consistent with acetylcholine having an important role in mediating the cerebral effects of mild hypoxia. These observations raise the possibility that treatments directed to cholinergic or other central neurotransmitter systems may benefit patients with cerebral syndromes secondary to chronic hypoxia.

  2. [Hemo- and neurodynamics of the human brain during exposure to moderate hypoxic hypoxia].

    Science.gov (United States)

    Alekseev, D A; Zubarev, A F; Krupina, T N; Iarullin, Kh Kh; Kuznets, E I

    1984-01-01

    Synchronous electro- and rheoencephalography were used to study tolerance to moderate hypoxic hypoxia for 30 min at an altitude of 5000 m without additional oxygen supply. As test subject, men with autonomic-vascular dystonia (29-39 years old), 15 men over 40 (41-56 years old), and 16 essentially healthy controls (23-36 years old) were used. The aged volunteers (41-56 years old) did not differ from the controls with respect to their tolerance to hypoxic hypoxia. The men with early symptoms of hypertonic-type dystonia also showed high tolerance to hypoxic hypoxia. The subjects with hypotonic-type dystonia displayed lower tolerance.

  3. Selective vulnerability in brain hypoxia

    DEFF Research Database (Denmark)

    Cervos-Navarro, J.; Diemer, Nils Henrik

    1991-01-01

    Neuropathology, selective vulnerability, brain hypoxia, vascular factors, excitotoxicity, ion homeostasis......Neuropathology, selective vulnerability, brain hypoxia, vascular factors, excitotoxicity, ion homeostasis...

  4. Hypoxia and brain development

    NARCIS (Netherlands)

    Nyakas, Csaba; Buwalda, Bauke; Luiten, P.

    1996-01-01

    Hypoxia threatens brain function during the entire life-span starting from early fetal age up to senescence. This review compares the short-term, long-term and life-spanning effects of fetal chronic hypoxia and neonatal anoxia on several behavioural paradigms including novelty-induced spontaneous an

  5. Moderate hypoxia followed by reoxygenation results in blood-brain barrier breakdown via oxidative stress-dependent tight-junction protein disruption.

    Directory of Open Access Journals (Sweden)

    Christoph M Zehendner

    Full Text Available Re-canalization of cerebral vessels in ischemic stroke is pivotal to rescue dysfunctional brain areas that are exposed to moderate hypoxia within the penumbra from irreversible cell death. Goal of the present study was to evaluate the effect of moderate hypoxia followed by reoxygenation (MHR on the evolution of reactive oxygen species (ROS and blood-brain barrier (BBB integrity in brain endothelial cells (BEC. BBB integrity was assessed in BEC in vitro and in microvessels of the guinea pig whole brain in situ preparation. Probes were exposed to MHR (2 hours 67-70 mmHg O2, 3 hours reoxygenation, BEC or towards occlusion of the arteria cerebri media (MCAO with or without subsequent reperfusion in the whole brain preparation. In vitro BBB integrity was evaluated using trans-endothelial electrical resistance (TEER and transwell permeability assays. ROS in BEC were evaluated using 2',7'-dichlorodihydrofluorescein diacetate (DCF, MitoSox and immunostaining for nitrotyrosine. Tight-junction protein (TJ integrity in BEC, stainings for nitrotyrosine and FITC-albumin extravasation in the guinea pig brain preparation were assessed by confocal microscopy. Diphenyleneiodonium (DPI was used to investigate NADPH oxidase dependent ROS evolution and its effect on BBB parameters in BEC. MHR impaired TJ proteins zonula occludens 1 (ZO-1 and claudin 5 (Cl5, decreased TEER, and significantly increased cytosolic ROS in BEC. These events were blocked by the NADPH oxidase inhibitor DPI. MCAO with or without subsequent reoxygenation resulted in extravasation of FITC-albumin and ROS generation in the penumbra region of the guinea pig brain preparation and confirmed BBB damage. BEC integrity may be impaired through ROS in MHR on the level of TJ and the BBB is also functionally impaired in moderate hypoxic conditions followed by reperfusion in a complex guinea pig brain preparation. These findings suggest that the BBB is susceptible towards MHR and that ROS play a key role

  6. Moderate hypoxia followed by reoxygenation results in blood-brain barrier breakdown via oxidative stress-dependent tight-junction protein disruption.

    Science.gov (United States)

    Zehendner, Christoph M; Librizzi, Laura; Hedrich, Jana; Bauer, Nina M; Angamo, Eskedar A; de Curtis, Marco; Luhmann, Heiko J

    2013-01-01

    Re-canalization of cerebral vessels in ischemic stroke is pivotal to rescue dysfunctional brain areas that are exposed to moderate hypoxia within the penumbra from irreversible cell death. Goal of the present study was to evaluate the effect of moderate hypoxia followed by reoxygenation (MHR) on the evolution of reactive oxygen species (ROS) and blood-brain barrier (BBB) integrity in brain endothelial cells (BEC). BBB integrity was assessed in BEC in vitro and in microvessels of the guinea pig whole brain in situ preparation. Probes were exposed to MHR (2 hours 67-70 mmHg O2, 3 hours reoxygenation, BEC) or towards occlusion of the arteria cerebri media (MCAO) with or without subsequent reperfusion in the whole brain preparation. In vitro BBB integrity was evaluated using trans-endothelial electrical resistance (TEER) and transwell permeability assays. ROS in BEC were evaluated using 2',7'-dichlorodihydrofluorescein diacetate (DCF), MitoSox and immunostaining for nitrotyrosine. Tight-junction protein (TJ) integrity in BEC, stainings for nitrotyrosine and FITC-albumin extravasation in the guinea pig brain preparation were assessed by confocal microscopy. Diphenyleneiodonium (DPI) was used to investigate NADPH oxidase dependent ROS evolution and its effect on BBB parameters in BEC. MHR impaired TJ proteins zonula occludens 1 (ZO-1) and claudin 5 (Cl5), decreased TEER, and significantly increased cytosolic ROS in BEC. These events were blocked by the NADPH oxidase inhibitor DPI. MCAO with or without subsequent reoxygenation resulted in extravasation of FITC-albumin and ROS generation in the penumbra region of the guinea pig brain preparation and confirmed BBB damage. BEC integrity may be impaired through ROS in MHR on the level of TJ and the BBB is also functionally impaired in moderate hypoxic conditions followed by reperfusion in a complex guinea pig brain preparation. These findings suggest that the BBB is susceptible towards MHR and that ROS play a key role in this

  7. Brain hypoxia imaging

    Energy Technology Data Exchange (ETDEWEB)

    Song, Ho Chun [Chonnam National University Medical School, Gwangju (Korea, Republic of)

    2007-04-15

    The measurement of pathologically low levels of tissue pO{sub 2} is an important diagnostic goal for determining the prognosis of many clinically important diseases including cardiovascular insufficiency, stroke and cancer. The target tissues nowadays have mostly been tumors or the myocardium, with less attention centered on the brain. Radiolabelled nitroimidazole or derivatives may be useful in identifying the hypoxic cells in cerebrovascular disease or traumatic brain injury, and hypoxic-ischemic encephalopathy. In acute stroke, the target of therapy is the severely hypoxic but salvageable tissue. {sup 18}F-MISO PET and {sup 99m}Tc-EC-metronidazole SPECT in patients with acute ischemic stroke identified hypoxic tissues and ischemic penumbra, and predicted its outcome. A study using {sup 123}I-IAZA in patient with closed head injury detected the hypoxic tissues after head injury. Up till now these radiopharmaceuticals have drawbacks due to its relatively low concentration with hypoxic tissues associated with/without low blood-brain barrier permeability and the necessity to wait a long time to achieve acceptable target to background ratios for imaging in acute ischemic stroke. It is needed to develop new hypoxic marker exhibiting more rapid localization in the hypoxic region in the brain. And then, the hypoxic brain imaging with imidazoles or non-imidazoles may be very useful in detecting the hypoxic tissues, determining therapeutic strategies and developing therapeutic drugs in several neurological disease, especially, in acute ischemic stroke.

  8. Effect of Fasting on Tolerance to Moderate Hypoxia,

    Science.gov (United States)

    Blood pressure response to moderate hypoxia was compared in a fasting and a control (non- fasting ) state in 10 seated subjects. End-tidal gas tensions...exposure to a simulated altitude of 17,000 ft. When exposed to the same stress after fasting for 18 hours, the MAP fell to 87% (P less than 0.01) of...its resting value. The mean end-tidal Po2 was significantly lower in the fasting state and the end-tidal Pco2 was unchanged. It is concluded that

  9. Effect of acute exposure to moderate altitude on muscle power: hypobaric hypoxia vs. normobaric hypoxia.

    Science.gov (United States)

    Feriche, Belén; García-Ramos, Amador; Calderón-Soto, Carmen; Drobnic, Franchek; Bonitch-Góngora, Juan G; Galilea, Pedro A; Riera, Joan; Padial, Paulino

    2014-01-01

    When ascending to a higher altitude, changes in air density and oxygen levels affect the way in which explosive actions are executed. This study was designed to compare the effects of acute exposure to real or simulated moderate hypoxia on the dynamics of the force-velocity relationship observed in bench press exercise. Twenty-eight combat sports athletes were assigned to two groups and assessed on two separate occasions: G1 (n = 17) in conditions of normoxia (N1) and hypobaric hypoxia (HH) and G2 (n = 11) in conditions of normoxia (N2) and normobaric hypoxia (NH). Individual and complete force-velocity relationships in bench press were determined on each assessment day. For each exercise repetition, we obtained the mean and peak velocity and power shown by the athletes. Maximum power (Pmax) was recorded as the highest P(mean) obtained across the complete force-velocity curve. Our findings indicate a significantly higher absolute load linked to P(max) (∼ 3%) and maximal strength (1 RM) (∼ 6%) in G1 attributable to the climb to altitude (Ppress.

  10. Influence of moderate hypoxia on vaccine efficacy against Vibrio anguillarum in Oreochromis niloticus (Nile tilapia).

    Science.gov (United States)

    Gallage, Sanchala; Katagiri, Takayuki; Endo, Makoto; Futami, Kunihiko; Endo, Masato; Maita, Masashi

    2016-04-01

    Hypoxia is known as a potential immunomodulator in fish. This study therefore assesses the impact of chronic, moderate hypoxia on vaccine efficacy in Oreochromis niloticus. Serum antibody titer was used as a surrogate marker to detect vaccine efficacy. The fish were acclimatized to either moderate hypoxia (55 ± 5% DO) or normoxia (85 ± 5%DO) and immunized with formalin inactivated Vibrio anguillarum. Significantly, a higher antibody titer was found in normoxic fish than in moderate hypoxia. The normoxic group titer peaked at 14th dpv (days post vaccination) while the moderate hypoxic group peaked at 21st or 28th dpv. The absolute blood lymphocyte counts and serum bactericidal activities against V. anguillarum were significantly higher in normoxic fish. Serum killing of V. anguillarum appeared to be mainly via antibody-dependent classical complement pathway. Furthermore, the first week following vaccination appears critical for antibody production. This view was further supported by results obtained from gene expression assay, where the transcription level of all the detected immune related genes (IgM, IL-1 β, TCR-β, MHC-II β), except B cell activating factor, were significantly suppressed following exposure to moderate hypoxia. The overall results highlight that even though moderate hypoxia is not easily detectable in Oreochromis niloticus, it negatively affects antibody production by suppressing and delaying antibody response, ultimately affecting vaccine efficacy.

  11. Mild systemic inflammation and moderate hypoxia transiently alter neuronal excitability in mouse somatosensory cortex.

    Science.gov (United States)

    Mordel, Jérôme; Sheikh, Aminah; Tsohataridis, Simeon; Kanold, Patrick O; Zehendner, Christoph M; Luhmann, Heiko J

    2016-04-01

    During the perinatal period, the brain is highly vulnerable to hypoxia and inflammation, which often cause white matter injury and long-term neuronal dysfunction such as motor and cognitive deficits or epileptic seizures. We studied the effects of moderate hypoxia (HYPO), mild systemic inflammation (INFL), or the combination of both (HYPO+INFL) in mouse somatosensory cortex induced during the first postnatal week on network activity and compared it to activity in SHAM control animals. By performing in vitro electrophysiological recordings with multi-electrode arrays from slices prepared directly after injury (P8-10), one week after injury (P13-16), or in young adults (P28-30), we investigated how the neocortical network developed following these insults. No significant difference was observed between the four groups in an extracellular solution close to physiological conditions. In extracellular 8mM potassium solution, slices from the HYPO, INFL, and HYPO+INFL group were more excitable than SHAM at P8-10 and P13-16. In these two age groups, the number and frequency of spontaneous epileptiform events were significantly increased compared to SHAM. The frequency of epileptiform events was significantly reduced by the NMDA antagonist D-APV in HYPO, INFL, and HYPO+INFL, but not in SHAM, indicating a contribution of NMDA receptors to this pathophysiological activity. In addition, the AMPA/kainate receptor antagonist CNQX suppressed the remaining epileptiform activity. Electrical stimulation evoked prominent epileptiform activity in slices from HYPO, INFL and HYPO+INFL animals. Stimulation threshold to elicit epileptiform events was lower in these groups than in SHAM. Evoked events spread over larger areas and lasted longer in treated animals than in SHAM. In addition, the evoked epileptiform activity was reduced in the older (P28-30) group indicating that cortical dysfunction induced by hypoxia and inflammation was transient and compensated during early development.

  12. Regulation of human skeletal muscle perfusion and its heterogeneity during exercise in moderate hypoxia

    DEFF Research Database (Denmark)

    Heinonen, Ilkka H; Kemppainen, Jukka; Kaskinoro, Kimmo

    2010-01-01

    Although many effects of both acute and chronic hypoxia on the circulation are well characterized, the distribution and regulation of blood flow (BF) heterogeneity in skeletal muscle during systemic hypoxia is not well understood in humans. We measured muscle BF within the thigh muscles of nine...... healthy young men using positron emission tomography during one-leg dynamic knee extension exercise in normoxia and moderate physiological systemic hypoxia (14% O(2) corresponding to approximately 3,400 m of altitude) without and with local adenosine receptor inhibition with femoral artery infusion...

  13. Locomotory fatigue during moderate and severe hypoxia and hypercapnia in the Atlantic blue crab, Callinectes sapidus.

    Science.gov (United States)

    Stover, Kristin K; Burnett, Karen G; McElroy, Eric J; Burnett, Louis E

    2013-04-01

    The Atlantic blue crab, Callinectes sapidus (Rathbun), is a highly mobile crustacean that must locomote to find food, evade predators, find mates, and avoid adverse conditions such as hypoxia. In this study we tested the effects of two levels of hypoxia (10.4 kPa, 50% air saturation = moderate hypoxia; 4 kPa, 20% air saturation = severe hypoxia) and hypercapnic hypoxia (50% air saturation O(2) with Pco(2) = 2 kPa) on fatigue during sustained continuous exercise. Fatigue was induced by an exercise trial that entailed continuous sideways hexapedal walking on an underwater treadmill. Fatigue was quantified using two methods: (1) a pull force test that measures the holding strength of the legs, and (2) the number of fatigue-resisting behaviors (180° turns and stopping). Fatigue was defined as a pull force of 67% or less of the initial pre-exercise pull force and was reached after 6.12 h of walking for crabs in well-aerated normoxic seawater, 4 h in 50% air saturation, 2.07 h in 20% air saturation, and 4.58 h in 50% air saturation and hypercapnia. The number of fatigue-resisting behaviors increased with walking time in all treatments. Performance decreased in hypoxia, with fatigue being reached more quickly as the level of hypoxia intensified. Hypercapnia in moderate hypoxia did not have a deleterious influence on behavior and lengthened slightly the time it took crabs to fatigue. In addition, severe hypoxia exacerbated changes in gait kinematics as crabs became fatigued, by significantly increasing stride length and decreasing stride frequency.

  14. Ghrelin, GLP-1, and leptin responses during exposure to moderate hypoxia.

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    Morishima, Takuma; Goto, Kazushige

    2016-04-01

    Severe hypoxia has been indicated to cause acute changes in appetite-related hormones, which attenuate perceived appetite. However, the effects of moderate hypoxia on appetite-related hormonal regulation and perceived appetite have not been elucidated. Therefore, we examined the effects of moderate hypoxia on appetite-related hormonal regulation and perceived appetite. Eight healthy males (21.0 ± 0.6 years; 173 ± 2.3 cm; 70.6 ± 5.0 kg; 23.4 ± 1.1 kg/m(2)) completed two experimental trials on separate days: a rest trial in normoxia (FiO2 = 20.9%) and a rest trial in hypoxia (FiO2 = 15.0%). The experimental trials were performed over 7 h in an environmental chamber. Blood samples and scores of subjective appetite were collected over 7 h. Standard meals were provided 1 h (745 kcal) and 4 h (731 kcal) after initiating exposure to hypoxia or normoxia within the chamber. Although each meal significantly reduced plasma active ghrelin concentrations (P ghrelin concentrations over 7 h were observed between the two trials. No significant differences were observed in glucagon-like peptide 1 or leptin concentrations over 7 h between the trials. The subjective feeling of hunger and fullness acutely changed in response to meal ingestions. However, these responses were not affected by exposure to moderate hypoxia. In conclusion, 7 h of exposure to moderate hypoxia did not change appetite-related hormonal responses or perceived appetite in healthy males.

  15. NO INFLUENCE OF HYPOXIA ON COORDINATION BETWEEN RESPIRATORY AND LOCOMOTOR RHYTHMS DURING ROWING AT MODERATE INTENSITY

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    Nicolas Fabre

    2007-12-01

    Full Text Available Besides neuro-mechanical constraints, chemical or metabolic stimuli have also been proposed to interfere with the coordination between respiratory and locomotor rhythms. In the light of the conflicting data observed in the literature, this study aimed to assess whether acute hypoxia modifies the degree of coordination between respiratory and locomotor rhythms during rowing exercises in order to investigate competitive interactions between neuro-mechanical (movement and chemical (hypoxia respiratory drives. Nine male healthy subjects performed one submaximal 6-min rowing exercise on a rowing ergometer in both normoxia (altitude: 304 m and acute hypoxia (altitude: 2877 m. The exercise intensity was about 40 % and 35 % (for normoxia and hypoxia conditions, respectively of the individual maximal power output measured during an incremental rowing test to volitional exhaustion carried out in normoxia. Metabolic rate and minute ventilation were continuously collected throughout exercise. Locomotor movement and breathing rhythms were continuously recorded and synchronized cycle-by-cycle. The degree of coordination was expressed as a percentage of breaths starting during the same phase of the locomotor cycle. For a same and a constant metabolic rate, acute hypoxia did not influence significantly the degree of coordination (mean ± SEM, normoxia: 20.0 ± 6.2 %, hypoxia: 21.3 ± 11.1 %, p > 0.05 while ventilation and breathing frequency were significantly greater in hypoxia. Our results may suggest that during rowing exercise at a moderate metabolic load, neuro-mechanical locomotion-linked respiratory stimuli appear "stronger" than peripheral chemoreceptors- linked respiratory stimuli induced by hypoxia, in the context of our study

  16. No influence of hypoxia on coordination between respiratory and locomotor rhythms during rowing at moderate intensity.

    Science.gov (United States)

    Fabre, Nicolas; Perrey, Stéphane; Passelergue, Philippe; Rouillon, Jean-Denis

    2007-01-01

    Besides neuro-mechanical constraints, chemical or metabolic stimuli have also been proposed to interfere with the coordination between respiratory and locomotor rhythms. In the light of the conflicting data observed in the literature, this study aimed to assess whether acute hypoxia modifies the degree of coordination between respiratory and locomotor rhythms during rowing exercises in order to investigate competitive interactions between neuro-mechanical (movement) and chemical (hypoxia) respiratory drives. Nine male healthy subjects performed one submaximal 6-min rowing exercise on a rowing ergometer in both normoxia (altitude: 304 m) and acute hypoxia (altitude: 2877 m). The exercise intensity was about 40 % and 35 % (for normoxia and hypoxia conditions, respectively) of the individual maximal power output measured during an incremental rowing test to volitional exhaustion carried out in normoxia. Metabolic rate and minute ventilation were continuously collected throughout exercise. Locomotor movement and breathing rhythms were continuously recorded and synchronized cycle-by-cycle. The degree of coordination was expressed as a percentage of breaths starting during the same phase of the locomotor cycle. For a same and a constant metabolic rate, acute hypoxia did not influence significantly the degree of coordination (mean ± SEM, normoxia: 20.0 ± 6.2 %, hypoxia: 21.3 ± 11.1 %, p > 0.05) while ventilation and breathing frequency were significantly greater in hypoxia. Our results may suggest that during rowing exercise at a moderate metabolic load, neuro-mechanical locomotion-linked respiratory stimuli appear "stronger "than peripheral chemoreceptors- linked respiratory stimuli induced by hypoxia, in the context of our study. Key pointsChanges in breathing frequency and ventilation induced by altitude have no effect on the degree of coordination between locomotor and breathing rhythms during moderate rowing exercise.During moderate rowing exercise in hypoxia, the

  17. Impact of exercise and moderate hypoxia on glycemic regulation and substrate oxidation pattern.

    Directory of Open Access Journals (Sweden)

    Takuma Morishima

    Full Text Available OBJECTIVE: We examined metabolic and endocrine responses during rest and exercise in moderate hypoxia over a 7.5 h time courses during daytime. METHODS: Eight sedentary, overweight men (28.6 ± 0.8 kg/m2 completed four experimental trials: a rest trial in normoxia (FiO2 = 20.9%, NOR-Rest, an exercise trial in normoxia (NOR-Ex, a rest trial in hypoxia (FiO2 = 15.0%, HYP-Rest, and an exercise trial in hypoxia (HYP-Ex. Experimental trials were performed from 8:00 to 15:30 in an environmental chamber. Blood and respiratory gas samples were collected over 7.5 h. In the exercise trials, subjects performed 30 min of pedaling exercise at 60% of VO2max at 8:00, 10:30, and 13:00, and rested during the remaining period in each environment. Standard meals were provided at 8:30, 11:00, and 13:30. RESULTS: The areas under the curves for blood glucose and serum insulin concentrations over 7.5 h did not differ among the four trials. At baseline, %carbohydrate contribution was significantly higher in the hypoxic trials than in the normoxic trials (P<0.05. Although exercise promoted carbohydrate oxidation in the NOR-Ex and HYP-Ex trials, %carbohydrate contribution during each exercise and post-exercise period were significantly higher in the HYP-Ex trial than in the NOR-Ex trial (P<0.05. CONCLUSION: Three sessions of 30 min exercise (60% of VO2max in moderate hypoxia over 7.5 h did not attenuate postprandial glucose and insulin responses in young, overweight men. However, carbohydrate oxidation was significantly enhanced when the exercise was conducted in moderate hypoxia.

  18. ASYMMETRY OF THE BRAIN AT ADAPTATION TO HYPOXIA

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    V. I. Portnichenko

    2012-11-01

    Full Text Available Association between cerebral blood flow and higher nervous activity in people at different stages of adaptation to the midlands was studied. Investigation were performed before, during and after a three-week stay in the mountains at an altitude of 2100 m, as well as during short-term ups without the physical load on the height of 3900 m. In the initial period of adaptation to hypoxia desynchronization between the nerve processes in the cerebral cortex and brain blood flow was observed. There was an inversion and an increase in the asymmetry of cerebral blood flow in the direction of the dominance of the left hemisphere of the brain. After the three-week stay in the mountains asymmetry of cerebral blood flow was disappeared, blood flow to the brain was reduced, hemispheric symmetry was formed, and blood flow synchronized with the nerve processes in the cerebral cortex again was restored.

  19. Adenosine mediates decreased cerebral metabolic rate and increased cerebral blood flow during acute moderate hypoxia in the near-term fetal sheep.

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    Blood, Arlin B; Hunter, Christian J; Power, Gordon G

    2003-12-15

    Exposure of the fetal sheep to moderate to severe hypoxic stress results in both increased cortical blood flow and decreased metabolic rate. Using intravenous infusion of 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), a selective adenosine A1 receptor antagonist that is permeable to the blood brain barrier, we examine the role of adenosine A1 receptors in mediating cortical blood flow and metabolic responses to moderate hypoxia. The effects of DPCPX blockade are compared to controls as well as animals receiving intravenous 8-(p-sulfophenyl)-theophylline) (8-SPT), a non-selective adenosine receptor antagonist which has been found to be blood brain barrier impermeable. Laser Doppler flow probes, tissue PO2, and thermocouples were implanted in the cerebral cortices of near-term fetal sheep. Catheters were placed in the brachial artery and sagittal sinus vein for collection of samples for blood gas analysis. Three to seven days later responses to a 30-min period of fetal hypoxemia (arterial PO2 10-12 mmHg) were studied with administration of 8-SPT, DPCPX, or vehicle. Cerebral metabolic rate was determined by calculation of both brain heat production and oxygen consumption. In response to hypoxia, control experiments demonstrated a 42 +/- 7 % decrease in cortical heat production and a 35 +/- 10 % reduction in oxygen consumption. In contrast, DPCPX infusion during hypoxia resulted in no significant change in brain heat production or oxygen consumption, suggesting the adenosine A1 receptor is involved in lowering metabolic rate during hypoxia. The decrease in cerebral metabolic rate was not altered by 8-SPT infusion, suggesting that the response is not mediated by adenosine receptors located outside the blood brain barrier. In response to hypoxia, control experiments demonstrated a 35 +/- 7 % increase in cortical blood flow. DPCPX infusion did not change this increase in cortical blood flow, however 8-SPT infusion attenuated increases in flow, indicating that hypoxic

  20. Hypobaric Hypoxia Imbalances Mitochondrial Dynamics in Rat Brain Hippocampus

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    Khushbu Jain

    2015-01-01

    Full Text Available Brain is predominantly susceptible to oxidative stress and mitochondrial dysfunction during hypobaric hypoxia, and therefore undergoes neurodegeneration due to energy crisis. Evidences illustrate a high degree of association for mitochondrial fusion/fission imbalance and mitochondrial dysfunction. Mitochondrial fusion/fission is a recently reported dynamic mechanism which frequently occurs among cellular mitochondrial network. Hence, the study investigated the temporal alteration and involvement of abnormal mitochondrial dynamics (fusion/fission along with disturbed mitochondrial functionality during chronic exposure to hypobaric hypoxia (HH. The Sprague-Dawley rats were exposed to simulated high altitude equivalent to 25000 ft for 3, 7, 14, 21, and 28 days. Mitochondrial morphology, distribution within neurons, enzyme activity of respiratory complexes, Δψm, ADP: ATP, and expression of fission/fusion key proteins were determined. Results demonstrated HH induced alteration in mitochondrial morphology by damaged, small mitochondria observed in neurons with disturbance of mitochondrial functionality and reduced mitochondrial density in neuronal processes manifested by excessive mitochondrial fragmentation (fission and decreased mitochondrial fusion as compared to unexposed rat brain hippocampus. The study suggested that imbalance in mitochondrial dynamics is one of the noteworthy mechanisms occurring in hippocampal neurons during HH insult.

  1. Using laser confocal scanning microscope to study ischemia-hypoxia injury in rat brain slice

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    The level of lipid peroxidation and cellular necrosis in rat living brain slices during brain ischemia-hypoxia injury have been observed using a laser confocal scanning microscope (LCSM) with double labeling of fluorescent probes D-399 (2,7-dichlorofluorescin diacetate) and propidium iodide (PI).The hypoxia and/or reoxygenation injury in rat brain slices is markedly decreased by pretreatment with L-NG-nitro-arginine (L-NNA) and N-acetylcysteine (NAC),showing that the nitric oxide (NO) and other free radicals play an important role in brain ischemia-hypoxia injury.

  2. Effect of hypoxia on cerebrovascular and cognitive function during moderate intensity exercise.

    Science.gov (United States)

    Lefferts, Wesley K; Babcock, Matthew C; Tiss, Matthew J; Ives, Stephen J; White, Corey N; Brutsaert, Tom D; Heffernan, Kevin S

    2016-10-15

    Exercise in hypoxia places added demands on the brain and cerebrovasculature that can impact cognitive function. The purpose of this study was to investigate the effect of acute hypoxia on cerebrovascular hemodynamics, markers of neuro-steroidal modulation and brain-blood barrier (BBB) integrity, and cognition during exercise. Thirty healthy participants (21±4yrs., BMI 24.0±2.6kg∙m(-2); 15 men) were randomized to both a≈2.5h normoxic (FiO2 20.0%) and hypoxic (FiO2 12.5%) condition on two separate days. After 1.25h, participants underwent 10min of exercise-alone (cycling at 55% HRmax) and 15min of exercise+cognitive testing. Prefrontal cortex (PFC) tissue oxygenation and middle cerebral artery (MCA) mean blood velocity (MnV) were measured using near-infrared spectroscopy and transcranial Doppler respectively at rest, during exercise-alone, and during exercise+cognitive testing. Salivary levels of dehydroepiandosterone [DHEA], DHEA-sulfate [DHEAS]) and neuron specific enolase (NSE) were measured pre and post exercise. Cognition was assessed using standard metrics of accuracy and reaction time (RT), and advanced metrics from drift-diffusion modeling across memory recognition, N-Back and Flanker tasks. MCA MnV increased from rest to exercise (pDHEA and NSE increased and decreased post-exercise, respectively, in both normoxia and hypoxia (pmemory recognition (pmemory RT were due to increases in caution (p<0.01). Overall cognitive performance is maintained during exercise in hypoxia concomitant with slower RT in select cognitive tasks and reduced oxygenation in the PFC. These changes were accompanied by slight increases in neuro-steroidal modulation but appear independent of changes in NSE, a biomarker of BBB integrity. Maintained accuracy and select increases in RT during hypoxic exercise may be related behavioral changes in caution. Copyright © 2016 Elsevier Inc. All rights reserved.

  3. Protective effects of intermittent hypoxia on brain and memory in a mouse model of apnea of prematurity

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    Bouslama, Myriam; Adle-Biassette, Homa; Ramanantsoa, Nelina; Bourgeois, Thomas; Bollen, Bieke; Brissaud, Olivier; Matrot, Boris; Gressens, Pierre; Gallego, Jorge

    2015-01-01

    Apnea of prematurity (AOP) is considered a risk factor for neurodevelopmental disorders in children based on epidemiological studies. This idea is supported by studies in newborn rodents in which exposure to intermittent hypoxia (IH) as a model of AOP significantly impairs development. However, the severe IH used in these studies may not fully reflect the broad spectrum of AOP severity. Considering that hypoxia appears neuroprotective under various conditions, we hypothesized that moderate IH would protect the neonatal mouse brain against behavioral stressors and brain damage. On P6, each pup in each litter was randomly assigned to one of three groups: a group exposed to IH while separated from the mother (IH group), a control group exposed to normoxia while separated from the mother (AIR group), and a group of untreated unmanipulated pups left continuously with their mother until weaning (UNT group). Exposure to moderate IH (8% O2) consisted of 20 hypoxic events/hour, 6 h per day from postnatal day 6 (P6) to P10. The stress generated by maternal separation in newborn rodents is known to impair brain development, and we expected this effect to be smaller in the IH group compared to the AIR group. In a separate experiment, we combined maternal separation with excitotoxic brain lesions mimicking those seen in preterm infants. We analyzed memory, angiogenesis, neurogenesis and brain lesion size. In non-lesioned mice, IH stimulated hippocampal angiogenesis and neurogenesis and improved short-term memory indices. In brain-lesioned mice, IH decreased lesion size and prevented memory impairments. Contrary to common perception, IH mimicking moderate apnea may offer neuroprotection, at least in part, against brain lesions and cognitive dysfunctions related to prematurity. AOP may therefore have beneficial effects in some preterm infants. These results support the need for stratification based on AOP severity in clinical trials of treatments for AOP, to determine whether in

  4. Protective effects of intermittent hypoxia on brain and memory in a mouse model of apnea of prematurity

    Directory of Open Access Journals (Sweden)

    Myriam eBouslama

    2015-11-01

    Full Text Available Apnea of prematurity (AOP is considered a risk factor for neurodevelopmental disorders in children based on epidemiological studies. This idea is supported by studies in newborn rodents in which exposure to intermittent hypoxia (IH as a model of AOP significantly impairs development. However, the severe IH used in these studies may not fully reflect the broad spectrum of AOP severity. Considering that hypoxia appears neuroprotective under various conditions, we hypothesized that moderate IH would protect the neonatal mouse brain against behavioral stressors and brain damage. On P6, each pup in each litter was randomly assigned to one of three groups: a group exposed to IH while separated from the mother (IH group, a control group exposed to normoxia while separated from the mother (AIR group, and a group of untreated unmanipulated pups left continuously with their mother until weaning (UNT group. Exposure to moderate IH consisted of 20 hypoxic events/hour, 6 hours per day from postnatal day 6 (P6 to P10. The stress generated by maternal separation in newborn rodents is known to impair brain development, and we expected this effect to be smaller in the IH group compared to the AIR group. In a separate experiment, we combined maternal separation with excitotoxic brain lesions mimicking those seen in preterm infants. We analyzed memory, angiogenesis, neurogenesis and brain lesion size. In non-lesioned mice, IH stimulated hippocampal angiogenesis and neurogenesis and improved short-term memory indices. In brain-lesioned mice, IH decreased lesion size and prevented memory impairments. Contrary to common perception, IH mimicking moderate apnea may offer neuroprotection, at least in part, against brain lesions and cognitive dysfunctions related to prematurity. AOP may therefore have beneficial effects in some preterm infants. These results support the need for stratification based on AOP severity in clinical trials of treatments for AOP, to determine

  5. Protective effects of intermittent hypoxia on brain and memory in a mouse model of apnea of prematurity.

    Science.gov (United States)

    Bouslama, Myriam; Adla-Biassette, Homa; Ramanantsoa, Nelina; Bourgeois, Thomas; Bollen, Bieke; Brissaud, Olivier; Matrot, Boris; Gressens, Pierre; Gallego, Jorge

    2015-01-01

    Apnea of prematurity (AOP) is considered a risk factor for neurodevelopmental disorders in children based on epidemiological studies. This idea is supported by studies in newborn rodents in which exposure to intermittent hypoxia (IH) as a model of AOP significantly impairs development. However, the severe IH used in these studies may not fully reflect the broad spectrum of AOP severity. Considering that hypoxia appears neuroprotective under various conditions, we hypothesized that moderate IH would protect the neonatal mouse brain against behavioral stressors and brain damage. On P6, each pup in each litter was randomly assigned to one of three groups: a group exposed to IH while separated from the mother (IH group), a control group exposed to normoxia while separated from the mother (AIR group), and a group of untreated unmanipulated pups left continuously with their mother until weaning (UNT group). Exposure to moderate IH (8% O2) consisted of 20 hypoxic events/hour, 6 h per day from postnatal day 6 (P6) to P10. The stress generated by maternal separation in newborn rodents is known to impair brain development, and we expected this effect to be smaller in the IH group compared to the AIR group. In a separate experiment, we combined maternal separation with excitotoxic brain lesions mimicking those seen in preterm infants. We analyzed memory, angiogenesis, neurogenesis and brain lesion size. In non-lesioned mice, IH stimulated hippocampal angiogenesis and neurogenesis and improved short-term memory indices. In brain-lesioned mice, IH decreased lesion size and prevented memory impairments. Contrary to common perception, IH mimicking moderate apnea may offer neuroprotection, at least in part, against brain lesions and cognitive dysfunctions related to prematurity. AOP may therefore have beneficial effects in some preterm infants. These results support the need for stratification based on AOP severity in clinical trials of treatments for AOP, to determine whether in

  6. Comparative and Experimental Studies on the Genes Altered by Chronic Hypoxia in Human Brain Microendothelial Cells

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    Eugenia Mata-Greenwood

    2017-05-01

    Full Text Available Background : Hypoxia inducible factor 1 alpha (HIF1A is a master regulator of acute hypoxia; however, with chronic hypoxia, HIF1A levels return to the normoxic levels. Importantly, the genes that are involved in the cell survival and viability under chronic hypoxia are not known. Therefore, we tested the hypothesis that chronic hypoxia leads to the upregulation of a core group of genes with associated changes in the promoter DNA methylation that mediates the cell survival under hypoxia.Results : We examined the effect of chronic hypoxia (3 days; 0.5% oxygen on human brain micro endothelial cells (HBMEC viability and apoptosis. Hypoxia caused a significant reduction in cell viability and an increase in apoptosis. Next, we examined chronic hypoxia associated changes in transcriptome and genome-wide promoter methylation. The data obtained was compared with 16 other microarray studies on chronic hypoxia. Nine genes were altered in response to chronic hypoxia in all 17 studies. Interestingly, HIF1A was not altered with chronic hypoxia in any of the studies. Furthermore, we compared our data to three other studies that identified HIF-responsive genes by various approaches. Only two genes were found to be HIF dependent. We silenced each of these 9 genes using CRISPR/Cas9 system. Downregulation of EGLN3 significantly increased the cell death under chronic hypoxia, whereas downregulation of ERO1L, ENO2, adrenomedullin, and spag4 reduced the cell death under hypoxia.Conclusions : We provide a core group of genes that regulates cellular acclimatization under chronic hypoxic stress, and most of them are HIF independent.

  7. Moderate Hypoxia Down-Regulates Interleukin-6 Secretion and TLR4 Expression in Human Sw.71 Placental Cells

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    Koumei Shirasuna

    2015-07-01

    Full Text Available Background/Aims: The placenta is a vital organ for pregnancy. Many in vitro placental experiments are conducted under 21% O2; however, O2 tension could influence cellular functions, including cytokine secretion. We investigated the effects of oxygen tension between moderate hypoxia (5% O2 and normoxia (21% O2 by testing the hypothesis that moderate hypoxia regulates cellular phenotypes differently from normoxia in human trophoblast cells. Methods and Results: Sw.71 trophoblast cells were incubated under normoxic or moderately hypoxic conditions. Cells were also treated with lipopolysaccharide (LPS as a Toll-like receptor 4 (TLR4 ligand inducing inflammation. Interleukin-6 (IL-6 as an inflammatory cytokine was determined, and TLR4, hypoxia-induced factor-1α (HIF1α, and reactive oxygen species (ROS production were detected. Moderate hypoxia increased HIF1α expression and cell proliferation and acted by two different mechanisms to decrease IL-6 secretion compared with normoxia: it limits the TLR4 expression and ROS production. Treatment with cobalt chloride as an HIF1 activator inhibited IL-6 secretion and TLR4 expression; this effect was reversed on treatment with PX-12 as an HIF1 suppressor. Conclusion: IL-6 secretion, TLR4 expression, and ROS production, classical markers of inflammation, are down-regulated by moderate hypoxia, and HIF1α and ROS have a potential to regulate these responses in human trophoblast cells.

  8. Hypoxic hypoxia at moderate altitudes: review of the state of the science.

    Science.gov (United States)

    Petrassi, Frank A; Hodkinson, Peter D; Walters, P Lynne; Gaydos, Steven J

    2012-10-01

    Unpressurized aircraft routinely operate at altitudes where hypoxia may be of concern. A systematic literature review was conducted regarding hypoxic impairment, including mental functions, sensory deficits, and other pertinent research findings that may affect aviation-related duties at moderate altitude (8000 to 15,000 ft/2438 to 4572 m). The results of this review suggest that cognitive and psychomotor deficits may include learning, reaction time, decision-making, and certain types of memory. However, results are difficult to quantify and reliably reproduce. Inconsistency of results may be related to the subtlety of deficits compared to high altitude, differences among individual compensatory mechanisms, variation in methodology or sensitivity of metrics, presence or absence of exercise, heterogeneous neuronal central nervous system (CNS) response, and interindividual variation. Literature regarding hypoxic visual decrements is more consistent. Rod photoreceptors are more susceptible to hypoxia; visual degradation has been demonstrated at 4000 to 5000 ft (1219 to 1524 m) under scotopic and 10,000 ft (3048 m) under photopic conditions. Augmented night vision goggle resolution demonstrates more resilience to mild hypoxic effects than the unaided eye under starlight conditions. Hypocapnia enhances visual sensitivity and contrast discrimination. Hyperventilation with resulting respiratory alkalosis and cerebral vasoconstriction may confound both cognitive/ psychomotor and visual experimental results. Future research should include augmentation of validated neuropsychological metrics (surrogate investigational end points) with actual flight metrics, investigation of mixed gas formulations, contribution of hypocapnic vasoconstrictive effects on hypoxic performance, and further investigation into cellular- and systems-level approaches for heterogeneous CNS response. Research is also required into the contribution of mild-moderate hypoxia in human factors- and spatial

  9. Brain adaptation to hypoxia and hyperoxia in mice

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    Laura Terraneo

    2017-04-01

    Conclusion: Prolonged mild hyperoxia leads to persistent cerebral damage, comparable to that inferred by prolonged mild hypoxia. The underlying mechanism appears related to a model whereby the imbalance between ROS generation and anti-ROS defense is similar, but occurs at higher levels in hypoxia than in hyperoxia.

  10. Scutellarein inhibits hypoxia- and moderately-high glucose-induced proliferation and VEGF expression in human retinal endothelial cells

    Institute of Scientific and Technical Information of China (English)

    Rong GAO; Bang-hao ZHU; Shi-bo TANG; Jiang-feng WANG; Jun REN

    2008-01-01

    Aim: This study was designed to examine the effect of scutellarein on high glu-cose- and hypoxia-stimulated proliferation of human retinal endothelial cells (HREC). Methods: HREC were cultured under normal glucose (NG), moderate, and high glucose (NG supplemented with 10 or 25 mmol/L D-glucose) and/or hypoxic (cobalt chloride treated) conditions. Cell proliferation was evaluated by a cell counting kit. The expression of vascular endothelial growth factor (VEGF) was assessed by Western blot analysis. Results: The proliferation of HREC was significantly elevated in response to moderately-high glucose and hypoxic conditions. The combination of high glucose and hypoxia did not have any additive effects on cell proliferation. Consistent with the proliferation data, the expression of VEGF was also upregulated under both moderately-high glucose and hypoxic conditions. The treatment with scutellarein (1 × 10-11-1 × 10-5 mol/L) significantly inhibited high glucose- or hypoxia-induced cell proliferation and VEGF expression. Conclusion: Both hypoxia and moderately-high glucose were potent stimuli for cell proliferation and VEGF expression in HREC without any significant additive effects. Scutellarein is capable of inhibiting the proliferation of HREC, which is possibly related to its ability to suppress the VEGF expression.

  11. Expression of manganese superoxide dismutase in rat blood, heart and brain during induced systemic hypoxia

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    Septelia I. Wanandi

    2011-02-01

    Full Text Available Background: Hypoxia results in an increased generation of ROS. Until now, little is known about the role of MnSOD - a major endogenous antioxidant enzyme - on the cell adaptation response against hypoxia. The aim of this study was to  determine the MnSOD mRNA expression and levels of specific activity in blood, heart and brain of rats during induced systemic hypoxia.Methods: Twenty-five male Sprague Dawley rats were subjected to systemic hypoxia in an hypoxic chamber (at 8-10% O2 for 0, 1, 7, 14 and 21 days, respectively. The mRNA relative expression of MnSOD was analyzed using Real Time RT-PCR. MnSOD specific activity was determined using xanthine oxidase inhibition assay.Results: The MnSOD mRNA relative expression in rat blood and heart was decreased during early induced systemic hypoxia (day 1 and increased as hypoxia continued, whereas the mRNA expression in brain was increased since day 1 and reached its maximum level at day 7. The result of MnSOD specific activity during early systemic hypoxia was similar to the mRNA expression. Under very late hypoxic condition (day 21, MnSOD specific activity in blood, heart and brain was significantly decreased. We demonstrate a positive correlation between MnSOD mRNA expression and specific activity in these 3 tissues during day 0-14 of induced systemic hypoxia. Furthermore, mRNA expression and specific activity levels in heart strongly correlate with those in blood.Conclusion: The MnSOD expression at early and late phases of induced systemic hypoxia is distinctly regulated. The MnSOD expression in brain differs from that in blood and heart revealing that brain tissue can  possibly survive better from induced systemic hypoxia than heart and blood. The determination of MnSOD expression in blood can be used to describe its expression in heart under systemic hypoxic condition. (Med J Indones 2011; 20:27-33Keywords: MnSOD, mRNA expression, ROS, specific activity, systemic hypoxia

  12. [Protective effect of salidroside against high altitude hypoxia-induced brain injury in rats].

    Science.gov (United States)

    Dong, Xiaoru; Zhang, Xiangnan; Li, Dan; Li, Bin; Wang, Jiye; Meng, Shanshan; Luo, Wenjing; Zhang, Wenbin

    2015-10-01

    To observe the protective effect of salidroside against brain injury in rats exposed to hypobaric hypoxia, and investigate the molecular mechanism of salidroside in the prevention of hypobaric hypoxia-induced brain injury. Rats were placed in experiment module simulating 6000 m altitude to establish acute hypobaric hypoxia-induced brain injury models. Their respiratory frequency was observed and recorded. Cell apoptosis in the hippocampal dentate gyrus (DG) was detected by TUNEL assay; the expressions of Ras homolog family member A (RhoA), phosphorylated extracellular signal-regulated kinase (p-ERK) and phosphorylated c-Jun N-terminal kinase (p-JNK) were detected by Western blotting. After acute exposure to 6000 m altitude, the respiratory frequency of the rats increased remarkably. The simulation of hypobaric hypoxia induced cell apoptosis in hippocampal DG region, and salidroside intervention inhibited the process of cell apoptosis. The expressions of RhoA, p-ERK, p-JNK decreased after hypobaric hypoxia exposure. Salidroside intervention reversed RhoA expression and raised the levels of p-ERK and p-JNK. Acute exposure to hypobaric hypoxia can induce cell apoptosis in rat hippocampal DG, and salidroside can protect the cells from the exposure-induced apoptosis.

  13. Features of microelement maintenance in rat's brain tissues at experimental hypoxia of different degree.

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    Tarasova I.V.

    2011-01-01

    Full Text Available Features of microelement maintenance (iron, zinc, copper, manganese, and cobalt, conditionally toxic chrome and toxic lead were studied in newborn rat's brain tissues at experimental hypoxia of different degree. Tissues of newborn rat’s brain are characterized by high level of saturation and considerable dynamism of microelement maintenance. Till the end of the first week of life, the maintenance of these microelements decreases in 1,5 – 10 times. The level of the toxic lead decreases more than in 2,5 times. The hypoxia of easy degree of newborn rats invokes reduction cobalt level 3 times, iron level 2 times, manganese – on 27,65 %, chrome – on 25,84%, zinc – on 16,43%. It means that considerable deficiency and disbalance of microelement maintenance rat's brain tissues. The heavy degree of hypoxia is characterized by further increase of deficiency and disbalance of microelements.

  14. Non-injurious neonatal hypoxia confers resistance to brain senescence in aged male rats.

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    Nicolas Martin

    Full Text Available Whereas brief acute or intermittent episodes of hypoxia have been shown to exert a protective role in the central nervous system and to stimulate neurogenesis, other studies suggest that early hypoxia may constitute a risk factor that influences the future development of mental disorders. We therefore investigated the effects of a neonatal "conditioning-like" hypoxia (100% N₂, 5 min on the brain and the cognitive outcomes of rats until 720 days of age (physiologic senescence. We confirmed that such a short hypoxia led to brain neurogenesis within the ensuing weeks, along with reduced apoptosis in the hippocampus involving activation of Erk1/2 and repression of p38 and death-associated protein (DAP kinase. At 21 days of age, increased thicknesses and cell densities were recorded in various subregions, with strong synapsin activation. During aging, previous exposure to neonatal hypoxia was associated with enhanced memory retrieval scores specifically in males, better preservation of their brain integrity than controls, reduced age-related apoptosis, larger hippocampal cell layers, and higher expression of glutamatergic and GABAergic markers. These changes were accompanied with a marked expression of synapsin proteins, mainly of their phosphorylated active forms which constitute major players of synapse function and plasticity, and with increases of their key regulators, i.e. Erk1/2, the transcription factor EGR-1/Zif-268 and Src kinase. Moreover, the significantly higher interactions between PSD-95 scaffolding protein and NMDA receptors measured in the hippocampus of 720-day-old male animals strengthen the conclusion of increased synaptic functional activity and plasticity associated with neonatal hypoxia. Thus, early non-injurious hypoxia may trigger beneficial long term effects conferring higher resistance to senescence in aged male rats, with a better preservation of cognitive functions.

  15. L-DEPRENYL REDUCES BRAIN-DAMAGE IN RATS EXPOSED TO TRANSIENT HYPOXIA-ISCHEMIA

    NARCIS (Netherlands)

    KNOLLEMA, S; AUKEMA, W; HOM, H; KORF, J; TERHORST, GJ

    1995-01-01

    Background and Purpose L-Deprenyl (Selegiline) protects animal brains against toxic substances such as 1-methyl-1,2,3,6-tetrahydropyridine and 6-hydroxydopamine. Experiments were conducted to test whether L-deprenyl prevents or reduces cerebral damage in a transient hypoxia/ischemia rat model. Metho

  16. Hypoxia and exercise provoke both lactate release and lactate oxidation by the human brain

    DEFF Research Database (Denmark)

    Overgaard, Morten; Rasmussen, Peter; Bohm, Aske M

    2012-01-01

    Lactate is shuttled between organs, as demonstrated in the Cori cycle. Although the brain releases lactate at rest, during physical exercise there is a cerebral uptake of lactate. Here, we evaluated the cerebral lactate uptake and release in hypoxia, during exercise and when the two interventions...

  17. Potential Moderators of Physical Activity on Brain Health

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    Regina L. Leckie

    2012-01-01

    Full Text Available Age-related cognitive decline is linked to numerous molecular, structural, and functional changes in the brain. However, physical activity is a promising method of reducing unfavorable age-related changes. Physical activity exerts its effects on the brain through many molecular pathways, some of which are regulated by genetic variants in humans. In this paper, we highlight genes including apolipoprotein E (APOE, brain derived neurotrophic factor (BDNF, and catechol-O-methyltransferase (COMT along with dietary omega-3 fatty acid, docosahexaenoic acid (DHA, as potential moderators of the effect of physical activity on brain health. There are a growing number of studies indicating that physical activity might mitigate the genetic risks for disease and brain dysfunction and that the combination of greater amounts of DHA intake with physical activity might promote better brain function than either treatment alone. Understanding whether genes or other lifestyles moderate the effects of physical activity on neurocognitive health is necessary for delineating the pathways by which brain health can be enhanced and for grasping the individual variation in the effectiveness of physical activity interventions on the brain and cognition. There is a need for future research to continue to assess the factors that moderate the effects of physical activity on neurocognitive function.

  18. Methodical approach to brain hypoxia/ischemia as a fundamental problem in forensic neuropathology.

    Science.gov (United States)

    Oehmichen, Manfred; Meissner, Christoph; von Wurmb-Schwark, Nicole; Schwark, Thorsten

    2003-12-01

    A review is given summarizing different methods that have been applied to the specific forensic neuropathological question of brain hypoxia/ischemia. On the microscopic level the authors applied routine stains and immunohistochemistry (MAP2, ALZ 50, GFAP, CD68, beta-APP) for characterization of the functional activity of neurons as well as of different cell types in various brain areas. Moreover, using molecular techniques for evaluation of the mitochondrial 4977-bp deletion in correlation to hypoxia and to age brain tissue and single cell analyses are described. The demonstrated scope of methods and results give evidence of the wide spectrum of possibilities to visualize hypoxic brain injuries for determining the cause (and matter) of death and for reconstructing the time-dependent process.

  19. Detection of Hypoxia in Human Brain Tumor Xenografts Using a Modified Comet Assay

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    Jingli Wang

    2003-07-01

    Full Text Available We used the standard comet assay successfully to generate in vitro dose-response curves under oxic and hypoxic conditions. We then made mixtures of cells that had been irradiated with 3 and 9 Gy of X-rays to simulate two subpopulations in a tumor, but efforts to accurately detect and quantify the subpopulations using the standard comet assay were unsuccessful. Therefore, we investigated a modified comet assay to determine whether it could be used for measuring hypoxia in our model systems. U251 MG cells were grown as subcutaneous tumors in athymic mice; U251 MG and U87 MG cells were grown as intracerebral (i.c. tumors in athymic rats. Animals were injected with RSU 1069, irradiated, and euthanized. Tumors and normal brains were removed, and the cells were analyzed using a modified comet assay. Differences in comet tail moment distributions between tumor and contralateral normal brain, using tail moments at either the 25th or 50th percentile in each distribution, were taken as measures of the degree of tumor hypoxia. For U251 MG tumors, there was a positive relationship between tumor size and the degree of hypoxia, whereas preliminary data from U87 MG i.c. tumors showed less hypoxia and no apparent relationship between tumor size and hypoxia.

  20. Alterations of monocarboxylate transporter densities during hypoxia in brain and breast tumour cells

    DEFF Research Database (Denmark)

    Cheng, Chang; Edin, Nina F Jeppesen; Lauritzen, Knut H

    2012-01-01

    Tumour cells are characterized by aerobic glycolysis, which provides biomass for tumour proliferation and leads to extracellular acidification through efflux of lactate via monocarboxylate transporters (MCTs). Deficient and spasm-prone tumour vasculature causes variable hypoxia, which favours...... tumour cell survival and metastases. Brain metastases frequently occur in patients with advanced breast cancer.Effective treatment strategies are therefore needed against brain metastasis from breast carcinoma....

  1. Killing of Brain Tumor Cells by Hypoxia-Responsive Element Mediated Expression of BAX

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    Hangjun Ruan

    1999-11-01

    Full Text Available The presence of radioresistant hypoxic cells in human brain tumors limits the overall effectiveness of conventional fractionated radiation therapy. Tumor-specific therapies that target hypoxic cells are clearly needed. We have investigated the expression of suicide genes under hypoxia by a hypoxia-responsive element (HRE, which can be activated through hypoxia-inducible factor-1 (HIF-1. We transfected plasmids containing multiple copies of HIRE into U-87 MG and U-251 MG-NCI human brain tumor cells and tested their ability to induce LacZ gene expression under anoxia. Gene expression under anoxia versus oxia was increased about 12-fold for U-87 MG cells and about fourfold for U-251 MG-NCI cells. At intermediate hypoxic conditions, increased LacZ gene expression in U-87 MG cells was induced by the plasmid that contained three HREs, but not by the plasmid with two HREs. Lastly, when we placed a suicide gene BAX under the control of HREs, cells transfected with the BAX plasmids were preferentially killed through apoptosis under anoxia. Our studies demonstrate that HRE-regulated gene expression is active in brain tumor cells, and that the amount of increased gene expression obtained is dependent on the cell line, the HIRE copy number, and the degree of hypoxia.

  2. Light-scattering signal may indicate critical time zone to rescue brain tissue after hypoxia

    Science.gov (United States)

    Kawauchi, Satoko; Sato, Shunichi; Uozumi, Yoichi; Nawashiro, Hiroshi; Ishihara, Miya; Kikuchi, Makoto

    2011-02-01

    A light-scattering signal, which is sensitive to cellular/subcellular structural integrity, is a potential indicator of brain tissue viability because metabolic energy is used in part to maintain the structure of cells. We previously observed a unique triphasic scattering change (TSC) at a certain time after oxygen/glucose deprivation for blood-free rat brains; TSC almost coincided with the cerebral adenosine triphosphate (ATP) depletion. We examine whether such TSC can be observed in the presence of blood in vivo, for which transcranial diffuse reflectance measurement is performed for rat brains during hypoxia induced by nitrogen gas inhalation. At a certain time after hypoxia, diffuse reflectance intensity in the near-infrared region changes in three phases, which is shown by spectroscopic analysis to be due to scattering change in the tissue. During hypoxia, rats are reoxygenated at various time points. When the oxygen supply is started before TSC, all rats survive, whereas no rats survive when the oxygen supply is started after TSC. Survival is probabilistic when the oxygen supply is started during TSC, indicating that the period of TSC can be regarded as a critical time zone for rescuing the brain. The results demonstrate that light scattering signal can be an indicator of brain tissue reversibility.

  3. Intranasal pyrrolidine dithiocarbamate decreases brain inflammatory mediators and provides neuroprotection after brain hypoxia-ischemia in neonatal rats.

    Science.gov (United States)

    Wang, Zhi; Zhao, Huijuan; Peng, Shuling; Zuo, Zhiyi

    2013-11-01

    Brain injury due to birth asphyxia is the major cause of death and long-term disabilities in newborns. We determined whether intranasal pyrrolidine dithiocarbamate (PDTC) could provide neuroprotection in neonatal rats after brain hypoxia-ischemia (HI). Seven-day old male and female Sprague-Dawley rats were subjected to brain HI. They were then treated with intranasal PDTC. Neurological outcomes were evaluated 7 or 30 days after the brain HI. Brain tissues were harvested 6 or 24 h after the brain HI for biochemical analysis. Here, PDTC dose-dependently reduced brain HI-induced brain tissue loss with an effective dose (ED)50 at 27 mg/kg. PDTC needed to be applied within 45 min after the brain HI for this neuroprotection. This treatment reduced brain tissue loss and improved neurological and cognitive functions assessed 30 days after the HI. PDTC attenuated brain HI-induced lipid oxidative stress, nuclear translocation of nuclear factor κ-light-chain-enhancer of activated B cells, and various inflammatory mediators in the brain tissues. Inhibition of inducible nitric oxide synthase after brain HI reduced brain tissue loss. Our results suggest that intranasal PDTC provides neuroprotection possibly via reducing inflammation and oxidative stress. Intranasal PDTC may have a potential to provide neuroprotection to human neonates after birth asphyxia.

  4. Immunoreactivity of neurogenic factor in the guinea pig brain after prenatal hypoxia.

    Science.gov (United States)

    Chung, Yoonyoung; So, Keumyoung; Kim, Eunyoung; Kim, Seokwon; Jeon, Yonghyun

    2015-07-01

    Chronic prenatal hypoxia is considered to cause perinatal brain injury. It can result in neurological disorders such as cerebral palsy or learning disabilities. These neurological problems are related to chronic placental insufficiency (CPI), which leads to chronic hypoxemia and hypoglycemia. The effects of hypoxia on neurogenesis during development have been a matter of controversy. We therefore investigated the effect of chronic prenatal hypoxia in the brain of the fetal guinea pig using the guinea pig CPI model. Chronic placental insufficiency was induced by unilateral uterine artery ligation at 30-32 days of gestation (dg: with term defined as ∼67dg). At 50 and 60dg, fetuses were sacrificed and assigned to either the growth-restricted (GR) or control (no ligation) group. Immunohistochemistry was performed with HIF-1α, PCNA, NeuN and BDNF antibodies in the cerebral cortex and dentate gyrus. The number of NeuN-IR and BDNF-IR cells was lesser in GR fetuses than in controls in the cerebral cortex and dentate gyrus at 60dg (pcerebral cortex is decreased by chronic prenatal hypoxia at 60dg.

  5. [Brain hypoxia and the role of active forms of oxygen and of energy deficit in the neuron degeneration].

    Science.gov (United States)

    Ivanov, K P

    2012-01-01

    The concepts about physiological mechanisms of oxygen transport to the brain have recently changed substantially. Precise data on the capillary blood flow rate, on a substantial dispersion of corresponding values, on the influence of the capillary blood flow rate on pO2 in the capillaries and tissues have evolved. Krog's paradigm about an exclusive role of capillaries in the gas exchange between the blood and tissues amounting to almost 100 years was abandoned. All these data also changed the concepts about the development of various types of hypoxia in the brain tissues. The study of pO2 in the brain at normoxia showed that pO2 exhibits the fluctuations from 1-2 to 80-85 mm Hg. This means, in particular, that hypoxic phenomena take place in the normal healthy brain. During hypoxia the mass adhesion of leukocytes to the walls of microvessels was shown to hamper the capillary blood flow and can become one of the reasons for the death of the brain during hypoxia. The brain hypoxia is not an occasional pathologic process. It exists in an intact brain owing to physiological fluctuations of pO2 in various microregions of the brain. It occurs during various physiological states in the norm and also during various illnesses associated with the changes and disruptions in the oxygen transport. The final stage of hypoxia is the destruction of the cells. The development of this process and its particular reasons are nowadays the subject of multiple physiological and biochemical studies. Certain changes are introduced into modern ideas about the reasons for the degradation of the nervous cells upon hypoxia. The degradation of the neurons during hypoxia or anemia is postulated to be associated not only with the cell generation of active forms of oxygen (AFO), but also with the energy deficiency. This means a deficient synthesis or a complete absence of ATP in a cell during hypoxia, anemia, and ishemia.

  6. The influence of intermittent hypobaric hypoxia on the brain iron metabolism in adult Sprague dawley rats

    Institute of Scientific and Technical Information of China (English)

    Wu Qiong; Li Yaru; Chang Yanzhong

    2015-01-01

    Objective:Iron is an essential element in all living organisms and is required as a cofactor for oxygen-binding proteins. Iron metabolism, oxygen homeostasis and erythropoiesis are consequently strongly inter-connected. In mammalian cells, exposure to a low-oxygen environment triggers a hypoxic response pathway cen-tered on the regulated expression of the hypoxia-inducible transcription factor ( HIF) . Hypoxia has been shown to increase the expression of a variety of proteins involved in iron homeostasis. However, little is known about brain iron metabolism after intermittent hypobaric hypoxia ( IHH) treatment. In this study, adult Sprague dawley ( SD) rats were treated with IHH for 28 days, 8h per day and then we detected iron homeostasis in different brain areas of SD rats. Results:The protein level of hippocampus transferrin receptor 1 ( TfR1 ) , divalent metal transporter 1 (DMT1) with IRE, DMT1 (-IRE), ferritin-H, iron regulatory protein (IRP) 2 and ceruloplasmin (CP) is ele-vated significantly while ferritin-L decreased. We have also found the down regulation of IRP1. We observe the same results in the cerebral cortex in the brain. Conclusions:We first discover that IHH has an influence on the brain iron homeostasis and the decreased ferritin-L corresponds to the down regulation of IRP1 indicating hypoxia can affect the expression of ferritin-L through IRE/IRP system. Although there is a marked increase in TfR1 ex-pression that would lead to the raised level of LIP in cells. It can finally result in the higher ROS which can damage the cells. The concerned mechanisms involved in it remain to be deliberated.

  7. Stem cells for brain repair in neonatal hypoxia-ischemia.

    Science.gov (United States)

    Chicha, L; Smith, T; Guzman, R

    2014-01-01

    Neonatal hypoxic-ischemic insults are a significant cause of pediatric encephalopathy, developmental delays, and spastic cerebral palsy. Although the developing brain's plasticity allows for remarkable self-repair, severe disruption of normal myelination and cortical development upon neonatal brain injury are likely to generate life-persisting sensory-motor and cognitive deficits in the growing child. Currently, no treatments are available that can address the long-term consequences. Thus, regenerative medicine appears as a promising avenue to help restore normal developmental processes in affected infants. Stem cell therapy has proven effective in promoting functional recovery in animal models of neonatal hypoxic-ischemic injury and therefore represents a hopeful therapy for this unmet medical condition. Neural stem cells derived from pluripotent stem cells or fetal tissues as well as umbilical cord blood and mesenchymal stem cells have all shown initial success in improving functional outcomes. However, much still remains to be understood about how those stem cells can safely be administered to infants and what their repair mechanisms in the brain are. In this review, we discuss updated research into pathophysiological mechanisms of neonatal brain injury, the types of stem cell therapies currently being tested in this context, and the potential mechanisms through which exogenous stem cells might interact with and influence the developing brain.

  8. Effect of voluntary hypocapnic hyperventilation or moderate hypoxia on metabolic and heart rate responses during high-intensity intermittent exercise.

    Science.gov (United States)

    Dobashi, Kohei; Fujii, Naoto; Watanabe, Kazuhito; Tsuji, Bun; Sasaki, Yosuke; Fujimoto, Tomomi; Tanigawa, Satoru; Nishiyasu, Takeshi

    2017-08-01

    To investigate the effect of voluntary hypocapnic hyperventilation or moderate hypoxia on metabolic and heart rate responses during high-intensity intermittent exercise. Ten males performed three 30-s bouts of high-intensity cycling [Ex1 and Ex2: constant-workload at 80% of the power output in the Wingate anaerobic test (WAnT), Ex3: WAnT] interspaced with 4-min recovery periods under normoxic (Control), hypocapnic or hypoxic (2500 m) conditions. Hypocapnia was developed through voluntary hyperventilation for 20 min prior to Ex1 and during each recovery period. End-tidal CO2 pressure was lower before each exercise in the hypocapnia than control trials. Oxygen uptake ([Formula: see text]) was lower in the hypocapnia than control trials (822 ± 235 vs. 1645 ± 245 mL min(-1); mean ± SD) during Ex1, but not Ex2 or Ex3, without a between-trial difference in the power output during the exercises. Heart rates (HRs) during Ex1 (127 ± 8 vs. 142 ± 10 beats min(-1)) and subsequent post-exercise recovery periods were lower in the hypocapnia than control trials, without differences during or after Ex2, except at 4 min into the second recovery period. [Formula: see text] did not differ between the control and hypoxia trials throughout. These results suggest that during three 30-s bouts of high-intensity intermittent cycling, (1) hypocapnia reduces the aerobic metabolic rate with a compensatory increase in the anaerobic metabolic rate during the first but not subsequent exercises; (2) HRs during the exercise and post-exercise recovery periods are lowered by hypocapnia, but this effect is diminished with repeated exercise bouts, and (3) moderate hypoxia (2500 m) does not affect the metabolic response during exercise.

  9. Dopamine treatment during acute hypoxia is neuroprotective in the developing sheep brain.

    Science.gov (United States)

    Brew, N; Azhan, A; den Heijer, I; Boomgardt, M; Davies, G I; Nitsos, I; Miller, S L; Walker, A M; Walker, D W; Wong, F Y

    2016-03-01

    Dopamine is often used to treat hypotension in preterm infants; these infants are at risk of developing brain injury due to impaired autoregulation and cerebral hypoperfusion. However the effects of dopamine on the immature brain under conditions of cerebral hypoxia are not known. We hypothesized that pretreatment with dopamine would protect the immature brain from injury caused by cerebral hypoxia. Preterm fetal sheep were used to determine the effects of intravenous dopamine on hypoxia-induced brain injury. In 16 pregnant sheep at 90days of gestation (0.6 of term, term=147days) catheters were implanted aseptically into the fetal carotid artery and jugular vein; an inflatable occluder was placed loosely around the umbilical cord for later induction of fetal hypoxemia. At 5days after surgery, dopamine (10μg/kg/min, n=7 fetuses) or saline (n=9 fetuses) was infused for 74h. Two hours after commencing the dopamine/saline infusion, we induced umbilical cord occlusion (UCO) for up to 25min to produce fetal asphyxia. Fetuses were allowed to recover, and brains were collected 72h later for assessment of neuropathology. Un-operated twin fetuses were used as age-matched non-UCO controls (n=8). In UCO+saline fetuses, microglial and apoptotic cell density in the subcortical and periventricular white matter, caudate nucleus and hippocampus was greater than that in age-matched controls; oxidative stress was elevated in the subcortical and periventricular white matter and caudate nucleus compared to that in age-matched controls. In UCO+dopamine fetuses microglial density and oxidative stress in the cerebral white matter and caudate nucleus were not different to that of age-matched controls. Apoptotic cell death was decreased in the cerebral white matter of UCO+dopamine brains, relative to UCO+saline brains. We conclude that pretreatment with dopamine does not exacerbate hypoxia-induced injury in the immature brain and may be neuroprotective because it led to decreased apoptosis

  10. MLKL inhibition attenuates hypoxia-ischemia induced neuronal damage in developing brain.

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    Qu, Yi; Shi, Jing; Tang, Ying; Zhao, Fengyan; Li, Shiping; Meng, Junjie; Tang, Jun; Lin, Xuemei; Peng, Xiaodong; Mu, Dezhi

    2016-05-01

    Mixed lineage kinase domain-like protein (MLKL) is a critical molecule mediating cell necroptosis. However, its role in brain injury remains obscure. We first investigated the functions and mechanisms of MLKL in mediating neuronal damage in developing brain after hypoxia-ischemia. Neuronal necroptosis was induced by oxygen-glucose deprivation (OGD) plus caspase inhibitor zVAD treatment (OGD/zVAD). We found that two important necroptosis related proteins, receptor-interacting protein 1 and 3 (RIP1, RIP3) were upregulated. Furthermore, the interaction of RIP1-RIP3 with MLKL increased. Inhibition of MLKL through siRNA diminished RIP1-RIP3-MLKL interaction and attenuated neuronal death induced by OGD/zVAD. The translocation of oligomerized MLKL to the neuronal membrane leading to the injury of cellular membrane is the possible new mechanism of neuronal necroptosis. Animal experiment with neonatal rats further proved that MLKL inhibition attenuated brain damage induced by hypoxia-ischemia. These findings suggest that MLKL is a target to attenuate brain damage in developing brain.

  11. Sumoylation of hypoxia-inducible factor-1α ameliorates failure of brain stem cardiovascular regulation in experimental brain death.

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    Julie Y H Chan

    Full Text Available BACKGROUND: One aspect of brain death is cardiovascular deregulation because asystole invariably occurs shortly after its diagnosis. A suitable neural substrate for mechanistic delineation of this aspect of brain death resides in the rostral ventrolateral medulla (RVLM. RVLM is the origin of a life-and-death signal that our laboratory detected from blood pressure of comatose patients that disappears before brain death ensues. At the same time, transcriptional upregulation of heme oxygenase-1 in RVLM by hypoxia-inducible factor-1α (HIF-1α plays a pro-life role in experimental brain death, and HIF-1α is subject to sumoylation activated by transient cerebral ischemia. It follows that sumoylation of HIF-1α in RVLM in response to hypoxia may play a modulatory role on brain stem cardiovascular regulation during experimental brain death. METHODOLOGY/PRINCIPAL FINDINGS: A clinically relevant animal model that employed mevinphos as the experimental insult in Sprague-Dawley rat was used. Biochemical changes in RVLM during distinct phenotypes in systemic arterial pressure spectrum that reflect maintained or defunct brain stem cardiovascular regulation were studied. Western blot analysis, EMSA, ELISA, confocal microscopy and immunoprecipitation demonstrated that drastic tissue hypoxia, elevated levels of proteins conjugated by small ubiquitin-related modifier-1 (SUMO-1, Ubc9 (the only known conjugating enzyme for the sumoylation pathway or HIF-1α, augmented sumoylation of HIF-1α, nucleus-bound translocation and enhanced transcriptional activity of HIF-1α in RVLM neurons took place preferentially during the pro-life phase of experimental brain death. Furthermore, loss-of-function manipulations by immunoneutralization of SUMO-1, Ubc9 or HIF-1α in RVLM blunted the upregulated nitric oxide synthase I/protein kinase G signaling cascade, which sustains the brain stem cardiovascular regulatory machinery during the pro-life phase. CONCLUSIONS

  12. Influence of posttraumatic hypoxia on behavioral recovery and histopathological outcome following moderate spinal cord injury in rats.

    Science.gov (United States)

    Yanagawa, Y; Marcillo, A; Garcia-Rojas, R; Loor, K E; Dietrich, W D

    2001-06-01

    Pulmonary dysfunction leading to secondary hypoxia is a common complication of spinal cord injury (SCI). The purpose of this study was to clarify the behavioral and histopathological consequences of posttraumatic hypoxia in an established model of traumatic SCI. Forty-five female Sprague-Dawley rats were randomly assigned to one of four groups, including (1) laminectomy and normoxia (n = 10), (2) laminectomy and hypoxia (n = 11), (3) NYU weight-drop and normoxia (n = 12), and (4) NYU weight-drop and hypoxia (n = 11). For these studies, a moderate injury was induced by adjusting the height of the weight drop (10 g) to 12.5 mm above the exposed spinal cord (T10). Immediately after injury, PaO2 in the hypoxic rats was kept between 30 and 35 mm Hg for 30 min. PaO2 in the normoxic group was maintained over 100 mm Hg, while PaCO2 in all rats was maintained at 35-40 mm Hg. The behavior of the rats was checked every 7 days using the Basso, Beattie, and Bresnahan (BBB) locomotor rating scale. Rats were sacrificed at 8 weeks for quantitative histopathological analysis of lesion areas. During the hypoxic insults, the mean arterial blood pressure dropped in both sham control and weight-drop rats (p < 0.01). At the end of the 8-week monitoring period, BBB scores were 12.5 +/- 3.1 (mean +/- SEM) and 14.2 +/- 3.4 in the normoxic and hypoxic traumatized rats, respectively. No significant difference between the traumatized groups was documented with BBB monitoring. In contrast, the percent of gray matter necrosis at the impact epicenter was significantly increased in hypoxic versus normoxic SCI rats (p < 0.01). These data demonstrate that posttraumatic hypoxia complicated by mild hypotension aggravates the histopathological consequences of SCI and further emphasize the need to control for secondary hypoxic insults after experimental and clinical SCI. Potential explanations for the lack of a correlation between the behavioral and histopathological findings are discussed.

  13. Hypoxia and exercise provoke both lactate release and lactate oxidation by the human brain.

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    Overgaard, Morten; Rasmussen, Peter; Bohm, Aske M; Seifert, Thomas; Brassard, Patrice; Zaar, Morten; Homann, Pernille; Evans, Kevin A; Nielsen, Henning B; Secher, Niels H

    2012-07-01

    Lactate is shuttled between organs, as demonstrated in the Cori cycle. Although the brain releases lactate at rest, during physical exercise there is a cerebral uptake of lactate. Here, we evaluated the cerebral lactate uptake and release in hypoxia, during exercise and when the two interventions were combined. We measured cerebral lactate turnover via a tracer dilution method ([1-(13)C]lactate), using arterial to right internal jugular venous differences in 9 healthy individuals (5 males and 4 females), at rest and during 30 min of submaximal exercise in normoxia and hypoxia (F(i)o(2) 10%, arterial oxygen saturation 72 ± 10%, mean ± sd). Whole-body lactate turnover increased 3.5-fold and 9-fold at two workloads in normoxia and 18-fold during exercise in hypoxia. Although middle cerebral artery mean flow velocity increased during exercise in hypoxia, calculated cerebral mitochondrial oxygen tension decreased by 13 mmHg (P<0.001). At the same time, cerebral lactate release increased from 0.15 ± 0.1 to 0.8 ± 0.6 mmol min(-1) (P<0.05), corresponding to ∼10% of cerebral energy consumption. Concurrently, cerebral lactate uptake was 1.0 ± 0.9 mmol min(-1) (P<0.05), of which 57 ± 9% was oxidized, demonstrating that lactate oxidation may account for up to ∼33% of the energy substrate used by the brain. These results support the existence of a cell-cell lactate shuttle that may involve neurons and astrocytes.

  14. Overexpression of Extracellular Superoxide Dismutase Protects against Brain Injury Induced by Chronic Hypoxia

    Science.gov (United States)

    Zaghloul, Nahla; Patel, Hardik; Codipilly, Champa; Marambaud, Philippe; Dewey, Stephen; Frattini, Stephen; Huerta, Patricio T.; Nasim, Mansoor; Miller, Edmund J.; Ahmed, Mohamed

    2014-01-01

    Extracellular superoxide dismutase (EC-SOD) is an isoform of SOD normally found both intra- and extra-cellularly and accounting for most SOD activity in blood vessels. Here we explored the role of EC-SOD in protecting against brain damage induced by chronic hypoxia. EC-SOD Transgenic mice, were exposed to hypoxia (FiO2.1%) for 10 days (H-KI) and compared to transgenic animals housed in room air (RA-KI), wild type animals exposed to hypoxia (H-WT or wild type mice housed in room air (RA-WT). Overall brain metabolism evaluated by positron emission tomography (PET) showed that H-WT mice had significantly higher uptake of 18FDG in the brain particularly the hippocampus, hypothalamus, and cerebellum. H-KI mice had comparable uptake to the RA-KI and RA-WT groups. To investigate the functional state of the hippocampus, electrophysiological techniques in ex vivo hippocampal slices were performed and showed that H-KI had normal synaptic plasticity, whereas H-WT were severely affected. Markers of oxidative stress, GFAP, IBA1, MIF, and pAMPK showed similar values in the H-KI and RA-WT groups, but were significantly increased in the H-WT group. Caspase-3 assay and histopathological studies showed significant apoptosis/cell damage in the H-WT group, but no significant difference in the H-KI group compared to the RA groups. The data suggest that EC-SOD has potential prophylactic and therapeutic roles in diseases with compromised brain oxygenation. PMID:25268361

  15. Overexpression of extracellular superoxide dismutase protects against brain injury induced by chronic hypoxia.

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    Nahla Zaghloul

    Full Text Available Extracellular superoxide dismutase (EC-SOD is an isoform of SOD normally found both intra- and extra-cellularly and accounting for most SOD activity in blood vessels. Here we explored the role of EC-SOD in protecting against brain damage induced by chronic hypoxia. EC-SOD Transgenic mice, were exposed to hypoxia (FiO2.1% for 10 days (H-KI and compared to transgenic animals housed in room air (RA-KI, wild type animals exposed to hypoxia (H-WT or wild type mice housed in room air (RA-WT. Overall brain metabolism evaluated by positron emission tomography (PET showed that H-WT mice had significantly higher uptake of 18FDG in the brain particularly the hippocampus, hypothalamus, and cerebellum. H-KI mice had comparable uptake to the RA-KI and RA-WT groups. To investigate the functional state of the hippocampus, electrophysiological techniques in ex vivo hippocampal slices were performed and showed that H-KI had normal synaptic plasticity, whereas H-WT were severely affected. Markers of oxidative stress, GFAP, IBA1, MIF, and pAMPK showed similar values in the H-KI and RA-WT groups, but were significantly increased in the H-WT group. Caspase-3 assay and histopathological studies showed significant apoptosis/cell damage in the H-WT group, but no significant difference in the H-KI group compared to the RA groups. The data suggest that EC-SOD has potential prophylactic and therapeutic roles in diseases with compromised brain oxygenation.

  16. Correlation between light scattering signal and tissue reversibility in rat brain exposed to hypoxia

    Science.gov (United States)

    Kawauchi, Satoko; Sato, Shunichi; Uozumi, Yoichi; Nawashiro, Hiroshi; Ishihara, Miya; Kikuchi, Makoto

    2010-02-01

    Light scattering signal is a potential indicator of tissue viability in brain because cellular and subcellular structural integrity should be associated with cell viability in brain tissue. We previously performed multiwavelength diffuse reflectance measurement for a rat global ischemic brain model and observed a unique triphasic change in light scattering at a certain time after oxygen and glucose deprivation. This triphasic scattering change (TSC) was shown to precede cerebral ATP exhaustion, suggesting that loss of brain tissue viability can be predicted by detecting scattering signal. In the present study, we examined correlation between light scattering signal and tissue reversibility in rat brain in vivo. We performed transcranial diffuse reflectance measurement for rat brain; under spontaneous respiration, hypoxia was induced for the rat by nitrogen gas inhalation and reoxygenation was started at various time points. We observed a TSC, which started at 140 +/- 15 s after starting nitrogen gas inhalation (mean +/- SD, n=8). When reoxygenation was started before the TSC, all rats survived (n=7), while no rats survived when reoxygenation was started after the TSC (n=8). When reoxygenation was started during the TSC, rats survived probabilistically (n=31). Disability of motor function was not observed for the survived rats. These results indicate that TSC can be used as an indicator of loss of tissue reversibility in brains, providing useful information on the critical time zone for treatment to rescue the brain.

  17. Acetylation of histones in neocortex and hippocampus of rats exposed to different modes of hypobaric hypoxia: Implications for brain hypoxic injury and tolerance.

    Science.gov (United States)

    Samoilov, Mikhail; Churilova, Anna; Gluschenko, Tatjana; Vetrovoy, Oleg; Dyuzhikova, Natalia; Rybnikova, Elena

    2016-03-01

    Acetylation of nucleosome histones results in relaxation of DNA and its availability for the transcriptional regulators, and is generally associated with the enhancement of gene expression. Although it is well known that activation of a variety of pro-adaptive genes represents a key event in the development of brain hypoxic/ischemic tolerance, the role of epigenetic mechanisms, in particular histone acetylation, in this process is still unexplored. The aim of the present study was to investigate changes in acetylation of histones in vulnerable brain neurons using original well-standardized model of hypobaric hypoxia and preconditioning-induced tolerance of the brain. Using quantitative immunohistochemistry and Western blot, effects of severe injurious hypobaric hypoxia (SH, 180mm Hg, 3h) and neuroprotective preconditioning mode (three episodes of 360mm Hg for 2h spaced at 24h) on the levels of the acetylated proteins and acetylated H3 Lys24 (H3K24ac) in the neocortex and hippocampus of rats were studied. SH caused global repression of the acetylation processes in the neocortex (layers II-III, V) and hippocampus (CA1, CA3) by 3-24h, and this effect was prevented by the preconditioning. Moreover, hypoxic preconditioning remarkably increased the acetylation of H3K24 in response to SH in the brain areas examined. The preconditioning hypoxia without subsequent SH also stimulated acetylation processes in the neocortex and hippocampus. The moderately enhanced expression of the acetylated proteins in the preconditioned rats was maintained for 24h, whereas acetylation of H3K24 was intense but transient, peaked at 3h. The novel data obtained in the present study indicate that large activation of the acetylation processes, in particular acetylation of histones might be essential for the development of brain hypoxic tolerance.

  18. Cerebral perfusion pressure and risk of brain hypoxia in severe head injury: a prospective observational study

    Science.gov (United States)

    Marín-Caballos, Antonio J; Murillo-Cabezas, Francisco; Cayuela-Domínguez, Aurelio; Domínguez-Roldán, Jose M; Rincón-Ferrari, M Dolores; Valencia-Anguita, Julio; Flores-Cordero, Juan M; Muñoz-Sánchez, M Angeles

    2005-01-01

    Introduction Higher and lower cerebral perfusion pressure (CPP) thresholds have been proposed to improve brain tissue oxygen pressure (PtiO2) and outcome. We study the distribution of hypoxic PtiO2 samples at different CPP thresholds, using prospective multimodality monitoring in patients with severe traumatic brain injury. Methods This is a prospective observational study of 22 severely head injured patients admitted to a neurosurgical critical care unit from whom multimodality data was collected during standard management directed at improving intracranial pressure, CPP and PtiO2. Local PtiO2 was continuously measured in uninjured areas and snapshot samples were collected hourly and analyzed in relation to simultaneous CPP. Other variables that influence tissue oxygen availability, mainly arterial oxygen saturation, end tidal carbon dioxide, body temperature and effective hemoglobin, were also monitored to keep them stable in order to avoid non-ischemic hypoxia. Results Our main results indicate that half of PtiO2 samples were at risk of hypoxia (defined by a PtiO2 equal to or less than 15 mmHg) when CPP was below 60 mmHg, and that this percentage decreased to 25% and 10% when CPP was between 60 and 70 mmHg and above 70 mmHg, respectively (p < 0.01). Conclusion Our study indicates that the risk of brain tissue hypoxia in severely head injured patients could be really high when CPP is below the normally recommended threshold of 60 mmHg, is still elevated when CPP is slightly over it, but decreases at CPP values above it. PMID:16356218

  19. Developmental changes of glutamate acid decarboxylase 67 in mouse brain after hypoxia ischemia

    Institute of Scientific and Technical Information of China (English)

    Fa-Lin XU; Chang-Lian ZHU; Xiao-Yang WANG

    2006-01-01

    Objective To study the developmental changes of glutamic acid decarboxylase-67 ( GAD-67, a GABA synthetic enzyme) in normal and hypoxic ischemic (HI) brain. Methods C57/BL6 mice on postnatal day (P) 5, 9, 21and 60, corresponding developmentally to premature, term, juvenile and adult human brain were investigated by using both Western blot and immunohistochemistry methods either in normal condition or after hypoxic ischemic insult. Results The immunoreactivity of GAD67 was up regulated with brain development and significant difference was seen between mature (P21, P60) and immature (P5, P9) brain. GAD67 immunoreactivity decreased in the ipsilateral hemisphere in all the ages after hypoxia ischemia (HI) insult, but, significant decrease was only seen in the immature brain. Double labeling of GAD67 and cell death marker, TUNEL, in the cortex at 8h post-HI in the P9 mice showed that (15.6 ±7.0)%TUNEL positive cells were GAD67 positive which was higher than that of P60 mice. Conclusion These data suggest that GABAergic neurons in immature brain were more vulnerable to HI insult than that of mature brain.

  20. Moderate head injury: completing the clinical spectrum of brain trauma.

    Science.gov (United States)

    Rimel, R W; Giordani, B; Barth, J T; Jane, J A

    1982-09-01

    predictors of outcome after moderate head injury are measures of the severity of injury; and (c) more attention should be directed to patients with moderate head injury than to those with the most severe injuries, in whom brain damage is probably irreversible and all forms of management have demonstrated little success.

  1. The costs of a big brain: extreme encephalization results in higher energetic demand and reduced hypoxia tolerance in weakly electric African fishes.

    Science.gov (United States)

    Sukhum, Kimberley V; Freiler, Megan K; Wang, Robert; Carlson, Bruce A

    2016-12-28

    A large brain can offer several cognitive advantages. However, brain tissue has an especially high metabolic rate. Thus, evolving an enlarged brain requires either a decrease in other energetic requirements, or an increase in overall energy consumption. Previous studies have found conflicting evidence for these hypotheses, leaving the metabolic costs and constraints in the evolution of increased encephalization unclear. Mormyrid electric fishes have extreme encephalization comparable to that of primates. Here, we show that brain size varies widely among mormyrid species, and that there is little evidence for a trade-off with organ size, but instead a correlation between brain size and resting oxygen consumption rate. Additionally, we show that increased brain size correlates with decreased hypoxia tolerance. Our data thus provide a non-mammalian example of extreme encephalization that is accommodated by an increase in overall energy consumption. Previous studies have found energetic trade-offs with variation in brain size in taxa that have not experienced extreme encephalization comparable with that of primates and mormyrids. Therefore, we suggest that energetic trade-offs can only explain the evolution of moderate increases in brain size, and that the energetic requirements of extreme encephalization may necessitate increased overall energy investment.

  2. Relative Expression of HIF-1α mRNA in Rat Heart, Brain and Blood During Induced Systemic Hypoxia

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    Syarifah Dewi

    2009-11-01

    Full Text Available Hypoxia is a pathological condition in which the body as a whole or region of the body (tissue or cell deprived of adequate oxygen supply. The transcriptional regulator hypoxia inducible factor-1 (HIF-1 is an essential mediator of O2 homeostasis. Unlike the β sub unit (HIF-1β, the activity of HIF-1α is controlled in an oxygen-dependent manner. It has been reported that the stability and expression of HIF-1α during hypoxia is remarkably higher than those under normoxic conditions.The aim of this study was to analyze the adaptive tissue responses during induced systemic hypoxia by comparation of relative expression of mRNA HIF-1α in rat heart, brain and blood. Twenty-five male Sprague Dawley rats were subjected to systemic hypoxia by placing them in the hypoxic chamber supplied by 8-10% of O2 for 0, 1, 7, 14 and 21 days, respectively. The relative expression level of HIF-1α mRNA in brain, heart and leucocyte cells were analyzed using quantitative RT-PCR assay (Real Time PCR based on Pfaff's formula. This study demonstrates that the increased of relative expression of HIF-1α mRNA during induced systemic hypoxia reached its maximum level at day 7 (in heart or at day 14 (in brain, whereas in leucocyte cells the stimulation of HIF-1α expression was intensively maintained up to 21 days although the expression has reached the remarkably high level. We could conclude that HIF-1α as an oxygen sensing during systemic hypoxia has different capacity and sensitivity in brain, heart and blood tissues, due to the importance of oxygen homeostasis in each tissue.

  3. The effects of levosimendan on brain metabolism during initial recovery from global transient ischaemia/hypoxia

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    Roehl Anna B

    2012-08-01

    Full Text Available Abstract Backround Neuroprotective strategies after cardiopulmonary resuscitation are currently the focus of experimental and clinical research. Levosimendan has been proposed as a promising drug candidate because of its cardioprotective properties, improved haemodynamic effects in vivo and reduced traumatic brain injury in vitro. The effects of levosimendan on brain metabolism during and after ischaemia/hypoxia are unknown. Methods Transient cerebral ischaemia/hypoxia was induced in 30 male Wistar rats by bilateral common carotid artery clamping for 15 min and concomitant ventilation with 6% O2 during general anaesthesia with urethane. After 10 min of global ischaemia/hypoxia, the rats were treated with an i.v. bolus of 24 μg kg-1 levosimendan followed by a continuous infusion of 0.2 μg kg-1 min-1. The changes in the energy-related metabolites lactate, the lactate/pyruvate ratio, glucose and glutamate were monitored by microdialysis. In addition, the effects on global haemodynamics, cerebral perfusion and autoregulation, oedema and expression of proinflammatory genes in the neocortex were assessed. Results Levosimendan reduced blood pressure during initial reperfusion (72 ± 14 vs. 109 ± 2 mmHg, p = 0.03 and delayed flow maximum by 5 minutes (p = 0.002. Whereas no effects on time course of lactate, glucose, pyruvate and glutamate concentrations in the dialysate could be observed, the lactate/pyruvate ratio during initial reperfusion (144 ± 31 vs. 77 ± 8, p = 0.017 and the glutamate release during 90 minutes of reperfusion (75 ± 19 vs. 24 ± 28 μmol·L-1 were higher in the levosimendan group. The increased expression of IL-6, IL-1ß TNFα and ICAM-1, extend of cerebral edema and cerebral autoregulation was not influenced by levosimendan. Conclusion Although levosimendan has neuroprotective actions in vitro and on the spinal cord in vivo and has been shown to cross the blood–brain barrier, the present

  4. Acute moderate exercise enhances compensatory brain activation in older adults.

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    Hyodo, Kazuki; Dan, Ippeita; Suwabe, Kazuya; Kyutoku, Yasushi; Yamada, Yuhki; Akahori, Mitsuya; Byun, Kyeongho; Kato, Morimasa; Soya, Hideaki

    2012-11-01

    A growing number of reports state that regular exercise enhances brain function in older adults. Recently a functional near-infrared spectroscopy (fNIRS) study revealed that an acute bout of moderate exercise enhanced activation of the left dorsolateral prefrontal cortex (L-DLPFC) associated with Stroop interference in young adults. Whether this acute effect is also applicable to older adults was examined. Sixteen older adults performed a color-word matching Stroop task before and after 10 minutes of exercise on a cycle ergometer at a moderate intensity. Cortical hemodynamics of the prefrontal area was monitored with a fNIRS during the Stroop task. We analyzed Stroop interference (incongruent-neutral) as Stroop performance. Though activation for Stroop interference was found in the bilateral prefrontal area before the acute bout of exercise, activation of the right frontopolar area (R-FPA) was enhanced after exercise. In the majority of participants, this coincided with improved performance reflected in Stroop interference results. Thus, an acute bout of moderate exercise improved Stroop performance in older adults, and this was associated with contralateral compensatory activation.

  5. Brain and skin do not contribute to the systemic rise in erythropoietin during acute hypoxia in humans

    DEFF Research Database (Denmark)

    Rasmussen, Peter; Nordsborg, Nikolai; Taudorf, Sarah;

    2012-01-01

    Erythropoietin (EPO) preserves arterial oxygen content by controlling red blood cell and plasma volumes. Synthesis of EPO was long thought to relate inversely to renal oxygenation, but in knockout mice, brain and skin have been identified as essential for the acute hypoxic EPO response. Whether...... these findings apply to humans remains unknown. We exposed healthy young subjects to hypoxia (equivalent to 3800 m) and measured EPO in arterial and jugular venous plasma and in cerebrospinal fluid. To examine the role of the skin for EPO production during hypoxia, subjects were exposed to 8 h of hypobaric...... hypoxia with or without breathing oxygen-enriched air to ensure systemic normoxemia. With 9 h of hypoxia, arterial EPO increased (from 6.0±2.2 to 22.0±6.0 mU/ml, n=11, P...

  6. Intermittent hypoxia with or without hypercapnia is associated with tumorigenesis by decreasing the expression of brain derived neurotrophic factor and miR-34a in rats

    Institute of Scientific and Technical Information of China (English)

    Zhang Jing; Guo Xu; Shi Yanwei; Ma Jing; Wang Guangfa

    2014-01-01

    Background Very recent studies revealed that obstructive sleep apnoea (OSA) is a contributor of the increased incidence and mortality of cancer in humans,but mechanisms of how OSA promotes tumorigenesis remains largely unknown.We investigated whether intermittent hypoxia with and without hypercapnia plays a role in tumorigenesis.Methods First,Sprague-Dawley (SD) male rats (12 weeks old) were subjected to different hypoxia exposures:intermittent hypoxia and intermittent hypoxia with hypercapnia; continuous hypoxia and normal air.The systemic application of chronic fast rate hypoxia with or without hypercapnia mimicked severe OSA patients with apnoea/hypopnea index equivalent to 60 events per hour.Then routine blood tests were performed and the levels of brain derived neurotrophic factor (BDNF) and miR-34a were examined.Results In contrast to intermittent hypoxia with hypercapnia,both intermittent hypoxia and continuous hypoxia treatments caused significantly higher levels of haematology parameters than normoxia treatments.Compared to normoxia,intermittent hypoxia with hypercapnia exposure resulted in substantial decrease of serum BDNF and,miR-34a in the lower brainstem,while less pronounced results were found in intermittent hypoxia and continuous hypoxia exposure.Conclusions The exposure of intermittent hypoxia with or without hypercapnia,mimicking the situations in severe OSA patients,was associated with,or even promoted tumorigenesis.

  7. Hypoxia inducible factor-1 alpha stabilization for regenerative therapy in traumatic brain injury

    Directory of Open Access Journals (Sweden)

    Mushfiquddin Khan

    2017-01-01

    Full Text Available Mild traumatic brain injury (TBI, also called concussion, initiates sequelae leading to motor deficits, cognitive impairments and subtly compromised neurobehaviors. While the acute phase of TBI is associated with neuroinflammation and nitroxidative burst, the chronic phase shows a lack of stimulation of the neurorepair process and regeneration. The deficiency of nitric oxide (NO, the consequent disturbed NO metabolome, and imbalanced mechanisms of S-nitrosylation are implicated in blocking the mechanisms of neurorepair processes and functional recovery in the both phases. Hypoxia inducible factor-1 alpha (HIF-1α, a master regulator of hypoxia/ischemia, stimulates the process of neurorepair and thus aids in functional recovery after brain trauma. The activity of HIF-1α is regulated by NO via the mechanism of S-nitrosylation of HIF-1α. S-nitrosylation is dynamically regulated by NO metabolites such as S-nitrosoglutathione (GSNO and peroxynitrite. GSNO stabilizes, and peroxynitrite destabilizes HIF-1α. Exogenously administered GSNO was found not only to stabilize HIF-1α and to induce HIF-1α-dependent genes but also to stimulate the regeneration process and to aid in functional recovery in TBI animals.

  8. Hypoxia-inducible factor-1α contributes to brain edema after stroke by regulating aquaporins and glycerol distribution in brain.

    Science.gov (United States)

    Higashida, Tetsuhiro; Peng, Changya; Li, Jie; Dornbos, David; Teng, Kailing; Li, Xiaohua; Kinni, Harish; Guthikonda, Murali; Ding, Yuchuan

    2011-02-01

    Brain edema following stroke is a critical clinical problem due to its association with increased morbidity and mortality. Despite its significance, present treatment for brain edema simply provides symptomatic relief due to the fact that molecular mechanisms underlying brain edema remain poorly understood. The present study investigated the role of hypoxia-inducible factor-1α (HIF-1α) and aquaporins (AQP-4 and -9) in regulating cerebral glycerol accumulation and inducing brain edema in a rodent model of stroke. Two-hours of middle cerebral artery occlusion (MCAO) followed by reperfusion was performed in male Sprague-Dawley rats (250-280 g). Anti-AQP-4 antibody, anti-AQP-9 antibody, or 2-Methoxyestradiol (2ME2, an inhibitor of HIF-1α) was given at the time of MCAO. The rats were sacrificed at 1 and 24 hours after reperfusion and their brains were examined. Extracellular and intracellular glycerol concentration of brain tissue was calculated with an enzymatic glycerol assay. The protein expressions of HIF-1α, AQP-4 and AQP-9 were determined by Western blotting. Brain edema was measured by brain water content. Compared to control, edema (p < 0.01), increased glycerol (p < 0.05), and enhanced expressions of HIF-1α, AQP-4, and AQP-9 (p < 0.05) were observed after stroke. With inhibition of AQP-4, AQP-9 or HIF-1α, edema and extracellular glycerol were significantly (p < 0.01) decreased while intracellular glycerol was increased (p < 0.01) 1 hour after stroke. Inhibition of HIF-1α with 2ME2 suppressed (p < 0.01) the expression of AQP-4 and AQP-9. These findings suggest that HIF-1α serves as an upstream regulator of cerebral glycerol concentrations and brain edema via a molecular pathway involving AQP-4 and AQP-9. Pharmacological blockade of this pathway in stroke patients may provide novel therapeutic strategies.

  9. Sildenafil Improves Brain Injury Recovery following Term Neonatal Hypoxia-Ischemia in Male Rat Pups.

    Science.gov (United States)

    Yazdani, Armin; Khoja, Zehra; Johnstone, Aaron; Dale, Laura; Rampakakis, Emmanouil; Wintermark, Pia

    2016-01-01

    Term asphyxiated newborns remain at risk of developing brain injury despite available neuropreventive therapies such as hypothermia. Neurorestorative treatments may be an alternative. This study investigated the effect of sildenafil on brain injury induced by neonatal hypoxia-ischemia (HI) at term-equivalent age. Neonatal HI was induced in male Long-Evans rat pups at postnatal day 10 (P10) by left common carotid ligation followed by a 2-hour exposure to 8% oxygen; sham-operated rat pups served as the control. Both groups were randomized to oral sildenafil or vehicle twice daily for 7 consecutive days. Gait analysis was performed on P27. At P30, the rats were sacrificed, and their brains were extracted. The surfaces of both hemispheres were measured on hematoxylin and eosin-stained brain sections. Mature neurons and endothelial cells were quantified near the infarct boundary zone using immunohistochemistry. HI caused significant gait impairment and a reduction in the size of the left hemisphere. Treatment with sildenafil led to an improvement in the neurological deficits as measured by gait analysis, as well as an improvement in the size of the left hemisphere. Sildenafil, especially at higher doses, also caused a significant increase in the number of neurons near the infarct boundary zone. In conclusion, sildenafil administered after neonatal HI may improve brain injury recovery by promoting neuronal populations.

  10. Moderate Hypothermia Significantly Decreases Hippocampal Cell Death Involving Autophagy Pathway after Moderate Traumatic Brain Injury.

    Science.gov (United States)

    Jin, Yichao; Lin, Yingying; Feng, Jun-feng; Jia, Feng; Gao, Guo-yi; Jiang, Ji-yao

    2015-07-15

    Here, we evaluated changes in autophagy after post-traumatic brain injury (TBI) followed by moderate hypothermia in rats. Adult male Sprague-Dawley rats were randomly divided into four groups: sham injury with normothermia group (37 °C); sham injury with hypothermia group (32 °C); TBI with normothermia group (TNG; 37 °C); and TBI with hypothermia group (THG; 32 °C). Injury was induced by a fluid percussion TBI device. Moderate hypothermia (32 °C) was achieved by partial immersion in a water bath (0 °C) under general anesthesia for 4 h. All rats were killed at 24 h after fluid percussion TBI. The ipsilateral hippocampus in all rats was analyzed with hematoxylin and eosin staining; terminal deoxynucleoitidyl transferase-mediated nick end labeling staining was used to determine cell death in ipsilateral hippocampus. Immunohistochemistry and western blotting of microtubule-associated protein light chain 3 (LC3), Beclin-1, as well as transmission electron microscopy performed to assess changes in autophagy. At 24 h after TBI, the cell death index was 27.90 ± 2.36% in TNG and 14.90 ± 1.52% in THG. Expression level of LC3 and Beclin-1 were significantly increased after TBI and were further up-regulated after post-TBI hypothermia. Further, ultrastructural observations showed that there was a marked increase of autophagosomes and autolysosomes in ipsilateral hippocampus after post-TBI hypothermia. Our data demonstrated that moderate hypothermia significantly attenuated cell death and increased autophagy in ipsilateral hippocampus after fluid percussion TBI. In conclusion, autophagy pathway may participate in the neuroprotective effect of post-TBI hypothermia.

  11. Ceftriaxone preserves glutamate transporters and prevents intermittent hypoxia-induced vulnerability to brain excitotoxic injury.

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    Rekha Jagadapillai

    Full Text Available Hypoxia alters cellular metabolism and although the effects of sustained hypoxia (SH have been extensively studied, less is known about chronic intermittent hypoxia (IH, commonly associated with cardiovascular morbidity and stroke. We hypothesize that impaired glutamate homeostasis after chronic IH may underlie vulnerability to stroke-induced excitotoxicity. P16 organotypic hippocampal slices, cultured for 7 days were exposed for 7 days to IH (alternating 2 min 5% O2-15 min 21% O2, SH (5% O2 or RA (21% O2, then 3 glutamate challenges. The first and last exposures were intended as a metabolic stimulus (200 µM glutamate, 15 min; the second emulated excitotoxicity (10 mM glutamate, 10 min. GFAP, MAP2, and EAAT1, EAAT2 glutamate transporters expression were assessed after exposure to each hypoxic protocol. Additionally, cell viability was determined at baseline and after each glutamate challenge, in presence or absence of ceftriaxone that increases glutamate transporter expression. GFAP and MAP2 decreased after 7 days IH and SH. Long-term IH but not SH decreased EAAT1 and EAAT2. Excitotoxic glutamate challenge decreased cell viability and the following 200 µM exposure further increased cell death, particularly in IH-exposed slices. Ceftriaxone prevented glutamate transporter decrease and improved cell viability after IH and excitotoxicity. We conclude that IH is more detrimental to cell survival and glutamate homeostasis than SH. These findings suggest that impaired regulation of extracellular glutamate levels is implicated in the increased brain susceptibility to excitotoxic insult after long-term IH.

  12. Circulating N-terminal brain natriuretic peptide and cardiac function in response to acute systemic hypoxia in healthy humans

    NARCIS (Netherlands)

    I. Heinonen (Ilkka); M. Luotolahti (Matti); O. Vuolteenaho (Olli); M. Nikinmaa (Mikko); A. Saraste (Antti); J. Hartiala (Jaakko); J. Koskenvuo (Juha); J. Knuuti (Juhani); O. Arjamaa (Olli)

    2014-01-01

    textabstractBackground: As it remains unclear whether hypoxia of cardiomyocytes could trigger the release of brain natriuretic peptide (BNP) in humans, we investigated whether breathing normobaric hypoxic gas mixture increases the circulating NT-proBNP in healthy male subjects.Methods: Ten healthy y

  13. Moderate GSK-3β inhibition improves neovascular architecture, reduces vascular leakage, and reduces retinal hypoxia in a model of ischemic retinopathy.

    Science.gov (United States)

    Hoang, Mien V; Smith, Lois E H; Senger, Donald R

    2010-09-01

    In ischemic retinopathies, unrelieved hypoxia induces the formation of architecturally abnormal, leaky blood vessels that damage retina and ultimately can cause blindness. Because these newly formed blood vessels are functionally defective, they fail to alleviate underlying hypoxia, resulting in more pathological neovascularization and more damage to retina. With an established model of ischemic retinopathy, we investigated inhibition of glycogen synthase kinase-3β (GSK-3β) as a means for improving the architecture and functionality of pathological blood vessels in retina. In vitro, hypoxia increased GSK-3β activity in retinal endothelial cells, reduced β-catenin, and correspondingly impaired integrity of cell/cell junctions. Conversely, GSK-3β inhibitors restored β-catenin, improved cell/cell junctions, and enhanced the formation of capillary cords in three-dimensional collagen matrix. In vivo, GSK-3β inhibitors, at appropriately moderate doses, strongly reduced abnormal vascular tufts, reduced abnormal vascular leakage, and improved vascular coverage and perfusion during the proliferative phase of ischemia-driven retinal neovascularization. Most importantly, these improvements in neovasculature were accompanied by marked reduction in retinal hypoxia, relative to controls. Thus, GSK-3β inhibitors offer a promising strategy for alleviating retinal hypoxia by correcting key vascular defects typically associated with ischemia-driven neovascularization.

  14. Intermittent hypoxia stimulates formation of binuclear neurons in brain cortex- a role of cell fusion in neuroprotection?

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    Paltsyn, Alexander A; Manukhina, Eugenia B; Goryacheva, Anna V; Downey, H Fred; Dubrovin, Ivan P; Komissarova, Svetlana V; Kubatiev, Aslan A

    2014-05-01

    Oligodendrocyte fusion with neurons in the brain cortex is a part of normal ontogenesis and is a possible means of neuroregeneration. Following such fusion, the oligodendrocyte nucleus undergoes neuron-specific reprogramming, resulting in the formation of binuclear neurons, which doubles the functional capability of the neuron. In this study, we tested the hypothesis that the formation of binuclear neurons is involved in long-term adaptation of the brain to intermittent hypobaric hypoxia, which is known to be neuroprotective. Rats were adapted to hypoxia in an altitude chamber at a simulated altitude of 4000 m above sea level for 14 days (30 min increasing to 4 h, daily). One micrometer sections of the left motor cortex were analyzed by light microscopy. Phases of the fusion and reprogramming process were recorded, and the number of binuclear neurons was counted for all section areas containing pyramidal neurons of layers III-V. For the control group subjected to sham hypoxia, the density of binuclear neurons was 4.49 ± 0.32 mm(2). In the hypoxia-adapted group, this density increased to 5.71 ± 0.39 mm(2) (P neurons did not differ from the number observed in the control group. We suggest that the increased content of binuclear neurons may serve as a structural basis for the neuroprotective effects of the adaptation to hypoxia.

  15. Cyclosporine treatment reduces oxygen free radical generation and oxidative stress in the brain of hypoxia-reoxygenated newborn piglets.

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    Richdeep S Gill

    Full Text Available Oxygen free radicals have been implicated in the pathogenesis of hypoxic-ischemic encephalopathy. It has previously been shown in traumatic brain injury animal models that treatment with cyclosporine reduces brain injury. However, the potential neuroprotective effect of cyclosporine in asphyxiated neonates has yet to be fully studied. Using an acute newborn swine model of hypoxia-reoxygenation, we evaluated the effects of cyclosporine on the brain, focusing on hydrogen peroxide (H(2O(2 production and markers of oxidative stress. Piglets (1-4 d, 1.4-2.5 kg were block-randomized into three hypoxia-reoxygenation experimental groups (2 h hypoxia followed by 4 h reoxygenation (n = 8/group. At 5 min after reoxygenation, piglets were given either i.v. saline (placebo, controls or cyclosporine (2.5 or 10 mg/kg i.v. bolus in a blinded-randomized fashion. An additional sham-operated group (n = 4 underwent no hypoxia-reoxygenation. Systemic hemodynamics, carotid arterial blood flow (transit-time ultrasonic probe, cerebral cortical H(2O(2 production (electrochemical sensor, cerebral tissue glutathione (ELISA and cytosolic cytochrome-c (western blot levels were examined. Hypoxic piglets had cardiogenic shock (cardiac output 40-48% of baseline, hypotension (mean arterial pressure 27-31 mmHg and acidosis (pH 7.04 at the end of 2 h of hypoxia. Post-resuscitation cyclosporine treatment, particularly the higher dose (10 mg/kg, significantly attenuated the increase in cortical H(2O(2 concentration during reoxygenation, and was associated with lower cerebral oxidized glutathione levels. Furthermore, cyclosporine treatment significantly attenuated the increase in cortical cytochrome-c and lactate levels. Carotid blood arterial flow was similar among groups during reoxygenation. Conclusively, post-resuscitation administration of cyclosporine significantly attenuates H(2O(2 production and minimizes oxidative stress in newborn piglets following hypoxia-reoxygenation.

  16. Cyclosporine Treatment Reduces Oxygen Free Radical Generation and Oxidative Stress in the Brain of Hypoxia-Reoxygenated Newborn Piglets

    Science.gov (United States)

    Liu, Jiang-Qin; Chaudhary, Hetal; Brocks, Dion R.; Bigam, David L.; Cheung, Po-Yin

    2012-01-01

    Oxygen free radicals have been implicated in the pathogenesis of hypoxic-ischemic encephalopathy. It has previously been shown in traumatic brain injury animal models that treatment with cyclosporine reduces brain injury. However, the potential neuroprotective effect of cyclosporine in asphyxiated neonates has yet to be fully studied. Using an acute newborn swine model of hypoxia-reoxygenation, we evaluated the effects of cyclosporine on the brain, focusing on hydrogen peroxide (H2O2) production and markers of oxidative stress. Piglets (1–4 d, 1.4–2.5 kg) were block-randomized into three hypoxia-reoxygenation experimental groups (2 h hypoxia followed by 4 h reoxygenation)(n = 8/group). At 5 min after reoxygenation, piglets were given either i.v. saline (placebo, controls) or cyclosporine (2.5 or 10 mg/kg i.v. bolus) in a blinded-randomized fashion. An additional sham-operated group (n = 4) underwent no hypoxia-reoxygenation. Systemic hemodynamics, carotid arterial blood flow (transit-time ultrasonic probe), cerebral cortical H2O2 production (electrochemical sensor), cerebral tissue glutathione (ELISA) and cytosolic cytochrome-c (western blot) levels were examined. Hypoxic piglets had cardiogenic shock (cardiac output 40–48% of baseline), hypotension (mean arterial pressure 27–31 mmHg) and acidosis (pH 7.04) at the end of 2 h of hypoxia. Post-resuscitation cyclosporine treatment, particularly the higher dose (10 mg/kg), significantly attenuated the increase in cortical H2O2 concentration during reoxygenation, and was associated with lower cerebral oxidized glutathione levels. Furthermore, cyclosporine treatment significantly attenuated the increase in cortical cytochrome-c and lactate levels. Carotid blood arterial flow was similar among groups during reoxygenation. Conclusively, post-resuscitation administration of cyclosporine significantly attenuates H2O2 production and minimizes oxidative stress in newborn piglets following hypoxia

  17. Living and training in moderate hypoxia does not improve VO2 max more than living and training in normoxia.

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    Henderson, K K; Clancy, R L; Gonzalez, N C

    2001-06-01

    The objective of these experiments was to determine whether living and training in moderate hypoxia (MHx) confers an advantage on maximal normoxic exercise capacity compared with living and training in normoxia. Rats were acclimatized to and trained in MHx [inspired PO2 (PI(O2)) = 110 Torr] for 10 wk (HTH). Rats living in normoxia trained under normoxic conditions (NTN) at the same absolute work rate: 30 m/min on a 10 degrees incline, 1 h/day, 5 days/wk. At the end of training, rats exercised maximally in normoxia. Training increased maximal O2 consumption (VO2 max) in NTN and HTH above normoxic (NS) and hypoxic (HS) sedentary controls. However, VO2 max and O2 transport variables were not significantly different between NTN and HTH: VO2 max 86.6 +/- 1.5 vs. 86.8 +/- 1.1 ml x min(-1) x kg(-1); maximal cardiac output 456 +/- 7 vs. 443 +/- 12 ml x min(-1) x kg(-1); tissue blood O2 delivery (cardiac output x arterial O2 content) 95 +/- 2 vs. 96 +/- 2 ml x min(-1) x kg(-1); and O2 extraction ratio (arteriovenous O2 content difference/arterial O2 content) 0.91 +/- 0.01 vs. 0.90 +/- 0.01. Mean pulmonary arterial pressure (Ppa, mmHg) was significantly higher in HS vs. NS (P < 0.05) at rest (24.5 +/- 0.8 vs. 18.1 +/- 0.8) and during maximal exercise (32.0 +/- 0.9 vs. 23.8 +/- 0.6). Training in MHx significantly attenuated the degree of pulmonary hypertension, with Ppa being significantly lower at rest (19.3 +/- 0.8) and during maximal exercise (29.2 +/- 0.5) in HTH vs. HS. These data indicate that, despite maintaining equal absolute training intensity levels, acclimatization to and training in MHx does not confer significant advantages over normoxic training. On the other hand, the pulmonary hypertension associated with acclimatization to hypoxia is reduced with hypoxic exercise training.

  18. Antimicrobial peptides and complement in neonatal hypoxia-ischemia induced brain damage

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    Eridan eRocha-Ferreira

    2015-02-01

    Full Text Available Hypoxic-ischemic encephalopathy (HIE is a clinical condition in the neonate, resulting from oxygen deprivation around the time of birth. HIE affects 1-5 per 1000 live births worldwide and is associated with the development of neurological deficits, including cerebral palsy, epilepsy and cognitive disabilities. Even though the brain is considered an immune-privileged site, it has innate and adaptive immune response and can produce complement (C components and antimicrobial peptides (AMPs. Dysregulation of cerebral expression of AMPs and C can exacerbate or ameliorate the inflammatory response within the brain.Brain ischemia triggers a prolonged inflammatory response affecting the progression of injury and secondary energy failure and involves both innate and adaptive immune systems, including immune-competent and non-competent cells. Following injury to the central nervous system (CNS, including neonatal hypoxia-ischemia (HI, resident microglia and astroglia are the main cells providing immune defence to the brain in a stimulus-dependent manner. They can express and secrete pro-inflammatory cytokines and therefore trigger prolonged inflammation resulting in neurodegeneration. Microglial cells express and release a wide range of inflammation-associated molecules including several components of the complement system. Complement activation following neonatal HI-injury has been reported to contribute to neurodegeneration. Astrocytes can significantly affect the immune response of the CNS under pathological conditions through production and release of pro-inflammatory cytokines and immunomodulatory AMPs. Astrocytes express β-defensins which can chemoattract and promote maturation of dendritic cells, and can also limit inflammation by controlling the viability of these same dendritic cells. This review will focus on the balance of complement components and AMPs within the CNS following neonatal HI-injury and the effect of that balance on the

  19. Long-term moderate dose exogenous erythropoietin treatment protects from intermittent hypoxia-induced spatial learning deficits and hippocampal oxidative stress in young rats.

    Science.gov (United States)

    Al-Qahtani, Jobran M; Abdel-Wahab, Basel A; Abd El-Aziz, Samy M

    2014-01-01

    Exposure to intermittent hypoxia (IH) is associated with cognitive impairments and oxidative stress in brain regions involved in learning and memory. In earlier studies, erythropoietin (EPO) showed a neuroprotective effect in large doses. The aim of the present study was to explore the effect of smaller doses of EPO, such as those used in the treatment of anemia, on IH-induced cognitive deficits and hippocampal oxidative stress in young rats. The effect of concurrent EPO treatment (500 and 1,000 IU/kg/day ip) on spatial learning and memory deficits induced by long-term exposure to IH for 6 weeks was tested using the Morris water maze (MWM) test and the elevated plus maze (EPM) test. Moreover, the effect on hippocampal glutamate and oxidative stress were assessed. Exposure to IH induced a significant impairment of spatial learning and cognition of animals in both MWM and EPM performance parameters. Moreover, hippocampal glutamate and thiobarbituric acid reactive substances (TBARS) increased while antioxidant defenses (GSH and GSH-Px) decreased. EPO in the tested doses significantly reduced the IH-induced spatial learning deficits in both MWM and EPM tests and dose-dependently antagonized the effects of IH on hippocampal glutamate, TBARS, GSH levels, and GSH-Px activity. Treatment with EPO in moderate doses that used for anemia, concurrently with IH exposure can antagonize IH-induced spatial learning deficits and protect hippocampal neurons from IH-induced lipid peroxidation and oxidative stress-induced damage in young rats, possibly through multiple mechanisms involving a potential antioxidative effect.

  20. Intermittent hypoxia hypobaric exposure minimized oxidative stress and antioxidants in brain cells of Sprague Dawleymice

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    Wardaya Wardaya

    2013-05-01

    antioxidants in Sprague Dawley male mice.Methods: The experimental study was in February-April 2010 consisted of one control group and four exposed groups of male mice Sprague Dawley. Each groups consisted of 5 mice. The control group did not have IHH. The exposed groups (with an interval of one week had once, twice, three, or four times IHH using a chamber flight. All exposed groups were treated hypobaric equivalent to: 35,000 ft altitude (1 minutes, 25,000 ft (5 minutes, and 18,000 ft (25 minutes. All of their brains had 8-OHdG and SOD measured.Results: The 8-OHdG level among three time IHH exposures had already returned to the control value (P = 0.843. The SOD level increased progressively among two, three, and four times IHH. However after the second exposure, it was found that the SOD level was similar to the control value, 0.231 ± 0.042 (P = 0.191.Conclusion: In conclusion, three times of IHH may improve the effect of hypoxia hypobaric on oxidative stress and specific activity of antioxidants in Sprague Dawley male mice. The SOD level was increased at an earlier exposure, which was after one IHH exposure.Keywords: intermittent hypoxia hypobaric, oxidative stress, antioxidants

  1. Expression of hypoxia-inducible factor 1 alpha and oligodendrocyte lineage gene-1 in cultured brain slices after oxygen-glucose deprivation

    Institute of Scientific and Technical Information of China (English)

    Hong Cui; Weijuan Han; Lijun Yang; Yanzhong Chang

    2013-01-01

    Oligodendrocyte lineage gene-1 expressed in oligodendrocytes may trigger the repair of neuronal myelin impairment, and play a crucial role in myelin repair. Hypoxia-inducible factor 1α, a transcription factor, is of great significance in premature infants with hypoxic-ischemic brain damage. There is little evidence of direct regulatory effects of hypoxia-inducible factor 1α on oligodendrocyte lineage gene-1. In this study, brain slices of Sprague-Dawley rats were cultured and subjected to oxygen-glucose deprivation. Then, slices were transfected with hypoxia-inducible factor 1α or oligodendrocyte lineage gene-1. The expression levels of hypoxia-inducible factor 1α and oligodendrocyte lineage gene-1 were significantly up-regulated in rat brains prior to transfection, as detected by immunohistochemical staining. Eight hours after transfection of slices with hypoxia-inducible factor 1α, oligodendrocyte lineage gene-1 expression was upregulated, and reached a peak 24 hours after transfection. Oligodendrocyte lineage gene-1 transfection induced no significant differences in hypoxia-inducible factor 1α levels in rat brain tissues with oxygen-glucose deprivation. These experimental findings indicate that hypoxia-inducible factor 1α can regulate oligodendrocyte lineage gene-1 expression in hypoxic brain tissue, thus repairing the neural impairment.

  2. Effect of β-sodium aescinate on hypoxia-inducible factor-1α expression in rat brain neurons after cardiopulmonary resuscitation

    Institute of Scientific and Technical Information of China (English)

    康健

    2013-01-01

    Objective To investigate the expression of the hypoxia-inducible factor(HIF)-1α in rat brain neuronsand the intervention of β-sodium aescinate after restoration of spontaneous circulation(ROSC).Methods Sixty

  3. Hypoxia induced amoeboid microglial cell activation in postnatal rat brain is mediated by ATP receptor P2X4

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    Li Fan

    2011-11-01

    Full Text Available Abstract Background Activation of amoeboid microglial cells (AMC and its related inflammatory response have been linked to the periventricular white matter damage after hypoxia in neonatal brain. Hypoxia increases free ATP in the brain and then induces various effects through ATP receptors. The present study explored the possible mechanism in ATP induced AMC activation in hypoxia. Results We first examined the immunoexpression of P2X4, P2X7 and P2Y12 in the corpus callosum (CC and subependyma associated with the lateral ventricles where both areas are rich in AMC. Among the three purinergic receptors, P2X4 was most intensely expressed. By double immunofluorescence, P2X4 was specifically localized in AMC (from P0 to P7 but the immunofluorescence in AMC was progressively diminished with advancing age (P14. It was further shown that P2X4 expression was noticeably enhanced in P0 day rats subjected to hypoxia and killed at 4, 24, 72 h and 7 d versus their matching controls by double labeling and western blotting analysis. P2X4 expression was most intense at 7 d whence the inflammatory response was drastic after hypoxia. We then studied the association of P2X4 with cytokine release in AMC after hypoxic exposure. In primary microglial cells exposed to hypoxia, IL-1β and TNF-α protein levels were up-regulated. Blockade of P2X4 receptor with 2', 3'-0-(2, 4, 6-Trinitrophenyl adenosine 5'-triphosphate, a selective P2X1-7 blocker resulted in partial suppression of IL-1β (24% vs hypoxic group and TNF-α expression (40% vs hypoxic group. However, pyridoxal phosphate-6-azo (benzene-2, 4-disulfonic acid tetrasodium salt hydrate, a selective P2X1-3, 5-7 blocker did not exert any significant effect on the cytokine expression. Conclusions It is concluded that P2X4 which is constitutively expressed by AMC in postnatal rats was enhanced in hypoxia. Hypoxia induced increase in IL-1β and TNF-α expression was reversed by 2', 3'-0-(2, 4, 6-Trinitrophenyl adenosine

  4. The GluN3A Subunit Exerts a Neuroprotective Effect in Brain Ischemia and the Hypoxia Process

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    Hui Wang

    2013-07-01

    Full Text Available NMDARs (N-methyl-d-aspartate receptors mediate the predominantly excitatory neurotransmission in the CNS (central nervous system. Excessive release of glutamate and overactivation of NMDARs during brain ischemia and the hypoxia process are causally linked to excitotoxicity and neuronal damage. GluN3 subunits, the third member of the NMDAR family with two isoforms, GluN3A and GluN3B, have been confirmed to display an inhibitory effect on NMDAR activity. However, the effect of GluN3 subunits in brain ischemia and hypoxia is not clearly understood. In the present study, the influence of ischemia and hypoxia on GluN3 subunit expression was observed by using the 2VO (two-vessel occlusion rat brain ischemia model and cell OGD (oxygen and glucose deprivation hypoxia model. It was found that GluN3A protein expression in rat hippocampus and the prefrontal cortex was increased quickly after brain ischemia and remained at a high level for at least 24 h. However, the expression of the GluN3B subunit was not remarkably changed in both the animal and cell models. After OGD exposure, rat hippocampal neurons with GluN3A subunit overexpression displayed more viability than the wild-type neurons. NG108-15 cells overexpressing GluN3A presented pronounced resistance to glutamate insult. Blocking the increase of intracellular Ca2+ concentration may underlie the neuroprotective mechanism of up-regulated GluN3A subunit. Suppressing the generation of hydroxyl radicals and NO (nitric oxide is probably also involved in the neuroprotection.

  5. Further evidence for the neuroprotective role of oleanolic acid in a model of focal brain hypoxia in rats.

    Science.gov (United States)

    Caltana, Laura; Rutolo, Damián; Nieto, María Luisa; Brusco, Alicia

    2014-12-01

    Ischemic brain injury is a dynamic process involving oxidative stress, inflammation, cell death and the activation of endogenous adaptive and regenerative mechanisms depending on the activation of transcription factors such as hypoxia-inducible factor 1-alpha. Accordingly, we have previously described a new focal hypoxia model by direct intracerebral cobalt chloride injection. In turn, oleanolic acid, a plant-derived triterpenoid, has been extensively used in Asian countries for its anti-inflammatory and anti-tumor properties. A variety of novel pharmacological effects have been attributed to this triterpenoid, including beneficial effects on neurodegenerative disorders--including experimental autoimmune encephalomyelitis--due to its immunomodulatory activities at systemic level, as well as within the central nervous system. In this context, we hypothesize that this triterpenoid may be capable of exerting neuroprotective effects in ischemic brain, suppressing glial activities that contribute to neurotoxicity while promoting those that support neuronal survival. In order to test this hypothesis, we used the intraperitoneal administration of oleanoic acid in adult rats for seven days previous to focal cortical hypoxia induced by cobalt chloride brain injection. We analyzed the neuroprotective effect of oleanoic acid from a morphological point of view, focusing on neuronal survival and glial reaction.

  6. Oligodendrocyte transcription factor 1 overexpression promotes oligodendrocyte transcription factor 2 expression in the brains of neonatal rats exposed to hypoxia****☆

    Institute of Scientific and Technical Information of China (English)

    Lijun Yang; Hong Cui; Aijun Yang; Wenxing Jiang

    2011-01-01

    To examine the expression profiles of oligodendrocyte transcription factors 1 and 2 (Olig1 and Olig2) and the interaction between these two proteins, Olig1 was transfected into the lateral ventricles of neonatal rats subjected to hypoxia. Immunohistochemistry demonstrated that Olig2 was expressed throughout the nuclei in the brain, and expression increased at 3 days following hypoxia and was higher than levels at 7 days following Ad5-Olig1 transfection. Western blot revealed that Olig1 and Olig2 expression increased in Olig1-transfected brain cells 3 days after hypoxia, but Olig1 and Olig2 expression decreased at 7 days. These results indicate that Olig1 overexpression enhances Olig2 expression in brain tissues of hypoxia rats.

  7. Alteration in rectification of potassium channels in perinatal hypoxia ischemia brain damage.

    Science.gov (United States)

    Chen, Penghui; Wang, Liyan; Deng, Qiyue; Ruan, Huaizhen; Cai, Wenqin

    2015-01-15

    Oligodendrocyte progenitor cells (OPCs) are susceptible to perinatal hypoxia ischemia brain damage (HIBD), which results in infant cerebral palsy due to the effects on myelination. The origin of OPC vulnerability in HIBD, however, remains controversial. In this study, we defined the HIBD punctate lesions by MRI diffuse excessive high signal intensity (DEHSI) in postnatal 7-day-old rats. The electrophysiological functional properties of OPCs in HIBD were recorded by patch-clamp in acute cerebral cortex slices. The slices were intracellularly injected with Lucifer yellow and immunohistochemically labeled with NG2 antibody to identify local OPCs. Passive membrane properties and K(+) channel functions in OPCs were analyzed to estimate the onset of vulnerability in HIBD. The resting membrane potential, membrane resistance, and membrane capacitance of OPCs were increased in both the gray and white matter of the cerebral cortex. OPCs in both the gray and white matter exhibited voltage-dependent K(+) currents, which consisted of the initiated rectified potassium currents (IA) and the sustained rectified currents (IK). The significant alternation in membrane resistance was influenced by the diversity of potassium channel kinetics. These findings suggest that the rectification of IA and IK channels may play a significant role in OPC vulnerability in HIBD.

  8. Long-Term Intermittent Hypoxia Elevates Cobalt Levels in the Brain and Injures White Matter in Adult Mice

    Science.gov (United States)

    Veasey, Sigrid C.; Lear, Jessica; Zhu, Yan; Grinspan, Judith B.; Hare, Dominic J.; Wang, SiHe; Bunch, Dustin; Doble, Philip A.; Robinson, Stephen R.

    2013-01-01

    Study Objectives: Exposure to the variable oxygenation patterns in obstructive sleep apnea (OSA) causes oxidative stress within the brain. We hypothesized that this stress is associated with increased levels of redox-active metals and white matter injury. Design: Participants were randomly allocated to a control or experimental group (single independent variable). Setting: University animal house. Participants: Adult male C57BL/6J mice. Interventions: To model OSA, mice were exposed to long-term intermittent hypoxia (LTIH) for 10 hours/day for 8 weeks or sham intermittent hypoxia (SIH). Measurements and Results: Laser ablation-inductively coupled plasma-mass spectrometry was used to quantitatively map the distribution of the trace elements cobalt, copper, iron, and zinc in forebrain sections. Control mice contained 62 ± 7 ng cobalt/g wet weight, whereas LTIH mice contained 5600 ± 600 ng cobalt/g wet weight (P Cobalt was concentrated within white matter regions of the brain, including the corpus callosum. Compared to that of control mice, the corpus callosum of LTIH mice had significantly more endoplasmic reticulum stress, fewer myelin-associated proteins, disorganized myelin sheaths, and more degenerated axon profiles. Because cobalt is an essential component of vitamin B12, serum methylmalonic acid (MMA) levels were measured. LTIH mice had low MMA levels (P cobalt, predominantly in the white matter. The increased cobalt is associated with endoplasmic reticulum stress, myelin loss, and axonal injury. Low plasma methylmalonic acid levels are associated with white matter injury in long-term intermittent hypoxia and possibly in obstructive sleep apnea. Citation: Veasey SC; Lear J; Zhu Y; Grinspan JB; Hare DJ; Wang S; Bunch D; Doble PA; Robinson SR. Long-term intermittent hypoxia elevates cobalt levels in the brain and injures white matter in adult mice. SLEEP 2013;36(10):1471-1481. PMID:24082306

  9. Moderate hyperglycemia augments ischemic brain damage: a neuropathologic study in the rat.

    Science.gov (United States)

    Pulsinelli, W A; Waldman, S; Rawlinson, D; Plum, F

    1982-11-01

    We compared the effects of glucose injection with those of saline or mannitol on ischemic brain damage and brain water content in a four-vessel occlusion (4-VO) rat model, which simultaneously causes severe forebrain ischemia and moderate hindbrain ischemia. Glucose given before onset of ischemia was followed by severe brain injury, with necrosis of the majority of neocortical neurons and glia, substantial neuronal damage throughout the remainder of forebrain, and severe brain edema. By comparison, saline injection before forebrain ischemia resulted in only scattered ischemic damage confined to neurons and no change in the brain water content. Mannitol injection before 4-VO or D-glucose injection during or after 4-VO produced no greater forebrain damage than did the saline injection. Morphologic damage in the cerebellum, however, was increased by D-glucose injection given either before or during 4-VO. The results demonstrate that hyperglycemia before severe brain ischemia or during moderate ischemia markedly augments morphologic brain damage.

  10. The Specific Protein Kinase R (PKR) Inhibitor C16 Protects Neonatal Hypoxia-Ischemia Brain Damages by Inhibiting Neuroinflammation in a Neonatal Rat Model

    Science.gov (United States)

    Xiao, Jinglei; Tan, Yongchang; Li, Yinjiao; Luo, Yan

    2016-01-01

    Background Brain injuries induced by hypoxia-ischemia in neonates contribute to increased mortality and lifelong neurological dysfunction. The specific PKR inhibitor C16 has been previously demonstrated to exert a neuroprotective role in adult brain injuries. However, there is no recent study available concerning its protective role in hypoxia-ischemia-induced immature brain damage. Therefore, we investigated whether C16 protects against neonatal hypoxia-ischemia injuries in a neonatal rat model. Material/Methods Postnatal day 7 (P7) rats were used to establish classical hypoxia-ischemia animal models, and C16 postconditioning with 100 ug/kg was performed immediately after hypoxia. Western blot analysis was performed to quantify the phosphorylation of the PKR at 0 h, 3 h, 6 h, 12 h, 24 h, and phosphorylation of NF-κB 24h after hypoxia exposure. The TTC stain for infarction area and TUNEL stain for apoptotic cells were assayed 24 h after the brain hypoxia. Gene expression of IL-1β, IL-6, and TNF-α was performed at 3 h, 6 h, 12 h, and 24 h. Results The level of PKR autophosphorylation was increased dramatically, especially at 3 h (C16 group vs. HI group, P<0.01). Intraperitoneal C16 administration reduced the infarct volume and apoptosis ratio after this insult (C16 group vs. HI group<0.01), and C16 reduced proinflammatory cytokines mRNA expression, partly through inhibiting NF-κB activation (C16 group vs. HI group<0.05). Conclusions C16 can protect immature rats against hypoxia-ischemia-induced brain damage by modulating neuroinflammation. PMID:28008894

  11. Differential Effect of Intrauterine Hypoxia on Caspase 3 and DNA Fragmentation in Fetal Guinea Pig Hearts and Brains

    Science.gov (United States)

    Evans, LaShauna C.; Liu, Hongshan; Thompson, Loren P.

    2012-01-01

    The aim of this study is to quantify the effect of intrauterine hypoxia (HPX) and the role of nitric oxide (NO) on the apoptotic enzyme, caspase 3, and DNA fragmentation in fetal heart and brain. Hypoxia and NO are important regulators of apoptosis, although this has been little studied in the fetal organs. We investigated the effect of intrauterine HPX on apoptosis and the role of NO in both fetal hearts and brains. Pregnant guinea pigs were exposed to room temperature (N = 14) or 10.5% O2 (N = 12) for 14 days prior to term (term = 65 days) and administered water or l-N6-(1-iminoethyl)-lysine (LNIL), an inducible nitric oxide synthase (iNOS) inhibitor, for 10 days. Fetal hearts and brains were excised from anesthetized near-term fetuses for study. Chronic HPX decreased pro- and active caspase 3, caspase 3 activity, and DNA fragmentation levels in fetal hearts compared with normoxic controls. l-N6-(1-iminoethyl)-lysine prevented the HPX-induced decrease in caspase 3 activity but did not alter DNA fragmentation levels. In contrast, chronic HPX increased both apoptotic indices in fetal brains, which were inhibited by LNIL. Thus, the effect of HPX on apoptosis differs between fetal organs, and NO may play an important role in modulating these effects. PMID:22383778

  12. Outcome prediction in moderate and severe traumatic brain injury: a focus on computed tomography variables

    NARCIS (Netherlands)

    Jacobs, B.; Beems, T.; Vliet, T.M. van der; Vugt, A.B. van; Hoedemaekers, C.W.; Horn, J.; Franschman, G.; Haitsma, I.; Naalt, J. van der; Andriessen, T.M.J.C.; Borm, G.F.; Vos, P.E.

    2013-01-01

    BACKGROUND: With this study we aimed to design validated outcome prediction models in moderate and severe traumatic brain injury (TBI) using demographic, clinical, and radiological parameters. METHODS: Seven hundred consecutive moderate or severe TBI patients were included in this observational pros

  13. Outcome Prediction in Moderate and Severe Traumatic Brain Injury : A Focus on Computed Tomography Variables

    NARCIS (Netherlands)

    Jacobs, Bram; Beems, Tjemme; van der Vliet, Ton M.; van Vugt, Arie B.; Hoedemaekers, Cornelia; Horn, Janneke; Franschman, Gaby; Haitsma, Ian; van der Naalt, Joukje; Andriessen, Teuntje M. J. C.; Borm, George F.; Vos, Pieter E.

    2013-01-01

    With this study we aimed to design validated outcome prediction models in moderate and severe traumatic brain injury (TBI) using demographic, clinical, and radiological parameters. Seven hundred consecutive moderate or severe TBI patients were included in this observational prospective cohort study.

  14. Mood after moderate and severe traumatic brain injury: A prospective cohort study

    NARCIS (Netherlands)

    L. Valk-Kleibeuker (Linda); M.H. Heijenbrok-Kal (Majanka); G.M. Ribbers (Gerard)

    2014-01-01

    textabstractObjective: To evaluate the course of mood and identify its determinants up to 3 years after moderate to severe traumatic brain injury (TBI). Design: Prospective cohort study. Patients: Patients hospitalised with moderate to severe TBI, who survived until hospital discharge. Methods: At 3

  15. Brain activation during a social attribution task in adolescents with moderate to severe traumatic brain injury.

    Science.gov (United States)

    Scheibel, Randall S; Newsome, Mary R; Wilde, Elisabeth A; McClelland, Michelle M; Hanten, Gerri; Krawczyk, Daniel C; Cook, Lori G; Chu, Zili D; Vásquez, Ana C; Yallampalli, Ragini; Lin, Xiaodi; Hunter, Jill V; Levin, Harvey S

    2011-01-01

    The ability to make accurate judgments about the mental states of others, sometimes referred to as theory of mind (ToM), is often impaired following traumatic brain injury (TBI), and this deficit may contribute to problems with interpersonal relationships. The present study used an animated social attribution task (SAT) with functional magnetic resonance imaging (fMRI) to examine structures mediating ToM in adolescents with moderate to severe TBI. The study design also included a comparison group of matched, typically developing (TD) adolescents. The TD group exhibited activation within a number of areas that are thought to be relevant to ToM, including the medial prefrontal and anterior cingulate cortex, fusiform gyrus, and posterior temporal and parietal areas. The TBI subjects had significant activation within many of these same areas, but their activation was generally more intense and excluded the medial prefrontal cortex. Exploratory regression analyses indicated a negative relation between ToM-related activation and measures of white matter integrity derived from diffusion tensor imaging, while there was also a positive relation between activation and lesion volume. These findings are consistent with alterations in the level and pattern of brain activation that may be due to the combined influence of diffuse axonal injury and focal lesions.

  16. Resveratrol ameliorates hypoxia/ischemia-induced brain injury in the neonatal rat via the miR-96/Bax axis.

    Science.gov (United States)

    Bian, Hongen; Shan, Haijun; Chen, Tuanying

    2017-07-18

    This study was aimed to investigate the mechanism of resveratrol on amelioration of hypoxia/ischemia (H/I)-induced brain injury. The RT-PCR and western blot were used to detect the mRNA and protein expressions, respectively. The PC12 cell induced by OGD/R was as in vitro H/I brain injury model. The luciferase reporter assay was used to prove the relationship between Bax and miR-96, and the cell apoptosis was detected by MTT assay. The loss of MBP+ area in neonatal rats analyzed by immunohistochemistry was to evaluate the extent of brain injury. The miR-96 expression was decreased in the hippocampus and cerebral cortex of neonatal rats with H/I brain injury and the oxygenglucose deprivation/re-oxygenation (OGD/R)-induced PC12 cell, while Bax expression was opposite. And then the H/I rats and OGD/R-induced PC12 cell were treated with resveratrol (RSV); the results showed that the RSV could reverse the miR-96 and Bax expressions. Next, the luciferase reporter assay proved that Bax was a target of miR-96. We used the miR-96 inhibitor to suppress miR-96 expression in OGD/R-induced PC12 cell, and found that RSV regulated Bax expression and prevented OGD/R-induced PC12 cell apoptosis via miR-96. In addition, the immunohistochemistry was used to analyze the loss of MBP+ area in neonatal rats, and the result showed that the RSV significantly reduced the brain damage, increased miR-96 expression, and decreased Bax expression, while inhibition of miR-96 aggravated the brain damage and reversed the effect of RSV. Resveratrol ameliorates hypoxia/ischemia-induced brain injury in neonatal rat via the miR-96/ Bax axis.

  17. Validation of Housekeeping Genes in the Brains of Rats Submitted to Chronic Intermittent Hypoxia, a Sleep Apnea Model

    Science.gov (United States)

    Julian, Guilherme Silva; de Oliveira, Renato Watanabe; Perry, Juliana Cini; Tufik, Sergio; Chagas, Jair Ribeiro

    2014-01-01

    Obstructive sleep apnea (OSA) is a syndrome characterized by intermittent nocturnal hypoxia, sleep fragmentation, hypercapnia and respiratory effort, and it has been associated with several complications, such as diabetes, hypertension and obesity. Quantitative real-time PCR has been performed in previous OSA-related studies; however, these studies were not validated using proper reference genes. We have examined the effects of chronic intermittent hypoxia (CIH), which is an experimental model mainly of cardiovascular consequences of OSA, on reference genes, including beta-actin, beta-2-microglobulin, glyceraldehyde-3-phosphate dehydrogenase, hypoxanthine guanine phosphoribosyl transferase and eukaryotic 18S rRNA, in different areas of the brain. All stability analyses were performed using the geNorm, Normfinder and BestKeeper software programs. With exception of the 18S rRNA, all of the evaluated genes were shown to be stable following CIH exposure. However, gene stability rankings were dependent on the area of the brain that was analyzed and varied according to the software that was used. This study demonstrated that CIH affects various brain structures differently. With the exception of the 18S rRNA, all of the tested genes are suitable for use as housekeeping genes in expression analyses. PMID:25289636

  18. Validation of housekeeping genes in the brains of rats submitted to chronic intermittent hypoxia, a sleep apnea model.

    Science.gov (United States)

    Julian, Guilherme Silva; de Oliveira, Renato Watanabe; Perry, Juliana Cini; Tufik, Sergio; Chagas, Jair Ribeiro

    2014-01-01

    Obstructive sleep apnea (OSA) is a syndrome characterized by intermittent nocturnal hypoxia, sleep fragmentation, hypercapnia and respiratory effort, and it has been associated with several complications, such as diabetes, hypertension and obesity. Quantitative real-time PCR has been performed in previous OSA-related studies; however, these studies were not validated using proper reference genes. We have examined the effects of chronic intermittent hypoxia (CIH), which is an experimental model mainly of cardiovascular consequences of OSA, on reference genes, including beta-actin, beta-2-microglobulin, glyceraldehyde-3-phosphate dehydrogenase, hypoxanthine guanine phosphoribosyl transferase and eukaryotic 18S rRNA, in different areas of the brain. All stability analyses were performed using the geNorm, Normfinder and BestKeeper software programs. With exception of the 18S rRNA, all of the evaluated genes were shown to be stable following CIH exposure. However, gene stability rankings were dependent on the area of the brain that was analyzed and varied according to the software that was used. This study demonstrated that CIH affects various brain structures differently. With the exception of the 18S rRNA, all of the tested genes are suitable for use as housekeeping genes in expression analyses.

  19. Validation of housekeeping genes in the brains of rats submitted to chronic intermittent hypoxia, a sleep apnea model.

    Directory of Open Access Journals (Sweden)

    Guilherme Silva Julian

    Full Text Available Obstructive sleep apnea (OSA is a syndrome characterized by intermittent nocturnal hypoxia, sleep fragmentation, hypercapnia and respiratory effort, and it has been associated with several complications, such as diabetes, hypertension and obesity. Quantitative real-time PCR has been performed in previous OSA-related studies; however, these studies were not validated using proper reference genes. We have examined the effects of chronic intermittent hypoxia (CIH, which is an experimental model mainly of cardiovascular consequences of OSA, on reference genes, including beta-actin, beta-2-microglobulin, glyceraldehyde-3-phosphate dehydrogenase, hypoxanthine guanine phosphoribosyl transferase and eukaryotic 18S rRNA, in different areas of the brain. All stability analyses were performed using the geNorm, Normfinder and BestKeeper software programs. With exception of the 18S rRNA, all of the evaluated genes were shown to be stable following CIH exposure. However, gene stability rankings were dependent on the area of the brain that was analyzed and varied according to the software that was used. This study demonstrated that CIH affects various brain structures differently. With the exception of the 18S rRNA, all of the tested genes are suitable for use as housekeeping genes in expression analyses.

  20. Effects of exogenous ganglioside-1 on learning and memory in a neonatal rat model of hypoxia-ischemia brain injury

    Institute of Scientific and Technical Information of China (English)

    Shizhi Li; Nong Xiao; Xiaoping Zhang; Ling Liu; Liyun Lin; Siyuan Chen; Yuxia Chen; Bei Xu

    2008-01-01

    BACKGROUND: Exogenous ganglioside-1 (GM1) can cross the blood-brain barrier and play a protective role against hypoxia-ischemia-induced brain damage. OBJECTIVE: To examine the possible mechanisms of exogenous GM1 protection in hypoxia-ischemia-induced brain damage in a neonatal rat model by measuring changes in brain mass, pathological morphology, growth-associated protein-43 expression, and neurobehavioral manifestations. DESIGN, TIME AND SETTING: A randomized block-design study was performed at the lmmunohistochemistry Laboratory of the Pediatric Research Institute, Children's Hospital of Chongqing Medical University from August 2005 to August 2006. MATERIALS: A total of 36 neonatal, 7-day-old, Sprague Dawley rats were used in this experiment. The hypoxia-ischemia-induced brain damage model was established by permanently occluding the right carotid artery, followed by oxygen inhalation at a low concentration (8% O2, 92% N2) for 2 hours. METHODS: All rats were randomly divided into the following groups: GM1, model, and sham operation, with 12 rats each group. Rats in the GM1 and model groups received hypoxic/ischemic-induced brain damage. Rats in the GM1 group received injections ofGM1 (i.p., 20 mg/kg) at 0, 24, 48, 72, 96, 120, and 144 hours following models established, and rats in the model group were administered (i.p.) the same amount of saline. The right carotid artery was separated, but not ligated, in the sham operation group rats. MAIN OUTCOME MEASURES: At 1 week after surgery, expression of growth-associated protein-43, a marker of neural development and plasticity, was detected in the hippocampal CA3 region by immunohistochemistry. Brain mass was measured, and the pathological morphology was observed. At 4 weeks after surgery, behavioral changes in the remaining rats were tested by Morris water maze, and growth-associated protein-43 expression was measured. RESULTS: (1) In the GM 1 and sham operation groups, growth-associated protein-43 expression was

  1. Hypoxia inducible factor-1alpha mediates protection of DL-3-n-butylphthalide in brain microvascular endothelial cells against oxygen glucose deprivation-induced injury

    Institute of Scientific and Technical Information of China (English)

    Weihong Yang; Ling Li; Ruxun Huang; Zhong Pei; Songjie Liao; Jinsheng Zeng

    2012-01-01

    Studies have demonstrated that DL-3-n-butylphthalide can significantly alleviate oxygen glucose deprivation-induced injury of human umbilical vein endothelial cells at least partly associated with its enhancement on oxygen glucose deprivation -induced hypoxia inducible factor-1α expression. In this study, we hypothesized that DL-3-n-butylphthalide can protect against oxygen glucose deprivation-induced injury of newborn rat brain microvascular endothelial cells by means of upregulating hypoxia inducible factor-1α expression. MTT assay and Hoechst staining results showed that DL-3-n-butylphthalide protected brain microvascular endothelial cells against oxygen glucose deprivation-induced injury in a dose-dependent manner. Western blot and immunofluorescent staining results further confirmed that the protective effect was related to upregulation of hypoxia inducible factor-1α. Real-time RT-PCR reaction results showed that DL-3-n-butylphthalide reduced apoptosis by inhibiting downregulation of pro-apoptotic gene caspase-3 mRNA expression and upregulation of apoptosis-executive protease bcl-2 mRNA expression; however, DL-3-n-butylphthalide had no protective effects on brain microvascular endothelial cells after knockdown of hypoxia inducible factor-1α by small interfering RNA. These findings suggest that DL-3-n-butylphthalide can protect brain microvascular endothelial cells against oxygen glucose deprivation-induced injury by upregulating bcl-2 expression and downregulating caspase-3 expression though hypoxia inducible factor-1α pathway.

  2. Early-Onset Convulsive Seizures Induced by Brain Hypoxia-Ischemia in Aging Mice: Effects of Anticonvulsive Treatments.

    Directory of Open Access Journals (Sweden)

    Justin Wang

    Full Text Available Aging is associated with an increased risk of seizures/epilepsy. Stroke (ischemic or hemorrhagic and cardiac arrest related brain injury are two major causative factors for seizure development in this patient population. With either etiology, seizures are a poor prognostic factor. In spite of this, the underlying pathophysiology of seizure development is not well understood. In addition, a standardized treatment regimen with anticonvulsants and outcome assessments following treatment has yet to be established for these post-ischemic seizures. Previous studies have modeled post-ischemic seizures in adult rodents, but similar studies in aging/aged animals, a group that mirrors a higher risk elderly population, remain sparse. Our study therefore aimed to investigate early-onset seizures in aging animals using a hypoxia-ischemia (HI model. Male C57 black mice 18-20-month-old underwent a unilateral occlusion of the common carotid artery followed by a systemic hypoxic episode (8% O2 for 30 min. Early-onset seizures were detected using combined behavioral and electroencephalographic (EEG monitoring. Brain injury was assessed histologically at different times post HI. Convulsive seizures were observed in 65% of aging mice post-HI but not in control aging mice following either sham surgery or hypoxia alone. These seizures typically occurred within hours of HI and behaviorally consisted of jumping, fast running, barrel-rolling, and/or falling (loss of the righting reflex with limb spasms. No evident discharges during any convulsive seizures were seen on cortical-hippocampal EEG recordings. Seizure development was closely associated with acute mortality and severe brain injury on brain histological analysis. Intra-peritoneal injections of lorazepam and fosphenytoin suppressed seizures and improved survival but only when applied prior to seizure onset and not after. These findings together suggest that seizures are a major contributing factor to acute

  3. Early-Onset Convulsive Seizures Induced by Brain Hypoxia-Ischemia in Aging Mice: Effects of Anticonvulsive Treatments.

    Science.gov (United States)

    Wang, Justin; Wu, Chiping; Peng, Jessie; Patel, Nisarg; Huang, Yayi; Gao, Xiaoxing; Aljarallah, Salman; Eubanks, James H; McDonald, Robert; Zhang, Liang

    2015-01-01

    Aging is associated with an increased risk of seizures/epilepsy. Stroke (ischemic or hemorrhagic) and cardiac arrest related brain injury are two major causative factors for seizure development in this patient population. With either etiology, seizures are a poor prognostic factor. In spite of this, the underlying pathophysiology of seizure development is not well understood. In addition, a standardized treatment regimen with anticonvulsants and outcome assessments following treatment has yet to be established for these post-ischemic seizures. Previous studies have modeled post-ischemic seizures in adult rodents, but similar studies in aging/aged animals, a group that mirrors a higher risk elderly population, remain sparse. Our study therefore aimed to investigate early-onset seizures in aging animals using a hypoxia-ischemia (HI) model. Male C57 black mice 18-20-month-old underwent a unilateral occlusion of the common carotid artery followed by a systemic hypoxic episode (8% O2 for 30 min). Early-onset seizures were detected using combined behavioral and electroencephalographic (EEG) monitoring. Brain injury was assessed histologically at different times post HI. Convulsive seizures were observed in 65% of aging mice post-HI but not in control aging mice following either sham surgery or hypoxia alone. These seizures typically occurred within hours of HI and behaviorally consisted of jumping, fast running, barrel-rolling, and/or falling (loss of the righting reflex) with limb spasms. No evident discharges during any convulsive seizures were seen on cortical-hippocampal EEG recordings. Seizure development was closely associated with acute mortality and severe brain injury on brain histological analysis. Intra-peritoneal injections of lorazepam and fosphenytoin suppressed seizures and improved survival but only when applied prior to seizure onset and not after. These findings together suggest that seizures are a major contributing factor to acute mortality in aging

  4. Resveratrol Induces the Expression of Interleukin-10 and Brain-Derived Neurotrophic Factor in BV2 Microglia under Hypoxia

    Science.gov (United States)

    Song, Juhyun; Cheon, So Yeong; Jung, Wonsug; Lee, Won Taek; Lee, Jong Eun

    2014-01-01

    Microglia are the resident macrophages of the central nervous system (CNS) and play an important role in neuronal recovery by scavenging damaged neurons. However, overactivation of microglia leads to neuronal death that is associated with CNS disorders. Therefore, regulation of microglial activation has been suggested to be an important target for treatment of CNS diseases. In the present study, we investigated the beneficial effect of resveratrol, a natural phenol with antioxidant effects, in the microglial cell line, BV2, in a model of hypoxia injury. Resveratrol suppressed the mRNA expression of the pro-inflammatory molecule, tumor necrosis factor-α, and promoted the mRNA expression of the anti-inflammatory molecule, interleukin-10, in BV2 microglia under hypoxic conditions. In addition, resveratrol inhibited the activation of the transcription factor, nuclear factor kappa-light-chain enhancer of activated B cells (NF-κB), which is upstream in the control of inflammatory reactions in hypoxia-injured BV2 microglia. Moreover, resveratrol promoted the expression of brain-derived neurotrophic factor (BDNF) in BV2 microglia under hypoxic stress. Overall, resveratrol may promote the beneficial function of microglia in ischemic brain injury. PMID:25184950

  5. Resveratrol induces the expression of interleukin-10 and brain-derived neurotrophic factor in BV2 microglia under hypoxia.

    Science.gov (United States)

    Song, Juhyun; Cheon, So Yeong; Jung, Wonsug; Lee, Won Taek; Lee, Jong Eun

    2014-09-02

    Microglia are the resident macrophages of the central nervous system (CNS) and play an important role in neuronal recovery by scavenging damaged neurons. However, overactivation of microglia leads to neuronal death that is associated with CNS disorders. Therefore, regulation of microglial activation has been suggested to be an important target for treatment of CNS diseases. In the present study, we investigated the beneficial effect of resveratrol, a natural phenol with antioxidant effects, in the microglial cell line, BV2, in a model of hypoxia injury. Resveratrol suppressed the mRNA expression of the pro-inflammatory molecule, tumor necrosis factor-α, and promoted the mRNA expression of the anti-inflammatory molecule, interleukin-10, in BV2 microglia under hypoxic conditions. In addition, resveratrol inhibited the activation of the transcription factor, nuclear factor kappa-light-chain enhancer of activated B cells (NF-κB), which is upstream in the control of inflammatory reactions in hypoxia-injured BV2 microglia. Moreover, resveratrol promoted the expression of brain-derived neurotrophic factor (BDNF) in BV2 microglia under hypoxic stress. Overall, resveratrol may promote the beneficial function of microglia in ischemic brain injury.

  6. Resveratrol Induces the Expression of Interleukin-10 and Brain-Derived Neurotrophic Factor in BV2 Microglia under Hypoxia

    Directory of Open Access Journals (Sweden)

    Juhyun Song

    2014-09-01

    Full Text Available Microglia are the resident macrophages of the central nervous system (CNS and play an important role in neuronal recovery by scavenging damaged neurons. However, overactivation of microglia leads to neuronal death that is associated with CNS disorders. Therefore, regulation of microglial activation has been suggested to be an important target for treatment of CNS diseases. In the present study, we investigated the beneficial effect of resveratrol, a natural phenol with antioxidant effects, in the microglial cell line, BV2, in a model of hypoxia injury. Resveratrol suppressed the mRNA expression of the pro-inflammatory molecule, tumor necrosis factor-α, and promoted the mRNA expression of the anti-inflammatory molecule, interleukin-10, in BV2 microglia under hypoxic conditions. In addition, resveratrol inhibited the activation of the transcription factor, nuclear factor kappa-light-chain enhancer of activated B cells (NF-κB, which is upstream in the control of inflammatory reactions in hypoxia-injured BV2 microglia. Moreover, resveratrol promoted the expression of brain-derived neurotrophic factor (BDNF in BV2 microglia under hypoxic stress. Overall, resveratrol may promote the beneficial function of microglia in ischemic brain injury.

  7. Assessment of impulsivity after moderate to severe traumatic brain injury.

    Science.gov (United States)

    Rochat, Lucien; Beni, Catia; Billieux, Joël; Azouvi, Philippe; Annoni, Jean-Marie; Van der Linden, Martial

    2010-10-01

    The aim of the study was to develop and validate a short questionnaire assessing four dimensions of impulsivity (urgency, lack of premeditation, lack of perseverance, sensation seeking) in patients with traumatic brain injury (TBI). To this end, 82 patients with TBI and their caregivers completed a short questionnaire adapted from the UPPS Impulsive Behavior Scale designed to assess impulsivity changes after TBI. Confirmatory factor analyses (CFAs) performed on the version of the scale completed by the relatives revealed that a hierarchical model holding that lack of premeditation and lack of perseverance are facets of a higher order construct (lack of conscientiousness), with urgency and sensation seeking as separate correlated factors, fit the data best. Urgency, lack of premeditation, and lack of perseverance increased after the TBI, whereas sensation seeking decreased. CFA failed to reveal a satisfactory model in the version of the scale completed by the patients. The psychological processes related to these impulsivity changes and the discrepancy observed between self-report and informant-report are discussed. This short questionnaire opens up interesting prospects for better comprehension and assessment of behavioural symptoms of TBI.

  8. High-Field MRI Reveals a Drastic Increase of Hypoxia-Induced Microhemorrhages upon Tissue Reoxygenation in the Mouse Brain with Strong Predominance in the Olfactory Bulb.

    Science.gov (United States)

    Hoffmann, Angelika; Kunze, Reiner; Helluy, Xavier; Milford, David; Heiland, Sabine; Bendszus, Martin; Pham, Mirko; Marti, Hugo H

    2016-01-01

    Human pathophysiology of high altitude hypoxic brain injury is not well understood and research on the underlying mechanisms is hampered by the lack of well-characterized animal models. In this study, we explored the evolution of brain injury by magnetic resonance imaging (MRI) and histological methods in mice exposed to normobaric hypoxia at 8% oxygen for 48 hours followed by rapid reoxygenation and incubation for further 24 h under normoxic conditions. T2*-, diffusion-weighted and T2-relaxometry MRI was performed before exposure, immediately after 48 hours of hypoxia and 24 hours after reoxygenation. Cerebral microhemorrhages, previously described in humans suffering from severe high altitude cerebral edema, were also detected in mice upon hypoxia-reoxygenation with a strong region-specific clustering in the olfactory bulb, and to a lesser extent, in the basal ganglia and cerebral white matter. The number of microhemorrhages determined immediately after hypoxia was low, but strongly increased 24 hours upon onset of reoxygenation. Histologically verified microhemorrhages were exclusively located around cerebral microvessels with disrupted interendothelial tight junction protein ZO-1. In contrast, quantitative T2 and apparent-diffusion-coefficient values immediately after hypoxia and after 24 hours of reoxygenation did not show any region-specific alteration, consistent with subtle multifocal but not with regional or global brain edema.

  9. High-Field MRI Reveals a Drastic Increase of Hypoxia-Induced Microhemorrhages upon Tissue Reoxygenation in the Mouse Brain with Strong Predominance in the Olfactory Bulb.

    Directory of Open Access Journals (Sweden)

    Angelika Hoffmann

    Full Text Available Human pathophysiology of high altitude hypoxic brain injury is not well understood and research on the underlying mechanisms is hampered by the lack of well-characterized animal models. In this study, we explored the evolution of brain injury by magnetic resonance imaging (MRI and histological methods in mice exposed to normobaric hypoxia at 8% oxygen for 48 hours followed by rapid reoxygenation and incubation for further 24 h under normoxic conditions. T2*-, diffusion-weighted and T2-relaxometry MRI was performed before exposure, immediately after 48 hours of hypoxia and 24 hours after reoxygenation. Cerebral microhemorrhages, previously described in humans suffering from severe high altitude cerebral edema, were also detected in mice upon hypoxia-reoxygenation with a strong region-specific clustering in the olfactory bulb, and to a lesser extent, in the basal ganglia and cerebral white matter. The number of microhemorrhages determined immediately after hypoxia was low, but strongly increased 24 hours upon onset of reoxygenation. Histologically verified microhemorrhages were exclusively located around cerebral microvessels with disrupted interendothelial tight junction protein ZO-1. In contrast, quantitative T2 and apparent-diffusion-coefficient values immediately after hypoxia and after 24 hours of reoxygenation did not show any region-specific alteration, consistent with subtle multifocal but not with regional or global brain edema.

  10. [Study of distribution of protein of the spine apparatus synaptopodin in cortical brain parts of rats submitted to hypoxia at different periods of embryogenesis].

    Science.gov (United States)

    Vasil'ev, D S; Tumanova, N L; Zhuravin, I A

    2010-01-01

    A comparative study of the nervous tissue and distribution of the spine apparatus protein synaptopodin was performed in all layers of the brain sensorymotor cortex and hippocampal CA1 area in control rats and in the rats submitted to hypoxia at E14 and E18. It was found that beginning from the 20th day of postnatal development, in rats submitted to hypoxia both at E14 and E18 there was observed a statistically significant decrease of the mean number of labile synaptopodin-positive spines in the stratum radiatum molecular of the hippocampus area CA1. The decrease of the number of labile spines in the sensorymotor brain cortex was revealed only in the I layer beginning from the 20th day after birth in the rats submitted to hypoxia at E14. Maximal differences in the studied brain areas were observed in adult rats (exposed to hypoxia at E14: in the neocortex--a decrease by 23 +/- 10%, in hippocampus--by 24 +/- 8%, respectively). In adult animals, the increased degeneration of neuzons was not detected. It is suggested that disturbances in cognitive functions and in the capability for learning observed in rats after prenatal hypoxia can be due to a decrease of the amount of the labile synaptopodin-positive spines, which leads to a change of the structural-functional properties of neuronal networks and to a decrease of their plasticity.

  11. The effects of breathing a helium-oxygen gas mixture on maximal pulmonary ventilation and maximal oxygen consumption during exercise in acute moderate hypobaric hypoxia.

    Science.gov (United States)

    Ogawa, Takeshi; Calbet, Jose A L; Honda, Yasushi; Fujii, Naoto; Nishiyasu, Takeshi

    2010-11-01

    To test the hypothesis that maximal exercise pulmonary ventilation (VE max) is a limiting factor affecting maximal oxygen uptake (VO2 max) in moderate hypobaric hypoxia (H), we examined the effect of breathing a helium-oxygen gas mixture (He-O(2); 20.9% O(2)), which would reduce air density and would be expected to increase VE max. Fourteen healthy young male subjects performed incremental treadmill running tests to exhaustion in normobaric normoxia (N; sea level) and in H (atmospheric pressure equivalent to 2,500 m above sea level). These exercise tests were carried out under three conditions [H with He-O(2), H with normal air and N] in random order. VO2 max and arterial oxy-hemoglobin saturation (SaO(2)) were, respectively, 15.2, 7.5 and 4.0% higher (all p max, 171.9 ± 16.1 vs. 150.1 ± 16.9 L/min; VO2 max, 52.50 ± 9.13 vs. 48.72 ± 5.35 mL/kg/min; arterial oxyhemoglobin saturation (SaO(2)), 79 ± 3 vs. 76 ± 3%). There was a linear relationship between the increment in VE max and the increment in VO2 max in H (r = 0.77; p VO2 max, both groups showed increased VE max and SaO(2) in H with He-O(2), but VO2 max was increased only in the high VO2 max group. These findings suggest that in acute moderate hypobaric hypoxia, air-flow resistance can be a limiting factor affecting VE max; consequently, VO2 max is limited in part by VE max especially in subjects with high VO2 max.

  12. Brain injury after moderate drowning: subtle alterations detected by functional magnetic resonance imaging.

    Science.gov (United States)

    Nucci, Mariana P; Lukasova, Katerina; Sato, João R; Amaro, Edson

    2016-10-12

    To describe cerebral (structural and functional MRI) and neuropsychological long term changes in moderate drowning victim's compared to healthy volunteers in working memory and motor domains. We studied 15 adult drowning victim's in chronic stage (DV - out of 157 eligible cases of sea water rescues with moderate drowning classification) paired to 18 healthy controls (HC). All participants were investigated using intelligence, memory, and attention neuropsychological standard tests and underwent functional (motor and working memory tasks) and structural magnetic resonance imaging (MRI) in a 3 T system. All images were preprocessed for head movement correction and quantitative analysis was performed using FSL and freesurfer software packages. We found no between group differences in neuropsychological assessments. No MRI brain lesion was observed in patients, neither difference on morphometric parameters in any cortical or subcortical brain structure. In constrast, functional MRI revealed that patients showed increased brain response in the motor (left putamen and insula) and memory (left cuneus and lingual gyrus - not the classical memory network) tasks. Functional brain changes in motor and visual brain regions in victims of moderate drowning may indicate reduced brain reserve, despite the lack of structural and behavior alterations. More attention should be given to investigate ageing effects in this nonfatal drowning group.

  13. Expression of c-jun in brain stem following moderate lateral fluid percussion brain injury in rats

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    AIM: To study the expression of c-jun in brain stem following moderate lateral fluid percussion brain injury in rats, and to observe the temporal patterns of its expressions following percussion.METHODS: Male Sprague-Dawley rats were divided into normal control, sham operation control and injury groups. The rats of injury group subjected to moderate lateral fluid percussion injury (0.2 mPa), and then were subdivided into 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 8 h and 12 h groups according to the time elapsed after injury. The expression of c-jun was studied by immunohistochemistry and in situ hybridization. RESULTS: After percussion for 15 min, Jun positive neurons increased in brain stem progressively, and peaked at 12h. At 5min after percussion, the induction of c-jun mRNA was increased, and remained elevated up to 1h-2h after brain injury. CONCLUSION: The induction and expression of the c-jun in brain stem after fluid percussion brain injury were increased rapidly and lasted for a long time.

  14. Statistical analysis plan for the Erythropoietin in Traumatic Brain Injury trial: a randomised controlled trial of erythropoietin versus placebo in moderate and severe traumatic brain injury.

    LENUS (Irish Health Repository)

    Presneill, Jeffrey

    2014-01-01

    The Erythropoietin in Traumatic Brain Injury (EPO-TBI) trial aims to determine whether the administration of erythropoietin to patients with moderate or severe traumatic brain injury improves patient-centred outcomes.

  15. Changes in brain iron concentration after exposure to high-altitude hypoxia measured by quantitative susceptibility mapping.

    Science.gov (United States)

    Chen, Lin; Cai, Congbo; Yang, Tianhe; Lin, Jianzhong; Cai, Shuhui; Zhang, Jiaxing; Chen, Zhong

    2017-02-15

    Hypoxia can induce physiological changes. This study aims to explore effects of high-altitude (HA) hypoxia on cerebral iron concentration. Twenty-nine healthy sea-level participants were tested shortly before and after approximately 4-week adaptation to the HA environment at fQinghai-Tibet Plateau (4200m), and were re-investigated after re-adaptation to the sea-level environment one year later. Iron concentration was quantified with quantitative susceptibility mapping (QSM), and the results were compared with transverse relaxation rate (R(*)2) measurements. The variations of magnetic susceptibility indicate that the iron concentration in gray matter regions, especially in basal ganglia, including caudate nucleus, putamen, globus pallidus and substantia nigra, increases significantly after HA exposure. This increase appears consistent with the conclusion from R(*)2 value variations. However, unlike QSM, the R(*)2 value fails to demonstrate the statistical difference of iron content in red nucleus. The re-investigation results show that most variations are recovered after sea-level re-adaptation for one year. Additionally, hemisphere- and gender-related differences in iron concentration changes were analyzed among cerebral regions. The results show greater possibilities in the right hemisphere and females. Further studies based on diffusion tensor imaging (DTI) suggest that the fractional anisotropy increases and the mean diffusivity decreases after HA exposure in six deep gray matter nuclei, with linear dependence on iron concentration only in putamen. In conclusion, the magnetic susceptibility value can serve as a quantitative marker of brain iron, and variations of regional susceptibility reported herein indicate that HA hypoxia can result in significant iron deposition in most deep gray matter regions. Additionally, the linear dependence of DTI metrics on iron concentration in putamen indicates a potential relationship between ferritin and water diffusion.

  16. Cognitive deficits in patients with mild to moderate traumatic brain injury

    Directory of Open Access Journals (Sweden)

    Eliane Correa Miotto

    2010-12-01

    Full Text Available Traumatic brain injury (TBI is one of the most frequent causes of brain damage. Cognitive deficits reported in the literature after moderate to severe TBI include memory, language, executive functions, attention and information processing speed impairments. However, systematic studies on patients with mild TBI are scarce although neuropsychological changes are present. OBJECTIVE: To investigate the cognitive functioning of patients with mild to moderate TBI. METHOD: We evaluated 12 patients with mild to moderate TBI using a comprehensive protocol (PN01 of neuropsychological tests. RESULTS: There were significant deficits of episodic memory including immediate and delayed verbal memory recall, verbal recognition, immediate and delayed visual memory recall, naming, verbal fluency and information processing speed. CONCLUSION: These results emphasize the importance of comprehensive neuropsychological assessments even in cases of mild TBI in order to identify impaired and preserved functions providing adequate managing including rehabilitation programs for each case.

  17. Hypoxia-ischemia or excitotoxin-induced tissue plasminogen activator- dependent gelatinase activation in mice neonate brain microvessels.

    Directory of Open Access Journals (Sweden)

    Priscilla L Omouendze

    Full Text Available Hypoxia-ischemia (HI and excitotoxicity are validated causes of neonatal brain injuries and tissue plasminogen activator (t-PA participates in the processes through proteolytic and receptor-mediated pathways. Brain microvascular endothelial cells from neonates in culture, contain and release more t-PA and gelatinases upon glutamate challenge than adult cells. We have studied t-PA to gelatinase (MMP-2 and MMP-9 activity links in HI and excitotoxicity lesion models in 5 day-old pups in wild type and in t-PA or its inhibitor (PAI-1 genes inactivated mice. Gelatinolytic activities were detected in SDS-PAGE zymograms and by in situ fluorescent DQ-gelatin microscopic zymographies. HI was achieved by unilateral carotid ligature followed by a 40 min hypoxia (8%O₂. Excitotoxic lesions were produced by intra parenchymal cortical (i.c. injections of 10 µg ibotenate (Ibo. Gel zymograms in WT cortex revealed progressive extinction of MMP-2 and MMP-9 activities near day 15 or day 8 respectively. MMP-2 expression was the same in all strains while MMP-9 activity was barely detectable in t-PA⁻/⁻ and enhanced in PAI-1⁻/⁻ mice. HI or Ibo produced activation of MMP-2 activities 6 hours post-insult, in cortices of WT mice but not in t-PA⁻/⁻ mice. In PAI-1⁻/⁻ mice, HI or vehicle i.c. injection increased MMP-2 and MMP-9 activities. In situ zymograms using DQ-gelatin revealed vessel associated gelatinolytic activity in lesioned areas in PAI-1⁻/⁻ and in WT mice. In WT brain slices incubated ex vivo, glutamate (200 µM induced DQ-gelatin activation in vessels. The effect was not detected in t-PA⁻/⁻ mice, but was restored by concomitant exposure to recombinant t-PA (20 µg/mL. In summary, neonatal brain lesion paradigms and ex vivo excitotoxic glutamate evoked t-PA-dependent gelatinases activation in vessels. Both MMP-2 and MMP-9 activities appeared t-PA-dependent. The data suggest that vascular directed protease inhibition may have

  18. Hypoxia-ischemia or excitotoxin-induced tissue plasminogen activator- dependent gelatinase activation in mice neonate brain microvessels.

    Science.gov (United States)

    Omouendze, Priscilla L; Henry, Vincent J; Porte, Baptiste; Dupré, Nicolas; Carmeliet, Peter; Gonzalez, Bruno J; Marret, Stéphane; Leroux, Philippe

    2013-01-01

    Hypoxia-ischemia (HI) and excitotoxicity are validated causes of neonatal brain injuries and tissue plasminogen activator (t-PA) participates in the processes through proteolytic and receptor-mediated pathways. Brain microvascular endothelial cells from neonates in culture, contain and release more t-PA and gelatinases upon glutamate challenge than adult cells. We have studied t-PA to gelatinase (MMP-2 and MMP-9) activity links in HI and excitotoxicity lesion models in 5 day-old pups in wild type and in t-PA or its inhibitor (PAI-1) genes inactivated mice. Gelatinolytic activities were detected in SDS-PAGE zymograms and by in situ fluorescent DQ-gelatin microscopic zymographies. HI was achieved by unilateral carotid ligature followed by a 40 min hypoxia (8%O₂). Excitotoxic lesions were produced by intra parenchymal cortical (i.c.) injections of 10 µg ibotenate (Ibo). Gel zymograms in WT cortex revealed progressive extinction of MMP-2 and MMP-9 activities near day 15 or day 8 respectively. MMP-2 expression was the same in all strains while MMP-9 activity was barely detectable in t-PA⁻/⁻ and enhanced in PAI-1⁻/⁻ mice. HI or Ibo produced activation of MMP-2 activities 6 hours post-insult, in cortices of WT mice but not in t-PA⁻/⁻ mice. In PAI-1⁻/⁻ mice, HI or vehicle i.c. injection increased MMP-2 and MMP-9 activities. In situ zymograms using DQ-gelatin revealed vessel associated gelatinolytic activity in lesioned areas in PAI-1⁻/⁻ and in WT mice. In WT brain slices incubated ex vivo, glutamate (200 µM) induced DQ-gelatin activation in vessels. The effect was not detected in t-PA⁻/⁻ mice, but was restored by concomitant exposure to recombinant t-PA (20 µg/mL). In summary, neonatal brain lesion paradigms and ex vivo excitotoxic glutamate evoked t-PA-dependent gelatinases activation in vessels. Both MMP-2 and MMP-9 activities appeared t-PA-dependent. The data suggest that vascular directed protease inhibition may have neuroprotection

  19. Chronic intermittent hypoxia-induced deficits in synaptic plasticity and neurocognitive functions: a role for brain-derived neurotrophic factor

    Institute of Scientific and Technical Information of China (English)

    Hui XIE; Wing-ho YUNG

    2012-01-01

    Obstructive sleep apnea (OSA) is well known for its metabolic as well as neurobehavioral consequences.Chronic intermittent hypoxia (IH) is a major component of OSA.In recent years,substantial advances have been made in elucidating the cellular and molecular mechanisms underlying the effect of chronic IH on neurocognitive functions,many of which are based on studies in animal models.A number of hypotheses have been put forward to explain chronic IH-induced neurological dysfunctions.Among these,the roles of oxidative stress and apoptosis-related neural injury are widely accepted.Here,focusing on results derived from animal studies,we highlight a possible role of reduced expression of brain-derived neurotrophic factor (BDNF) in causing impairment in long-term synaptic plasticity and neurocognitive functions during chronic IH.The possible relationship between BDNF and previous findings on this subject will be elucidated.

  20. 慢性亚致死性缺氧对未成熟脑结构和发育的影响%Chronic sublethal hypoxia: challenge to premature brain in structual and neurological development

    Institute of Scientific and Technical Information of China (English)

    平莉莉; 蒋泽栋

    2010-01-01

    With the advance of modern neonatal management, the increase of survival of infants born with ELBW has resulted in collateral increase in incidence of infants with serious chronic lung disease, typically brnchopulmonary dysplasia (BPD). Long-term sensory, motor and cognitive impairments are common outcomes in survivals with moderate and severe BPD and may persist during school years and adolescence. Increasing evidence suggest that BPD exerts a significant effect on brain growth and development and may be associated with chronic sublethal hypoxia which compond the risk of extended brain injury and NS complications such as cerebral palsy. Animal studies have demonstrated progressive gliosis and cerebral ventriculomegaly, injured subcortical white matter and corpus callosum, dysynchrony synaptic development and disrupted neurotransmitssion in the hypoxia newborn brain. In this literature we built upon the review of neurogical and congnitive outcome in preterm infants with BPD and structural, functional and neurochemical alterations in ainimals following clinical and experimental hypoxia respectively, which may underlie the primary or potential mle for chronic sublethal hypoxia on premature brain development.%现代新生儿学的发展促使极低体质量早产儿的存活率显著提高,同时严重慢性肺部疾病患儿增多,特别是支气管肺发育不良(BPD).中重度BPD患儿多数有远期感觉、运动和认知缺陷.有些功能缺陷可能发展至学龄期或成年甚至持续终生.越来越多的临床数据表明BPD显著影响新生儿脑生长和发育,其病程中伴随的慢性亚致死性缺氧是引起极低体质量早产儿远期脑损伤和脑瘫等神经系统并发症的重要因素之一.动物研究发现慢性缺氧导致新生鼠脑皮层下和胼胝体白质损伤、进行性脑室扩大和胶质增生,突触发育前后失衡及神经递质传导障碍,从而可能显著影响感觉、运动及认知等脑功能发育.

  1. Early environmental enrichment affects neurobehavioral development and prevents brain damage in rats submitted to neonatal hypoxia-ischemia.

    Science.gov (United States)

    Schuch, Clarissa Pedrini; Diaz, Ramiro; Deckmann, Iohanna; Rojas, Joseane Jiménez; Deniz, Bruna Ferrary; Pereira, Lenir Orlandi

    2016-03-23

    Our previous results demonstrated improved cognition in adolescent rats housed in environmental enrichment (EE) that underwent neonatal hypoxia-ischemia (HI). The aim of this study was to investigate the effects of early EE on neurobehavioral development and brain damage in rats submitted to neonatal HI. Wistar rats were submitted to the HI procedure on the 7th postnatal day (PND) and housed in an enriched environment (8th-20th PND). The maturation of physical characteristics and the neurological reflexes were evaluated and the volume of striatum, corpus callosum and neocortex was measured. Data analysis demonstrated a clear effect of EE on neurobehavioral development; also, daily performance was improved in enriched rats on righting, negative geotaxis and cliff aversion reflex. HI caused a transient motor deficit on gait latency. Brain atrophy was found in HI animals and this damage was partially prevented by the EE. In conclusion, early EE stimulated neurobehavioral development in neonate rats and also protects the neocortex and the corpus callosum from atrophy following HI. These findings reinforce the potential of EE as a strategy for rehabilitation following neonatal HI and provide scientific support to the use of this therapeutic strategy in the treatment of neonatal brain injuries in humans.

  2. Assessing the relationship between neurocognitive performance and brain volume in chronic moderate-severe traumatic brain injury

    Directory of Open Access Journals (Sweden)

    Nikos eKonstantinou

    2016-03-01

    Full Text Available Objectives. Characterize the scale and pattern of long-term atrophy in grey matter (GM, white matter (WM and cerebrospinal (CSF in chronic moderate-severe traumatic brain injury (TBI and its relationship to neurocognitive outcomes.Participants. The TBI group consisted of 17 males with primary diagnosis of moderate-severe closed head injury. Participants had not received any systematic, post-acute rehabilitation and were recruited on average 8.36 years post-injury. The control group consisted of 15 males matched on age and education.Main measures. Neurocognitive battery included widely used tests of verbal memory, visual memory, executive functioning, and attention/organization. GM,WM, and CSF volumes were calculated from segmented T1-weighted anatomical MR images. Voxel-based morphometry was employed to identify brain regions with differences in GM and WM between TBI and control groups.Results. Chronic TBI results in significant neurocognitive impairments, and significant loss of GM and WM volume, and significant increase in CSF volume. Brain atrophy is not widespread, but it is rather distributed in a fronto-thalamic network. The extent of volume loss is predictive of performance on the neurocognitive tests.Conclusion. Significant brain atrophy and associated neurocognitive impairments during the chronic stages of TBI support the notion that TBI results in a chronic condition with lifelong implications.

  3. Neither moderate hypoxia nor mild hypoglycaemia alone causes any significant increase in cerebral [Ca2+]i: only a combination of the two insults has this effect. A 31P and 19F NMR study.

    Science.gov (United States)

    Badar-Goffer, R S; Thatcher, N M; Morris, P G; Bachelard, H S

    1993-12-01

    (1) The energy state and free intracellular calcium concentration ([Ca2+]i) of superfused cortical slices were measured in moderate hypoxia (approximately 65 microM O2), in mild hypoglycaemia (0.5 mM glucose), and in combinations of the two insults using 19F and 31P NMR spectroscopy. (2) Neither hypoxia nor hypoglycaemia alone caused any significant change in [Ca2+]i. Hypoxia caused a 40% fall in phosphocreatine (PCr) content but not in ATP level, and hypoglycaemia produced a slight fall in both (as expected from previous studies). These changes in the energy state recovered on return to control conditions. (3) A combined sequential insult (hypoxia, followed by hypoxia plus hypoglycaemia) produced a 100% increase in [Ca2+]i and a decrease in PCr level to approximately 25% of control. The reverse combined sequential insult (hypoglycaemia, followed by hypoglycaemia plus hypoxia) had the same effect. On return to control conditions there was some decrease in [Ca2+]i and a small increase in PCr content, but neither recovered to control levels. (4) Exposure of the tissue to the combined simultaneous insult (hypoxia plus hypoglycaemia) immediately after the control spectra had been recorded resulted in a fivefold increase in [Ca2+]i and a similar decrease in PCr level to 20-25% of control. There was little if any change of [Ca2+]i or PCr level on return to control conditions. (5) These results are discussed in terms of metabolic adaptation of some but not all of the cortical cells to the single type of insult, which renders the tissues less vulnerable to the combined insult.

  4. A History of Mild Traumatic Brain Injury affects Peripheral Pulse Oximetry during Normobaric Hypoxia

    Directory of Open Access Journals (Sweden)

    Leonard Temme

    2016-09-01

    Full Text Available Introduction: Physiological and emotional stressors increase symptoms of concussion in recently injured individuals and both forms of stress induce symptoms in people recovering from mild traumatic brain injury (mTBI but who are asymptomatic when not stressed or are at rest. Methods: Healthy asymptomatic adults (25.0 ± 5.1 years with a history of mTBI (n = 36 and matched healthy controls (n = 36 with no mTBI history were exposed to three levels of normobaric hypoxic stress generated with the Reduced Oxygen Breathing Device (ROBD (Environics, Inc., Tollande, CT, which reduced the percent oxygen by mixing sea level air with nitrogen. The ROBD reduced the percent oxygen in the breathable air from the normal 21% to 15.5% O2, 14% O2, and 13% O2. Under these conditions: (a a standard pulse oximeter recorded peripheral oxygen saturation (SpO2 and pulse rate (beats per minute, and (b the FIT (PMI, Inc., Rockville, MD recorded saccadic velocity and pupillary response dynamics to a brief light flash. Results: For all three hypoxic stress conditions the mTBI group had significantly higher SpO2 during the final minute of exposure than did the controls F(2.17,151.8 = 5.29, p < .001, η2 = .852 and the rate of SpO2 change over time was significantly shallower for the mTBI than for the controls F(2.3,161.3 = 2.863, p < .001, η2 = .569, Greenhouse-Geisser corrected. Overall, mTBI had lower pulse rate but the difference was only significant for the 14% O2 condition. FIT oculomotor measures were not sensitive to group differences. When exposed to mild or moderate normobaric hypoxic stress (15% O2: (1 SpO2 differences emerged between the mTBI and matched healthy controls, (2 heart rate trended lower in the mTBI group, and (3 FIT measures were not sensitive to group differences. Conclusion: A relatively minor hypoxic challenge can reveal measurable differences in SpO2 and heart rate in otherwise asymptomatic individuals with a history of mTBI.

  5. Mesenchymal stem cells induce T-cell tolerance and protect the preterm brain after global hypoxia-ischemia.

    Directory of Open Access Journals (Sweden)

    Reint K Jellema

    Full Text Available Hypoxic-ischemic encephalopathy (HIE in preterm infants is a severe disease for which no curative treatment is available. Cerebral inflammation and invasion of activated peripheral immune cells have been shown to play a pivotal role in the etiology of white matter injury, which is the clinical hallmark of HIE in preterm infants. The objective of this study was to assess the neuroprotective and anti-inflammatory effects of intravenously delivered mesenchymal stem cells (MSC in an ovine model of HIE. In this translational animal model, global hypoxia-ischemia (HI was induced in instrumented preterm sheep by transient umbilical cord occlusion, which closely mimics the clinical insult. Intravenous administration of 2 x 10(6 MSC/kg reduced microglial proliferation, diminished loss of oligodendrocytes and reduced demyelination, as determined by histology and Diffusion Tensor Imaging (DTI, in the preterm brain after global HI. These anti-inflammatory and neuroprotective effects of MSC were paralleled by reduced electrographic seizure activity in the ischemic preterm brain. Furthermore, we showed that MSC induced persistent peripheral T-cell tolerance in vivo and reduced invasion of T-cells into the preterm brain following global HI. These findings show in a preclinical animal model that intravenously administered MSC reduced cerebral inflammation, protected against white matter injury and established functional improvement in the preterm brain following global HI. Moreover, we provide evidence that induction of T-cell tolerance by MSC might play an important role in the neuroprotective effects of MSC in HIE. This is the first study to describe a marked neuroprotective effect of MSC in a translational animal model of HIE.

  6. High-altitude hypoxia induces disorders of the brain-endocrine-immune network through activation of corticotropin-releasing factor and its type-1 receptors

    Institute of Scientific and Technical Information of China (English)

    Xue-qun CHEN; Fan-ping KONG; Yang ZHAO; Ji-zeng DU

    2012-01-01

    High-altitude hypoxia can induce physiological dysfunction and mountain sickness,but the underlying mechanism is not fully understood.Corticotrophin-releasing factor (CRF) and CRF type-1 receptors (CRFR1) are members of the CRF family and the essential controllers of the physiological activity of the hypothalamo-pituitary-adrenal (HPA) axis and modulators of endocrine and behavioral activity in response to various stressors.We have previously found that high-altitude hypoxia induces disorders of the brain-endocrine-immune network through activation of CRF and CRFR1 in the brain and periphery that include activation of the HPA axis in a time-and dose-dependent manner,impaired or improved learning and memory,and anxiety-like behavioral change.Meanwhile,hypoxia induces dysfunctions of the hypothalamo-pituitary-endocrine and immune systems,including suppression of growth and development,as well as inhibition of reproductive,metabolic and immune functions.In contrast,the small mammals that live on the Qinghai-Tibet Plateau alpine meadow display low responsiveness to extreme high-altitudehypoxia challenge,suggesting well-acclimatized genes and a physiological strategy that developed during evolution through interact-ions between the genes and environment.All the findings provide evidence for understanding the neuroendocrine mechanisms of hypoxia-induced physiological dysfunction.This review extends these findings.

  7. Region-specific effects on brain metabolites of hypoxia and hyperoxia overlaid on cerebral ischemia in young and old rats: a quantitative proton magnetic resonance spectroscopy study

    Directory of Open Access Journals (Sweden)

    Giuliani Patricia

    2010-02-01

    Full Text Available Abstract Background Both hypoxia and hyperoxia, deregulating the oxidative balance, may play a role in the pathology of neurodegenerative disorders underlain by cerebral ischemia. In the present study, quantitative proton magnetic resonance spectroscopy was used to evaluate regional metabolic alterations, following a 24-hour hypoxic or hyperoxic exposure on the background of ischemic brain insult, in two contrasting age-groups of rats: young - 3 months old and aged - 24 months old. Methods Cerebral ischemia was induced by ligation of the right common carotid artery. Concentrations of eight metabolites (alanine, choline-containing compounds, total creatine, γ-aminobutyric acid, glutamate, lactate, myo-inositol and N-acetylaspartate were quantified from extracts in three different brain regions (fronto-parietal and occipital cortices and the hippocampus from both hemispheres. Results In the control normoxic condition, there were significant increases in lactate and myo-inositol concentrations in the hippocampus of the aged rats, compared with the respective values in the young ones. In the ischemia-hypoxia condition, the most prevalent changes in the brain metabolites were found in the hippocampal regions of both young and aged rats; but the effects were more evident in the aged animals. The ischemia-hyperoxia procedure caused less dedicated changes in the brain metabolites, which may reflect more limited tissue damage. Conclusions We conclude that the hippocampus turns out to be particularly susceptible to hypoxia overlaid on cerebral ischemia and that old age further increases this susceptibility.

  8. Nitric oxide synthase activity and inhibition after neonatal hypoxia ischemia in the mouse brain.

    Science.gov (United States)

    Muramatsu, K; Sheldon, R A; Black, S M; Täuber, M; Ferriero, D M

    2000-10-28

    Despite the emergence of therapies for hypoxic-ischemic injury to the mature nervous system, there have been no proven efficacious therapies for the developing nervous system. Recent studies have shown that pharmacological blockade of neuronal nitric oxide synthase (nNOS) activity can ameliorate damage after ischemia in the mature rodent. We have previously shown that elimination of nNOS neurons, either by targeted disruption of the gene or by pharmacological depletion with intraparenchymal quisqualate, can decrease injury after hypoxia-ischemia. Using a simpler pharmacological approach, we studied the efficacy of a systemically administered NOS inhibitor, 7-nitroindazole, a relatively selective inhibitor of nNOS activity. Using multiple doses and concentrations administered after the insult, we found that there was only a trend for protection with higher doses of the drug. A significant decrease in NOS activity was seen at 18 h and 5 days in the cortex, and at 2 h and 18 h in the hippocampus after the hypoxia-ischemia. nNOS expression decreased and remained depressed for at least 18 h after the insult. When nNOS expression was normalized to MAP2 expression, a decrease was seen at 18 h in the cortex and at 2 and 18 h in the hippocampus. These data suggest that further inhibition of NOS activity at early timepoints may not provide substantial benefit. At 5 days after the insult, however, NOS activity and normalized nNOS expression returned to baseline or higher in the hippocampus, the region showing the most damage. These data suggest that delayed administration of nNOS inhibitor after hypoxic-ischemic injury might be beneficial.

  9. Disrupted small-world brain networks in moderate Alzheimer's disease: a resting-state FMRI study.

    Directory of Open Access Journals (Sweden)

    Xiaohu Zhao

    Full Text Available The small-world organization has been hypothesized to reflect a balance between local processing and global integration in the human brain. Previous multimodal imaging studies have consistently demonstrated that the topological architecture of the brain network is disrupted in Alzheimer's disease (AD. However, these studies have reported inconsistent results regarding the topological properties of brain alterations in AD. One potential explanation for these inconsistent results lies with the diverse homogeneity and distinct progressive stages of the AD involved in these studies, which are thought to be critical factors that might affect the results. We investigated the topological properties of brain functional networks derived from resting functional magnetic resonance imaging (fMRI of carefully selected moderate AD patients and normal controls (NCs. Our results showed that the topological properties were found to be disrupted in AD patients, which showing increased local efficiency but decreased global efficiency. We found that the altered brain regions are mainly located in the default mode network, the temporal lobe and certain subcortical regions that are closely associated with the neuropathological changes in AD. Of note, our exploratory study revealed that the ApoE genotype modulates brain network properties, especially in AD patients.

  10. Gender differences in self reported long term outcomes following moderate to severe traumatic brain injury

    Directory of Open Access Journals (Sweden)

    Ratcliff Graham

    2010-10-01

    Full Text Available Abstract Background The majority of research on health outcomes after a traumatic brain injury is focused on male participants. Information examining gender differences in health outcomes post traumatic brain injury is limited. The purpose of this study was to investigate gender differences in symptoms reported after a traumatic brain injury and to examine the degree to which these symptoms are problematic in daily functioning. Methods This is a secondary data analysis of a retrospective cohort study of 306 individuals who sustained a moderate to severe traumatic brain injury 8 to 24 years ago. Data were collected using the Problem Checklist (PCL from the Head Injury Family Interview (HIFI. Using Bonferroni correction, group differences between women and men were explored using Chi-square and Wilcoxon analysis. Results Chi-square analysis by gender revealed that significantly more men reported difficulty setting realistic goals and restlessness whereas significantly more women reported headaches, dizziness and loss of confidence. Wilcoxon analysis by gender revealed that men reported sensitivity to noise and sleep disturbances as significantly more problematic than women, whereas for women, lack of initiative and needing supervision were significantly more problematic in daily functioning. Conclusion This study provides insight into gender differences on outcomes after traumatic brain injury. There are significant differences between problems reported by men compared to women. This insight may facilitate health service planners and clinicians when developing programs for individuals with brain injury.

  11. Whole-brain proton MR spectroscopic imaging of mild-to-moderate traumatic brain injury and correlation with neuropsychological deficits.

    Science.gov (United States)

    Govind, Varan; Gold, Stuart; Kaliannan, Krithica; Saigal, Gaurav; Falcone, Steven; Arheart, Kristopher L; Harris, Leo; Jagid, Jonathan; Maudsley, Andrew A

    2010-03-01

    Changes in the distribution of the magnetic resonance (MR)-observable brain metabolites N-acetyl aspartate (NAA), total choline (Cho), and total creatine (Cre), following mild-to-moderate closed-head traumatic brain injury (mTBI) were evaluated using volumetric proton MR spectroscopic imaging (MRSI). Studies were carried out during the subacute time period following injury, and associations of metabolite indices with neuropsychological test (NPT) results were evaluated. Twenty-nine subjects with mTBI and Glasgow Coma Scale (GCS) scores of 10-15 were included. Differences in individual metabolite and metabolite ratio distributions relative to those of age-matched control subjects were evaluated, as well as analyses by hemispheric lobes and tissue types. Primary findings included a widespread decrease of NAA and NAA/Cre, and increases of Cho and Cho/NAA, within all lobes of the TBI subject group, and with the largest differences seen in white matter. Examination of the association between all of the metabolite measures and the NPT scores found the strongest negative correlations to occur in the frontal lobe and for Cho/NAA. No significant correlations were found between any of the MRSI or NPT measures and the GCS. These results demonstrate that significant and widespread alterations of brain metabolites occur as a result of mild-to-moderate TBI, and that these measures correlate with measures of cognitive performance.

  12. The family environment as a moderator of psychosocial outcomes following traumatic brain injury in young children.

    Science.gov (United States)

    Yeates, Keith Owen; Taylor, H Gerry; Walz, Nicolay Chertkoff; Stancin, Terry; Wade, Shari L

    2010-05-01

    This study sought to determine whether the family environment moderates psychosocial outcomes after traumatic brain injury (TBI) in young children. Participants were recruited prospectively from consecutive hospital admissions of 3- to 6-year-old children, and included 19 with severe TBI, 56 with complicated mild/moderate TBI, and 99 with orthopedic injuries (OI). They completed 4 assessments across the first 18 months postinjury. The initial assessment included measures of parenting style, family functioning, and the quality of the home. Children's behavioral adjustment, adaptive functioning, and social competence were assessed at each occasion. Mixed model analyses examined the relationship of the family environment to psychosocial outcomes across time. The OI and TBI groups differed significantly in social competence, but the family environment did not moderate the group difference, which was of medium magnitude. In contrast, group differences in behavioral adjustment became more pronounced across time at high levels of authoritarian and permissive parenting; among children with severe TBI, however, even those with low levels of permissive parenting showed increases in behavioral problems. For adaptive functioning, better home environments provided some protection following TBI, but not over time for the severe TBI group. These 3-way interactions of group, family environment, and time postinjury were all of medium magnitude. The findings indicate that the family environment moderates the psychosocial outcomes of TBI in young children, but the moderating influence may wane with time among children with severe TBI.

  13. Recovery of energy metabolism in rat brain after carbon monoxide hypoxia.

    OpenAIRE

    Brown, S D; Piantadosi, C. A.

    1992-01-01

    Carbon monoxide (CO) may inhibit mitochondrial electron transport in the brain and increase the toxic effects of the gas. This hypothesis was investigated in anesthetized rats during CO exposure and recovery at either normobaric or hyperbaric O2 concentrations. During exposure and recovery, we measured the oxidation level of cerebrocortical cytochrome c oxidase by differential spectroscopy and biochemical metabolites known to reflect aerobic energy provision in the brain. CO exposure (HbCO = ...

  14. Post-traumatic hypoxia is associated with prolonged cerebral cytokine production, higher serum biomarker levels, and poor outcome in patients with severe traumatic brain injury.

    Science.gov (United States)

    Yan, Edwin B; Satgunaseelan, Laveniya; Paul, Eldho; Bye, Nicole; Nguyen, Phuong; Agyapomaa, Doreen; Kossmann, Thomas; Rosenfeld, Jeffrey V; Morganti-Kossmann, Maria Cristina

    2014-04-01

    Secondary hypoxia is a known contributor to adverse outcomes in patients with traumatic brain injury (TBI). Based on the evidence that hypoxia and TBI in isolation induce neuroinflammation, we investigated whether TBI combined with hypoxia enhances cerebral cytokine production. We also explored whether increased concentrations of injury biomarkers discriminate between hypoxic (Hx) and normoxic (Nx) patients, correlate to worse outcome, and depend on blood-brain barrier (BBB) dysfunction. Forty-two TBI patients with Glasgow Coma Scale ≤8 were recruited. Cerebrospinal fluid (CSF) and serum were collected over 6 days. Patients were divided into Hx (n=22) and Nx (n=20) groups. Eight cytokines were measured in the CSF; albumin, S100, myelin basic protein (MBP) and neuronal specific enolase (NSE) were quantified in serum. CSF/serum albumin quotient was calculated for BBB function. Glasgow Outcome Scale Extended (GOSE) was assessed at 6 months post-TBI. Production of granulocye macrophage-colony stimulating factor (GM-CSF) was higher, and profiles of GM-CSF, interferon (IFN)-γ and, to a lesser extent, tumor necrosis factor (TNF), were prolonged in the CSF of Hx but not Nx patients at 4-5 days post-TBI. Interleukin (IL)-2, IL-4, IL-6, and IL-10 increased similarly in both Hx and Nx groups. S100, MBP, and NSE were significantly higher in Hx patients with unfavorable outcome. Among these three biomarkers, S100 showed the strongest correlations to GOSE after TBI-Hx. Elevated CSF/serum albumin quotients lasted for 5 days post-TBI and displayed similar profiles in Hx and Nx patients. We demonstrate for the first time that post-TBI hypoxia is associated with prolonged neuroinflammation, amplified extravasation of biomarkers, and poor outcome. S100 and MBP could be implemented to track the occurrence of post-TBI hypoxia, and prompt adequate treatment.

  15. The role of ceramides in selected brain pathologies: ischemia/hypoxia, Alzheimer disease

    Directory of Open Access Journals (Sweden)

    Halina Car

    2012-05-01

    Full Text Available  Ceramides, members of the sphingolipids, are produced in the central nervous system by de novo synthesis, sphingomyelin hydrolysis or the so-called salvage pathway. They are engaged in formation of lipid rafts that are essential in regulation and transduction of signals coming to the cell from the environment. Ceramides represent the major transmitters of the sphingomyelin pathway of signal transduction. They regulate proliferation, differentiation, programmed cell death and senescence. Ceramide overexpression, mainly as a result of sphingomyelin hydrolysis, is a component of brain damage caused by ischemia and early reperfusion. Their high concentrations induce mitochondria-dependent neuronal apoptosis, exacerbate the synthesis of reactive oxygen species, decrease ATP level, inhibit electron transport and release cytochrome c, and activate caspase-3. Reduced ceramide accumulation in the brain, dependent mainly on ceramide synthesized de novo, may exert an anti-apoptotic effect after pre-conditioning. The increase of ceramide content in the brain was observed in Alzheimer disease and its animal models. Enhanced ceramide concentration in this pathology is an effect of their synthesis de novo or sphingomyelin metabolism augmentation. The ceramide pathway can directly stimulate biochemical changes in the brain noted at the onset of disease: tau overphosphorylation and β-amyloid peptide accumulation. The higher concentration of ceramides in blood in the pre-clinical phase of the illness may mark early brain changes.

  16. [The role of ceramides in selected brain pathologies: ischemia/hypoxia, Alzheimer disease].

    Science.gov (United States)

    Car, Halina; Zendzian-Piotrowska, Małgorzata; Fiedorowicz, Anna; Prokopiuk, Sławomir; Sadowska, Anna; Kurek, Krzysztof

    2012-05-30

     Ceramides, members of the sphingolipids, are produced in the central nervous system by de novo synthesis, sphingomyelin hydrolysis or the so-called salvage pathway. They are engaged in formation of lipid rafts that are essential in regulation and transduction of signals coming to the cell from the environment. Ceramides represent the major transmitters of the sphingomyelin pathway of signal transduction. They regulate proliferation, differentiation, programmed cell death and senescence. Ceramide overexpression, mainly as a result of sphingomyelin hydrolysis, is a component of brain damage caused by ischemia and early reperfusion. Their high concentrations induce mitochondria-dependent neuronal apoptosis, exacerbate the synthesis of reactive oxygen species, decrease ATP level, inhibit electron transport and release cytochrome c, and activate caspase-3. Reduced ceramide accumulation in the brain, dependent mainly on ceramide synthesized de novo, may exert an anti-apoptotic effect after pre-conditioning. The increase of ceramide content in the brain was observed in Alzheimer disease and its animal models. Enhanced ceramide concentration in this pathology is an effect of their synthesis de novo or sphingomyelin metabolism augmentation. The ceramide pathway can directly stimulate biochemical changes in the brain noted at the onset of disease: tau overphosphorylation and β-amyloid peptide accumulation. The higher concentration of ceramides in blood in the pre-clinical phase of the illness may mark early brain changes.

  17. Moderate alcohol exposure during early brain development increases stimulus-response habits in adulthood.

    Science.gov (United States)

    Parker, Matthew O; Evans, Alexandra M-D; Brock, Alistair J; Combe, Fraser J; Teh, Muy-Teck; Brennan, Caroline H

    2016-01-01

    Exposure to alcohol during early central nervous system development has been shown variously to affect aspects of physiological and behavioural development. In extreme cases, this can extend to craniofacial defects, severe developmental delay and mental retardation. At more moderate levels, subtle differences in brain morphology and behaviour have been observed. One clear effect of developmental alcohol exposure is an increase in the propensity to develop alcoholism and other addictions. The mechanisms by which this occurs, however, are not currently understood. In this study, we tested the hypothesis that adult zebrafish chronically exposed to moderate levels of ethanol during early brain ontogenesis would show an increase in conditioned place preference for alcohol and an increased propensity towards habit formation, a key component of drug addiction in humans. We found support for both of these hypotheses and found that the exposed fish had changes in mRNA expression patterns for dopamine receptor, nicotinic acetylcholine receptor and μ-opioid receptor encoding genes. Collectively, these data show an explicit link between the increased proclivity for addiction and addiction-related behaviour following exposure to ethanol during early brain development and alterations in the neural circuits underlying habit learning.

  18. Acute Ischemic Stroke After Moderate to Severe Traumatic Brain Injury: Incidence and Impact on Outcome.

    Science.gov (United States)

    Kowalski, Robert G; Haarbauer-Krupa, Juliet K; Bell, Jeneita M; Corrigan, John D; Hammond, Flora M; Torbey, Michel T; Hofmann, Melissa C; Dams-O'Connor, Kristen; Miller, A Cate; Whiteneck, Gale G

    2017-07-01

    Traumatic brain injury (TBI) leads to nearly 300 000 annual US hospitalizations and increased lifetime risk of acute ischemic stroke (AIS). Occurrence of AIS immediately after TBI has not been well characterized. We evaluated AIS acutely after TBI and its impact on outcome. A prospective database of moderate to severe TBI survivors, admitted to inpatient rehabilitation at 22 Traumatic Brain Injury Model Systems centers and their referring acute-care hospitals, was analyzed. Outcome measures were AIS incidence, duration of posttraumatic amnesia, Functional Independence Measure, and Disability Rating Scale, at rehabilitation discharge. Between October 1, 2007, and March 31, 2015, 6488 patients with TBI were enrolled in the Traumatic Brain Injury Model Systems National Database. One hundred and fifty-nine (2.5%) patients had a concurrent AIS, and among these, median age was 40 years. AIS was associated with intracranial mass effect and carotid or vertebral artery dissection. High-velocity events more commonly caused TBI with dissection. AIS predicted poorer outcome by all measures, accounting for a 13.3-point reduction in Functional Independence Measure total score (95% confidence interval, -16.8 to -9.7; PIschemic stroke is observed acutely in 2.5% of moderate to severe TBI survivors and predicts worse functional and cognitive outcome. Half of TBI patients with AIS were aged ≤40 years, and AIS patients more often had cervical dissection. Vigilance for AIS is warranted acutely after TBI, particularly after high-velocity events. © 2017 American Heart Association, Inc.

  19. A Prospective Randomized Study of Brain Tissue Oxygen Pressure-Guided Management in Moderate and Severe Traumatic Brain Injury Patients

    Directory of Open Access Journals (Sweden)

    Chien-Min Lin

    2015-01-01

    Full Text Available The purpose of this study was to compare the effect of PbtO2-guided therapy with traditional intracranial pressure- (ICP- guided treatment on the management of cerebral variables, therapeutic interventions, survival rates, and neurological outcomes of moderate and severe traumatic brain injury (TBI patients. From 2009 to 2010, TBI patients with a Glasgow coma scale 20 mmHg, and 27 patients were treated with ICP-guided therapy (ICP 60 mmHg in the neurosurgical intensive care unit (NICU; demographic characteristics were similar across groups. The survival rate in the PbtO2-guided group was also significantly increased at 3 and 6 months after injury. Moreover, there was a significant correlation between the PbtO2 signal and Glasgow outcome scale-extended in patients from 1 to 6 months after injury. This finding demonstrates that therapy directed by PbtO2 monitoring is valuable for the treatment of patients with moderate and severe TBI and that increasing PaO2 to 150 mmHg may be efficacious for preventing cerebral hypoxic events after brain trauma.

  20. Effect of vitamin E on cerebral cortical oxidative stress and brain-derived neurotrophic factor gene expression induced by hypoxia and exercise in rats.

    Science.gov (United States)

    Sakr, H F; Abbas, A M; El Samanoudy, A Z

    2015-04-01

    Brain-derived neurotrophic factor (BDNF) is involved in the proliferation of neurons, and its expression increases significantly with exercise. We aimed to investigate the effects of chronic exercise (swimming) and sustained hypoxia on cortical BDNF expression in both the presence and absence of vitamin E. Sixty four male Sprague-Dawley rats were divided into two equal groups; a normoxic group and a hypoxic group. Both groups were equally subdivided into four subgroups: sedentary, sedentary with vitamin E, chronic exercise either with or without vitamin E supplementation. Arterial PO(2), and the levels of cortical malondialdehyde (MDA), antioxidants (reduced glutathione GSH, superoxide dismutase (SOD), catalase (CAT) and vitamin E) and BDNF gene expression were investigated. Hypoxia significantly increased MDA production and BDNF gene expression and decreased the antioxidants compared to control rats. Chronic exercise in hypoxic and normoxic rats increased MDA level and BDNF gene expression and decreased the antioxidants. Providing vitamin E supplementation to the hypoxic and normoxic rats significantly reduced MDA and BDNF gene expression and increased antioxidants. We conclude that sustained hypoxia and chronic exercise increased BDNF gene expression and induced oxidative stress. Moreover, vitamin E attenuated the oxidative stress and decreased BDNF gene expression in sustained hypoxia and chronic exercise which confirms the oxidative stress-induced stimulation of BDNF gene expression.

  1. Parents' experiences following children's moderate to severe traumatic brain injury: a clash of cultures.

    Science.gov (United States)

    Roscigno, Cecelia I; Swanson, Kristen M

    2011-10-01

    Little is understood about parents' experiences following children's moderate to severe traumatic brain injury (TBI). Using descriptive phenomenology, we explored common experiences of parents whose children were diagnosed with moderate to severe TBI. Parents from across the United States (N = 42, from 37 families) participated in two semistructured interviews (~ 90 minutes in length and 12 to 15 months apart) in the first 5 years following children's TBI. First interviews were in person. Second interviews, done in person or by phone, facilitated updating parents' experiences and garnering their critique of the descriptive model. Parent themes were (a) grateful to still have my child, (b) grieving for the child I knew, (c) running on nerves, and (d) grappling to get what my child and family need. Parents reported cultural barriers because of others' misunderstandings. More qualitative inquiry is needed to understand how the knowledge, attitudes, beliefs, and culture-based expectations of others influence parents' interactions and the family's adjustment and well-being.

  2. Parents' Experiences Following Children's Moderate to Severe Traumatic Brain Injury: A Clash of Cultures

    Science.gov (United States)

    Roscigno, Cecelia I.; Swanson, Kristen M.

    2012-01-01

    Little is understood about parents' experiences following children's moderate to severe traumatic brain injury (TBI). Using descriptive phenomenology we explored common experiences of parents whose children were diagnosed with moderate to severe TBI. Parents from across the United States (N = 42 from 37 families) participated in two semistructured interviews (~ 90 minutes and 12–15 months apart) in the first five years following children's TBI. First interviews were in person. Second interviews, done in person or by phone, facilitated updating parents' experiences and garnering their critique of the descriptive model. Parent themes were: (a) grateful to still have my child; (b) grieving for the child I knew; (c) running on nerves; and (d) grappling to get what your child and family need. Parents reported cultural barriers because of others' misunderstandings. More qualitative inquiry is needed to understand how the knowledge, attitudes, beliefs, and expectations of others (culture) influence parents' interactions and the family's adjustment and well-being. PMID:21613654

  3. Teleosts in hypoxia : Aspects of anaerobic metabolism

    NARCIS (Netherlands)

    Van den Thillart, G.; van Waarde, Aren

    1985-01-01

    Moderate hypoxia can be tolerated by many fish species, while only some species survive severe hypoxia or anoxia. Hypoxia usually activates anaerobic glycolysis, which may be temporary when the animals are able to improve their oxygen extraction capacity. Switching over to aerobic metabolism allows

  4. Progesterone treatment shows benefit in a pediatric model of moderate to severe bilateral brain injury.

    Directory of Open Access Journals (Sweden)

    Rastafa I Geddes

    Full Text Available PURPOSE: Controlled cortical impact (CCI models in adult and aged Sprague-Dawley (SD rats have been used extensively to study medial prefrontal cortex (mPFC injury and the effects of post-injury progesterone treatment, but the hormone's effects after traumatic brain injury (TBI in juvenile animals have not been determined. In the present proof-of-concept study we investigated whether progesterone had neuroprotective effects in a pediatric model of moderate to severe bilateral brain injury. METHODS: Twenty-eight-day old (PND 28 male Sprague Dawley rats received sham (n = 24 or CCI (n = 47 injury and were given progesterone (4, 8, or 16 mg/kg per 100 g body weight or vehicle injections on post-injury days (PID 1-7, subjected to behavioral testing from PID 9-27, and analyzed for lesion size at PID 28. RESULTS: The 8 and 16 mg/kg doses of progesterone were observed to be most beneficial in reducing the effect of CCI on lesion size and behavior in PND 28 male SD rats. CONCLUSION: Our findings suggest that a midline CCI injury to the frontal cortex will reliably produce a moderate TBI comparable to what is seen in the adult male rat and that progesterone can ameliorate the injury-induced deficits.

  5. Hypoxia Room

    Data.gov (United States)

    Federal Laboratory Consortium — The Hypoxia Room is a 8x8x8 ft. clear vinyl plastic and aluminum frame construction enclosure located within USAREIM laboratory 028. The Hypoxia Room (manufactured...

  6. Hypoxia Room

    Data.gov (United States)

    Federal Laboratory Consortium — The Hypoxia Room is a 8x8x8 ft. clear vinyl plastic and aluminum frame construction enclosure located within USAREIM laboratory 028. The Hypoxia Room (manufactured...

  7. Potent and Selective Triazole-Based Inhibitors of the Hypoxia-Inducible Factor Prolyl-Hydroxylases with Activity in the Murine Brain

    Science.gov (United States)

    Chan, Mun Chiang; Atasoylu, Onur; Hodson, Emma; Tumber, Anthony; Leung, Ivanhoe K. H.; Chowdhury, Rasheduzzaman; Gómez-Pérez, Verónica; Demetriades, Marina; Rydzik, Anna M.; Holt-Martyn, James; Tian, Ya-Min; Bishop, Tammie; Claridge, Timothy D. W.; Kawamura, Akane; Pugh, Christopher W.; Ratcliffe, Peter J.; Schofield, Christopher J.

    2015-01-01

    As part of the cellular adaptation to limiting oxygen availability in animals, the expression of a large set of genes is activated by the upregulation of the hypoxia-inducible transcription factors (HIFs). Therapeutic activation of the natural human hypoxic response can be achieved by the inhibition of the hypoxia sensors for the HIF system, i.e. the HIF prolyl-hydroxylases (PHDs). Here, we report studies on tricyclic triazole-containing compounds as potent and selective PHD inhibitors which compete with the 2-oxoglutarate co-substrate. One compound (IOX4) induces HIFα in cells and in wildtype mice with marked induction in the brain tissue, revealing that it is useful for studies aimed at validating the upregulation of HIF for treatment of cerebral diseases including stroke. PMID:26147748

  8. Potent and Selective Triazole-Based Inhibitors of the Hypoxia-Inducible Factor Prolyl-Hydroxylases with Activity in the Murine Brain.

    Directory of Open Access Journals (Sweden)

    Mun Chiang Chan

    Full Text Available As part of the cellular adaptation to limiting oxygen availability in animals, the expression of a large set of genes is activated by the upregulation of the hypoxia-inducible transcription factors (HIFs. Therapeutic activation of the natural human hypoxic response can be achieved by the inhibition of the hypoxia sensors for the HIF system, i.e. the HIF prolyl-hydroxylases (PHDs. Here, we report studies on tricyclic triazole-containing compounds as potent and selective PHD inhibitors which compete with the 2-oxoglutarate co-substrate. One compound (IOX4 induces HIFα in cells and in wildtype mice with marked induction in the brain tissue, revealing that it is useful for studies aimed at validating the upregulation of HIF for treatment of cerebral diseases including stroke.

  9. Prodigiosin inhibits gp91{sup phox} and iNOS expression to protect mice against the oxidative/nitrosative brain injury induced by hypoxia-ischemia

    Energy Technology Data Exchange (ETDEWEB)

    Chang, Chia-Che [Institute of Biomedical Sciences, National Chung-Hsing University, Taichung, Taiwan (China); Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan (China); Agricultural Biotechnology Center, National Chung-Hsing University, Taichung, Taiwan (China); Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan (China); Wang, Yea-Hwey [Department of Nursing, College of Medicine and Nursing, Hungkuang University, Taichung, Taiwan (China); Chern, Chang-Ming [Division of Neurovascular Disease, Neurological Institute, Taipei Veterans General Hospital and School of Medicine, National Yang-Ming University, Taipei, Taiwan (China); Liou, Kuo-Tong [Department of Chinese Martial Arts, Chinese Culture University, Taipei, Taiwan (China); Hou, Yu-Chang [Department of Chinese Medicine, Taoyuan General Hospital, Department of Health, Taiwan (China); Department of Nursing, Yuanpei University, Hsinchu, Taiwan (China); Department of Bioscience Technology, Chuan-Yuan Christian University, Taoyuan, Taiwan (China); Peng, Yu-Ta [Institute of Biomedical Sciences, National Chung-Hsing University, Taichung, Taiwan (China); Shen, Yuh-Chiang, E-mail: yuhcs@nricm.edu.tw [National Research Institute of Chinese Medicine, Taipei, Taiwan (China); Institute of Biomedical Sciences, National Chung-Hsing University, Taichung, Taiwan (China)

    2011-11-15

    This study aimed to explore the mechanisms by which prodigiosin protects against hypoxia-induced oxidative/nitrosative brain injury induced by middle cerebral artery occlusion/reperfusion (MCAo/r) injury in mice. Hypoxia in vitro was modeled using oxygen-glucose deprivation (OGD) followed by reoxygenation of BV-2 microglial cells. Our results showed that treatment of mice that have undergone MCAo/r injury with prodigiosin (10 and 100 {mu}g/kg, i.v.) at 1 h after hypoxia ameliorated MCAo/r-induced oxidative/nitrosative stress, brain infarction, and neurological deficits in the mice, and enhanced their survival rate. MCAo/r induced a remarkable production in the mouse brains of reactive oxygen species (ROS) and a significant increase in protein nitrosylation; this primarily resulted from enhanced expression of NADPH oxidase 2 (gp91{sup phox}), inducible nitric oxide synthase (iNOS), and the infiltration of CD11b leukocytes due to breakdown of blood-brain barrier (BBB) by activation of nuclear factor-kappa B (NF-{kappa}B). All these changes were significantly diminished by prodigiosin. In BV-2 cells, OGD induced ROS and nitric oxide production by up-regulating gp91{sup phox} and iNOS via activation of the NF-{kappa}B pathway, and these changes were suppressed by prodigiosin. In conclusion, our results indicate that prodigiosin reduces gp91{sup phox} and iNOS expression possibly by impairing NF-{kappa}B activation. This compromises the activation of microglial and/or inflammatory cells, which then, in turn, mediates prodigiosin's protective effect in the MCAo/r mice. -- Highlights: Black-Right-Pointing-Pointer Prodigiosin ameliorated brain infarction and deficits. Black-Right-Pointing-Pointer Prodigiosin protected against hypoxia/reperfusion-induced brain injury. Black-Right-Pointing-Pointer Prodigiosin diminished oxidative/nitrosativestress and leukocytes infiltration. Black-Right-Pointing-Pointer Prodigiosin reduced BBB breakdown. Black

  10. Pituitary and/or hypothalamic dysfunction following moderate to severe traumatic brain injury: Current perspectives

    Directory of Open Access Journals (Sweden)

    Zeeshan Javed

    2015-01-01

    Full Text Available There is an increasing deliberation regarding hypopituitarism following traumatic brain injury (TBI and recent data have suggested that pituitary dysfunction is very common among survivors of patients having moderate-severe TBI which may evolve or resolve over time. Due to high prevalence of pituitary dysfunction after moderate-severe TBI and its association with increased morbidity and poor recovery and the fact that it can be easily treated with hormone replacement, it has been suggested that early detection and treatment is necessary to prevent long-term neurological consequences. The cause of pituitary dysfunction after TBI is still not well understood, but evidence suggests few possible primary and secondary causes. Results of recent studies focusing on the incidence of hypopituitarism in the acute and chronic phases after TBI are varied in terms of severity and time of occurrence. Although the literature available does not show consistent values and there is difference in study parameters and diagnostic tests used, it is clear that pituitary dysfunction is very common after moderate to severe TBI and patients should be carefully monitored. The exact timing of development cannot be predicted but has suggested regular assessment of pituitary function up to 1 year after TBI. In this narrative review, we aim to explore the current evidence available regarding the incidence of pituitary dysfunction in acute and chronic phase post-TBI and recommendations for screening and follow-up in these patients. We will also focus light over areas in this field worthy of further investigation.

  11. Predictions of episodic memory following moderate to severe traumatic brain injury during inpatient rehabilitation.

    Science.gov (United States)

    Anderson, Jonathan W; Schmitter-Edgecombe, Maureen

    2009-05-01

    We examined memory self-awareness and memory self-monitoring abilities during inpatient rehabilitation in participants with moderate to severe traumatic brain injury (TBI). A total of 29 participants with moderate to severe TBI and 29 controls matched on age, gender, and education completed a performance prediction paradigm. To assess memory self-awareness, participants predicted the amount of information they would remember before completing list-learning tasks and visual-spatial memory tasks. Memory self-monitoring was assessed by participants' ability to increase accuracy of their predictions after experience with the tests. Although the TBI participants performed more poorly than controls on both episodic memory tasks, no significant group differences emerged in memory self-awareness or memory self-monitoring. The TBI participants predicted that their memory performances would be poorer than that of controls, accurately adjusted their predictions in accordance with the demands of the tasks, and successfully modified their predictions following experience with the tasks. The results indicate that moderate to severe TBI individuals in the early stages of recovery can competently assess the demands of externally driven metamemorial situations and utilize experience with task to accurately update their knowledge of memory abilities.

  12. Relative Expression of HIF-1α mRNA in Rat Heart, Brain and Blood During Induced Systemic Hypoxia

    OpenAIRE

    Syarifah Dewi; Reni Paramita; Septelia Inawati Wanandi

    2009-01-01

    Hypoxia is a pathological condition in which the body as a whole or region of the body (tissue or cell) deprived of adequate oxygen supply. The transcriptional regulator hypoxia inducible factor-1 (HIF-1) is an essential mediator of O2 homeostasis. Unlike the β sub unit (HIF-1β), the activity of HIF-1α is controlled in an oxygen-dependent manner. It has been reported that the stability and expression of HIF-1α during hypoxia is remarkably higher than those under normoxic conditions.The aim of...

  13. Uncovering latent deficits due to mild traumatic brain injury (mTBI by using normobaric hypoxia stress

    Directory of Open Access Journals (Sweden)

    Leonard eTemme

    2013-04-01

    Full Text Available Memory deficits and other cognitive symptoms frequently associated with mTBI are commonly thought to resolve within 7 to 10 days. This generalization is based principally on observations made in individuals who are in the unstressed environmental conditions typical to a clinic and so does not consider the impact of physiologic, environmental or psychological stress. Normobaric Hypoxia (NH stress can be generated by mixing normal mean sea level air (MSL containing 21% oxygen (O2 with nitrogen, which is biologically inert, so that the resultant mixed gas has a partial pressure of O2 approximating that of specified altitudes. This technique was used to generate NH equivalents of 8,000, 12,000 and 14,000 feet above MSL in a group of 36 volunteers with an mTBI history and an equal number of controls matched on the basis of age, gender, weight, etc. Short term visual memory was tested using Matching to Sample (M2S subtest of the BrainCheckers analogue of the Automated Neuropsychological Assessment Metrics (ANAM. Although there were no significant differences in M2S performance between the two groups of subjects at MSL, with increased altitude, performance deteriorated in the mTBI group as predicted to be significantly worse than that of the controls. When the subjects were returned to MSL, the difference disappeared. This finding suggests that the hypoxic challenge paradigm developed here has potential clinical utility for assessing the effects of mTBI in individuals who appear asymptomatic under normal conditions.

  14. Xenon and sevoflurane provide analgesia during labor and fetal brain protection in a perinatal rat model of hypoxia-ischemia.

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    Ting Yang

    Full Text Available It is not possible to identify all pregnancies at risk of neonatal hypoxic-ischemic encephalopathy (HIE. Many women use some form of analgesia during childbirth and some anesthetic agents have been shown to be neuroprotective when used as analgesics at subanesthetic concentrations. In this study we sought to understand the effects of two anesthetic agents with presumptive analgesic activity and known preconditioning-neuroprotective properties (sevoflurane or xenon, in reducing hypoxia-induced brain damage in a model of intrauterine perinatal asphyxia. The analgesic and neuroprotective effects at subanesthetic levels of sevoflurane (0.35% or xenon (35% were tested in a rat model of intrauterine perinatal asphyxia. Analgesic effects were measured by assessing maternal behavior and spinal cord dorsal horn neuronal activation using c-Fos. In separate experiments, intrauterine fetal asphyxia was induced four hours after gas exposure; on post-insult day 3 apoptotic cell death was measured by caspase-3 immunostaining in hippocampal neurons and correlated with the number of viable neurons on postnatal day (PND 7. A separate cohort of pups was nurtured by a surrogate mother for 50 days when cognitive testing with Morris water maze was performed. Both anesthetic agents provided analgesia as reflected by a reduction in the number of stretching movements and decreased c-Fos expression in the dorsal horn of the spinal cord. Both agents also reduced the number of caspase-3 positive (apoptotic neurons and increased cell viability in the hippocampus at PND7. These acute histological changes were mirrored by improved cognitive function measured remotely after birth on PND 50 compared to control group. Subanesthetic doses of sevoflurane or xenon provided both analgesia and neuroprotection in this model of intrauterine perinatal asphyxia. These data suggest that anesthetic agents with neuroprotective properties may be effective in preventing HIE and should be

  15. Predictors of quality of life after moderate to severe traumatic brain injury

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    Karina Tavares Weber

    2016-05-01

    Full Text Available ABSTRACT Objective To verify correlations between age, injury severity, length of stay (LOS, cognition, functional capacity and quality of life (QOL six months after hospital discharge (HD of victims of traumatic brain injury (TBI. Method 50 patients consecutively treated in a Brazilian emergency hospital were assessed at admission, HD and six months after HD. The assessment protocol consisted in Abbreviated Injury Scale, Injury Severity Score, Glasgow Coma Scale (GCS, Revised Trauma Score (RTS, Mini Mental Test, Barthel Index and World Health Organization QOL - Brief. Results Strong negative correlation was observed between LOS and GCS and LOS and RTS. An almost maximal correlation was found between RTS and GCS and functional capacity and GCS at HD. Age and LOS were considered independent predictors of QOL. Conclusion Age and LOS are independent predictors of QOL after moderate to severe TBI.

  16. NITRIC OXIDE (NO, CITRULLINE - NO CYCLE ENZYMES, GLUTAMINE SYNTHETASE AND OXIDATIVE STRESS IN ANOXIA (HYPOBARIC HYPOXIA AND REPERFUSION IN RAT BRAIN

    Directory of Open Access Journals (Sweden)

    M. Swamy, Mohd Jamsani Mat Salleh, K. N .S. Sirajudeen, Wan Roslina Wan Yusof, G. Chandran

    2010-01-01

    Full Text Available Nitric oxide is postulated to be involved in the pathophysiology of neurological disorders due to hypoxia/ anoxia in brain due to increased release of glutamate and activation of N-methyl-D-aspartate receptors. Reactive oxygen species have been implicated in pathophysiology of many neurological disorders and in brain function. To understand their role in anoxia (hypobaric hypoxia and reperfusion (reoxygenation, the nitric oxide synthase, argininosuccinate synthetase, argininosuccinate lyase, glutamine synthetase and arginase activities along with the concentration of nitrate /nitrite, thiobarbituric acid reactive substances and total antioxidant status were estimated in cerebral cortex, cerebellum and brain stem of rats subjected to anoxia and reperfusion. The results of this study clearly demonstrated the increased production of nitric oxide by increased activity of nitric oxide synthase. The increased activities of argininosuccinate synthetase and argininosuccinate lyase suggest the increased and effective recycling of citrulline to arginine in anoxia, making nitric oxide production more effective and contributing to its toxic effects. The decreased activity of glutamine synthetase may favor the prolonged availability of glutamic acid causing excitotoxicity leading to neuronal damage in anoxia. The increased formation of thiobarbituric acid reactive substances and decreased total antioxidant status indicate the presence of oxidative stress in anoxia and reperfusion. The increased arginase and sustained decrease of GS activity in reperfusion group likely to be protective.

  17. Moderate traumatic brain injury causes acute dendritic and synaptic degeneration in the hippocampal dentate gyrus.

    Directory of Open Access Journals (Sweden)

    Xiang Gao

    Full Text Available Hippocampal injury-associated learning and memory deficits are frequent hallmarks of brain trauma and are the most enduring and devastating consequences following traumatic brain injury (TBI. Several reports, including our recent paper, showed that TBI brought on by a moderate level of controlled cortical impact (CCI induces immature newborn neuron death in the hippocampal dentate gyrus. In contrast, the majority of mature neurons are spared. Less research has been focused on these spared neurons, which may also be injured or compromised by TBI. Here we examined the dendrite morphologies, dendritic spines, and synaptic structures using a genetic approach in combination with immunohistochemistry and Golgi staining. We found that although most of the mature granular neurons were spared following TBI at a moderate level of impact, they exhibited dramatic dendritic beading and fragmentation, decreased number of dendritic branches, and a lower density of dendritic spines, particularly the mushroom-shaped mature spines. Further studies showed that the density of synapses in the molecular layer of the hippocampal dentate gyrus was significantly reduced. The electrophysiological activity of neurons was impaired as well. These results indicate that TBI not only induces cell death in immature granular neurons, it also causes significant dendritic and synaptic degeneration in pathohistology. TBI also impairs the function of the spared mature granular neurons in the hippocampal dentate gyrus. These observations point to a potential anatomic substrate to explain, in part, the development of posttraumatic memory deficits. They also indicate that dendritic damage in the hippocampal dentate gyrus may serve as a therapeutic target following TBI.

  18. Recovery of motor spontaneous activity after intranasal delivery of human recombinant erythropoietin in a focal brain hypoxia model induced by CoCl2 in rats.

    Science.gov (United States)

    Merelli, Amalia; Caltana, Laura; Girimonti, Patricia; Ramos, Alberto Javier; Lazarowski, Alberto; Brusco, Alicia

    2011-08-01

    Stroke is a major human health problem inducing long-term disability without any efficient therapeutic option being currently available. Under hypoxia, hypoxia-inducible factor-1α (HIF-1α) activates several genes as erythropoietin receptor (Epo-R) related with O(2) supply, and the multidrug-resistance gene (MDR-1) related with drug-refractory phenotype. Brain cortical injection of CoCl(2) produces focal hypoxia-like lesion with neuronal and glial alterations, as well as HIF-1α stabilization and MDR-1 overexpression. Intranasal (IN) drug delivery can by-pass blood-brain barrier (BBB) where MDR-1 is normally expressed. We evaluated the effects of IN-rHu-Epo administration on spontaneous motor activity (SMA) and the brain pattern expression of HIF-1α, MDR-1, and Epo-R in our cobalt-induced hypoxia model. Adult male Wistar rats were injected by stereotaxic surgery in frontoparietal cortex, with CoCl(2) (2 μl-50 mM; n = 20) or saline (controls; n = 20). Ten rats of each group were treated with IN-rHu-Epo 24 U or IN-saline. In addition, erythropoietic stimulation was evaluated by reticulocytes (Ret) account during three consecutive days, after intraperitoneal (i.p.)-recombinant-human Epo (rHu-Epo) (950 U; n = 6) or IN-rHu-Epo (24 U; n = 6) administration. SMA was evaluated by open field and rotarod tests, before and after surgical procedures during five consecutive days. Histological and immunostaining studies of HIF-1α, MDR-1, and Epo-R were performed on brain slides. A significant difference in SMA was observed in the hypoxic rats of IN-rHu-Epo-administered group as compared with Co-Saline-treated subjects and controls (p < 0.001). HIF-1α, EPO-R, and MDR-1 were overexpressed in the hypoxic cortex areas, while in contralateral hemisphere or controls, they were negatives. Reticulocytes were only increased in intraperitoneal (i.p.)-rHu-Epo-administered group. In spite of MDR-1 overexpression being detected in neurons, the coexpression of Epo-R could

  19. Diagnostic protein biomarkers for severe, moderate and mild traumatic brain injury

    Science.gov (United States)

    Streeter, Jackson; Hayes, Ronald L.; Wang, Kevin K. W.

    2011-06-01

    Traumatic Brain Injury (TBI) is a major problem in military and civilian medicine. Yet, there are no simple non-invasive diagnostics for TBI. Our goal is to develop and clinically validate blood-based biomarker assays for the diagnosis, prognosis and management of mild, moderate and severe TBI patients. These assays will ultimately be suitable for deployment to far-forward combat environments. Using a proteomic and systems biology approach, we identified over 20 candidate biomarkers for TBI and developed robust ELISAs for at least 6 candidate biomarkers, including Ubiquitin C-terminal hydrolase- L1 (UCH-L1), Glial Fibrillary Acidic Protein (GFAP) and a 145 kDa breakdown products of αII-spectrin (SBDP 145) generated by calpain proteolysis. In a multi-center feasibility study (Biomarker Assessment For Neurotrauma Diagnosis And Improved Triage System (BANDITS), we analyzed CSF and blood samples from 101 adult patients with severe TBI [Glasgow Coma Scale (GCS) <= 8] at 6 sites and analyzed 27 mild TBI patients and 5 moderate TBI patients [GCS 9-15] from 2 sites in a pilot study. We identified that serum levels of UCH-L1, GFAP and SBDP145 have strong diagnostic and prognostic properties for severe TBI over controls. Similarly initial post-TBI serum levels (< 6 h) of UCH-L1 and GFAP have diagnostic characteristics for moderate and mild TBI. We are now furthering assay production, refining assay platforms (both benchtop and point-ofcare/ handheld) and planning a pivotal clinical study to seek FDA approval of these TBI diagnostic assays.

  20. The Evolution of Post-Traumatic Stress Disorder following Moderate-to-Severe Traumatic Brain Injury.

    Science.gov (United States)

    Alway, Yvette; Gould, Kate Rachel; McKay, Adam; Johnston, Lisa; Ponsford, Jennie

    2016-05-01

    Increasing evidence indicates that post-traumatic stress disorder (PTSD) may develop following traumatic brain injury (TBI), despite most patients having no conscious memory of their accident. This prospective study examined the frequency, timing of onset, symptom profile, and trajectory of PTSD and its psychiatric comorbidities during the first 4 years following moderate-to-severe TBI. Participants were 85 individuals (78.8% male) with moderate or severe TBI recruited following admission to acute rehabilitation between 2005 and 2010. Using the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Disorders (SCID-I), participants were evaluated for pre- and post-injury PTSD soon after injury and reassessed at 6 months, 12 months, 2 years, 3 years, and 4 years post-injury. Over the first 4 years post-injury, 17.6% developed injury-related PTSD, none of whom had PTSD prior to injury. PTSD onset peaked between 6 and 12 months post-injury. The majority of PTSD cases (66.7%) had a delayed-onset, which for a third was preceded by subsyndromal symptoms in the first 6 months post-injury. PTSD frequency increased over the first year post-injury, remained stable during the second year, and gradually declined thereafter. The majority of subjects with PTSD experienced a chronic symptom course and all developed one or more than one comorbid psychiatric disorder, with mood, other anxiety, and substance-use disorders being the most common. Despite event-related amnesia, post-traumatic stress symptoms, including vivid re-experiencing phenomena, may develop following moderate-to-severe TBI. Onset is typically delayed and symptoms may persist for several years post-injury.

  1. Extracellular brain pH with or without hypoxia is a marker of profound metabolic derangement and increased mortality after traumatic brain injury

    Science.gov (United States)

    Timofeev, Ivan; Nortje, Jurgens; Al-Rawi, Pippa G; Hutchinson, Peter JA; Gupta, Arun K

    2013-01-01

    Cerebral hypoxia and acidosis can follow traumatic brain injury (TBI) and are associated with increased mortality. This study aimed to evaluate a relationship between reduced pHbt and disturbances of cerebral metabolism. Prospective data from 56 patients with TBI, receiving microdialysis and Neurotrend monitoring, were analyzed. Four tissue states were defined based on pHbt and PbtO2: 1—low PbtO2/pHbt, 2—low pHbt/normal PbtO2, 3—normal pHbt/low PbtO2, and 4—normal pHbt/PbtO2). Microdialysis values were compared between the groups. The relationship between PbtO2 and lactate/pyruvate (LP) ratio was evaluated at different pHbt levels. Proportional contribution of each state was evaluated against mortality. As compared with the state 4, the state 3 was not different, the state 2 exhibited higher levels of lactate, LP, and glucose and the state 1—higher LP and reduced glucose (P<0.001). A significant negative correlation between LP and PbtO2 (rho=−0.159, P<0.001) was stronger at low pHbt (rho=−0.201, P<0.001) and nonsignificant at normal pHbt (P=0.993). The state 2 was a significant discriminator of mortality categories (P=0.031). Decreased pHbt is associated with impaired metabolism. Measuring pHbt with PbtO2 is a more robust way of detecting metabolic derangements. PMID:23232949

  2. T2 and T2* measurements of fetal brain oxygenation during hypoxia with MRI at 3T: correlation with fetal arterial blood oxygen saturation

    Energy Technology Data Exchange (ETDEWEB)

    Wedegaertner, Ulrike; Adam, Gerhard [Universitaetsklinikum Hamburg-Eppendorf, Department of Diagnostic and Interventional Radiology, Hamburg (Germany); Kooijman, Hendrik [Philips Medical Systems, Best (Netherlands); Andreas, Thomas; Beindorff, Nicola; Hecher, Kurt [University Hospital Hamburg-Eppendorf, Department of Obstetrics and Prenatal Medicine, Hamburg (Germany)

    2010-01-15

    The purpose of this prospective study was to determine the oxygen saturation of blood in the fetal brain based on T2 and T2* measurements in a fetal sheep model. Five sheep fetuses were investigated during normoxia and hypoxia by 3T MRI. Multi-echo gradient-echo and turbo-spin-echo sequences were performed on the fetal brain. MR-determined oxygen saturation (MR-sO{sub 2}) of blood in the fetal brain was calculated based on T2 and T2* values. Fetal arterial blood oxygen saturation (blood-sO{sub 2}) was measured during the two experimental phases. The slope of MR-sO{sub 2} as a function of blood-sO{sub 2} was estimated and tested for compatibility using the one-sample t-test. During normoxia, mean values for carotid blood oxygen saturation were 67%, 83 ms for T2*, 202 ms for T2 and 96% for MR-sO{sub 2}. During hypoxia, arterial blood oxygen saturation, T2* and calculated MR-sO{sub 2} decreased to 22%, 64 ms, and 68% respectively. The one-sample t-test revealed the slope to be significantly different from 0(T=5.023, df=4, P=0.007). It is feasible to perform quantitative T2 and T2* measurements in the fetal brain. MR-sO{sub 2} and fetal arterial blood oxygen saturation correlated significantly. However, based on these data a reliable quantification of fetal brain tissue oxygenation is not possible. (orig.)

  3. Expression of hypoxia inducible factor-1 alpha and ischemic erythropoietin tolerance in the brain of cerebral ischemic tolerance model rats

    Institute of Scientific and Technical Information of China (English)

    Renliang Zhao; Ruijian Dong; Zhongling Sun

    2006-01-01

    BACKGROUND: Hypoxia inducible factor-1 alpha (HIF-1 α) and erythropoietin(EPO), possessing neuroprotective effect in the cerebral ischemia, might play an important role in the formation of cerebral ischemic tolerance (IT).OBJECTIVE:To observe the neuroprotective effect of cerebral ischemic preconditioning(IPC) of rats, and the expression and mechanism of HIF-1α and target gene erythropoietin in the brain tissue following the formation of cerebral IT.DESIGN :A randomized and controlled observation.SETTING: Department of Neurology, the Affiliated Hospital of Medical College, Qingdao University.MATERIALS: Totally 84 enrolled adult healthy male Wistar rats of clean grade, weighing 250 to 300 g, were provided by the Animal Experimental Department, Tongji Medical College of Huazhong University of Science and Technology. Ready-to-use SABC reagent kit and rabbit anti-rat HIF-1α monoclonal antibody were purchased from Boshide Bioengineering Co. Ltd (Wuhan); Rabbit anti-rat EPO monoclonal antibody was purchased from Santa Cruz Company (USA).METHODS: This experiment was carried out in the Department of Anatomy, Medical College, Qingdao University during March 2005 to March 2006. ① The 84 rats were divided into 3 groups by a lot: IPC group (n=40),sham-operation group (n=40) and control group (n=4). In the IPC group, middle cerebral artery was occluded for 2 hours respectively on the 1st, 3rd, 7th, 14th and 21st days of the reperfusion following 10-minute preischemia was made using a modified middle cerebral artery second suture method from Zea-Longa. The rats were sacrificed 22 hours after reperfusion in the end of middle cerebral artery occlusion (MCAO). That was to say,after 10-minute preischemia, suture was exited to the external carotid artery and embedded subcutaneously.Middle cerebral artery was occluded again to form the second reperfusion at the set time point after reperfusion. Twenty-two hours later, rats were sacrificed; In the sham-operation group

  4. Effects of aspirin plus alpha-tocopherol on brain slices damage after hypoxia-reoxygenation in rats with type 1-like diabetes mellitus.

    Science.gov (United States)

    González-Correa, J A; Arrebola, M M; Cansino, A L; Muñoz-Marín, J; Guerrero, A; Sánchez de la Cuesta, F; De la Cruz, J P

    2006-06-12

    Diabetes mellitus is a risk factor for cerebrovascular ischemic disease. Aspirin (acetylsalicylic acid) is the most widely used drug for the secondary prevention of thrombotic phenomena. It has been also recently demonstrated that alpha-tocopherol influenced in vitro the antiplatelet effect of aspirin. The aim of the present study is to evaluate the effects aspirin plus alpha-tocopherol on cerebral oxidative stress, prostaglandin production and the nitric oxide pathway in a model of hypoxia-reoxygenation in rat brain slices. Our results show an imbalance in brain oxidative status (reflected mainly as the increase in lipid peroxides) as a result of diabetes itself rather than a failure of the glutathione-based antioxidant system. Moreover, our results also show a higher concentration of prostaglandins in the brain of diabetic animals and a higher nitric oxide concentration, mainly through a high iNOS activity. After 180 min of post-hypoxia reoxygenation, LDH activity was 40.6% higher in animals with diabetes, in comparison to non-diabetic animals. The increase of the LDH efflux observed in non-treated rats was reduced by 31.2% with aspirin, by 34.7% with alpha-tocopherol and by 69.8% with the association aspirin-alpha-tocopherol. The accumulation of prostaglandin E2 observed in diabetic non-treated rats was reduced statistically after the treatment with aspirin (34.2% inhibition), alpha-tocopherol (19.3% inhibition) or the association aspirin-alpha-tocopherol (54.4% inhibition). Nitric oxide production after 180 min reoxygenation was significantly reduced in aspirin (36.4%), alpha-tocopherol (22.7%) and aspirin-alpha-tocopherol (77.8%) treated rats with respect to diabetic non-treated animals; this was related mainly with a reduction in iNOS activity. The association between aspirin and alpha tocopherol could protects against brain ischemic-reperfusion damage with a better profile than aspirin alone.

  5. [Expression of c-fos mRNA following moderate lateral fluid percussion brain injury in rats].

    Science.gov (United States)

    Zhang, Y; Chen, G; Sun, G; Liu, M; Liao, Z; Wu, J; Wu, M

    2000-09-01

    This experiment was designed to study the expression of c-fos mRNA in brain following moderate lateral fluid percussion brain injury in rats and to observe the temporal pattern of its expressions following percussion. Male Sprague-Dawley rats were divided into normal control, sham operation control and injury groups. The rats of the injury group were subjected to moderate lateral fluid percussion injury (0.2 MPa). The injury group was then subdivided into 5 min, 15 min, 30 min, 1 h, 2 h groups according to the time elapsed after injury. The expression of c-fos mRNA was studied with reverse transcription polymerase chain reaction(RT-PCR) semi-quantitatively. c-fos mRNA in cortex and brain stem was expressed weakly in control groups. After 5 min of percussion, the expression of c-fos mRNA increased progressively and remained elevated up to 2 h after brain injury. This result suggested that the induction and expression of the c-fos mRNA in cortex and brain stem after fluid percussion brain injury were increased rapidly. The temporal pattern of induction in cortex was similar to that in brain stem.

  6. The status of the fourth ventricle and ambient cisterns predict outcome in moderate and severe traumatic brain injury

    NARCIS (Netherlands)

    Jacobs, Bram; Beems, Tjemme; van der Vliet, Ton M; Borm, George F; Vos, Pieter E

    2010-01-01

    Computed tomography (CT) of the head has become the diagnostic tool of choice, particularly for moderate and severe traumatic brain injury (TBI). Various CT characteristics are associated with outcome, and may therefore be used as outcome predictors. One of the most prominent predictors appears to b

  7. The status of the fourth ventricle and ambient cisterns predict outcome in moderate and severe traumatic brain injury.

    NARCIS (Netherlands)

    Jacobs, B.; Beems, T.; Vliet, A.M. van der; Borm, G.F.; Vos, P.E.

    2010-01-01

    Computed tomography (CT) of the head has become the diagnostic tool of choice, particularly for moderate and severe traumatic brain injury (TBI). Various CT characteristics are associated with outcome, and may therefore be used as outcome predictors. One of the most prominent predictors appears to b

  8. A functional brain-derived neurotrophic factor (BDNF) gene variant increases the risk of moderate-to-severe allergic rhinitis

    NARCIS (Netherlands)

    Jin, Peng; Andiappan, Anand Kumar; Quek, Jia Min; Lee, Bernett; Au, Bijin; Sio, Yang Yie; Irwanto, Astrid; Schurmann, Claudia; Grabe, Hans Joergen; Suri, Bani Kaur; Matta, Sri Anusha; Westra, Harm-Jan; Franke, Lude; Esko, Tonu; Sun, Liangdan; Zhang, Xuejun; Liu, Hong; Zhang, Furen; Larbi, Anis; Xu, Xin; Poidinger, Michael; Liu, Jianjun; Chew, Fook Tim; Rotzschke, Olaf; Shi, Li; Wang, De Yun

    2015-01-01

    Background: Brain-derived neurotrophic factor (BDNF) is a secretory protein that has been implicated in the pathogenesis of allergic rhinitis (AR), atopic asthma, and eczema, but it is currently unknown whether BDNF polymorphisms influence susceptibility to moderate-to-severe AR. Objective: We sough

  9. Epidemiology of Moderate-to-Severe Penetrating Versus Closed Traumatic Brain Injury in the Iraq and Afghanistan Wars

    Science.gov (United States)

    2012-01-01

    penetrating versus closed (mild, moderate, or severe) by ap- plying the DOD surveillance classification ( Athena Kendall- Robbins, Defense and Veterans Brain...intracranial injury without skull or facial fracture) 950.1 950.3 (injury to optic chiasm/pathways or visual cortex) 959.01 (head injury, unspecified

  10. Computed tomography and outcome in moderate and severe traumatic brain injury: hematoma volume and midline shift revisited

    NARCIS (Netherlands)

    Jacobs, B.; Beems, T.; Vliet, T.M. van der; Diaz-Arrastia, R.R.; Borm, G.F.; Vos, P.E.

    2011-01-01

    Intracranial lesion volume and midline shift are powerful outcome predictors in moderate and severe traumatic brain injury (TBI), and therefore they are used in TBI and computed tomography (CT) classification schemes, like the Traumatic Coma Data Bank (TCDB) classification. In this study we aimed to

  11. White matter disruption in moderate/severe pediatric traumatic brain injury: Advanced tract-based analyses

    Directory of Open Access Journals (Sweden)

    Emily L. Dennis

    2015-01-01

    Full Text Available Traumatic brain injury (TBI is the leading cause of death and disability in children and can lead to a wide range of impairments. Brain imaging methods such as DTI (diffusion tensor imaging are uniquely sensitive to the white matter (WM damage that is common in TBI. However, higher-level analyses using tractography are complicated by the damage and decreased FA (fractional anisotropy characteristic of TBI, which can result in premature tract endings. We used the newly developed autoMATE (automated multi-atlas tract extraction method to identify differences in WM integrity. 63 pediatric patients aged 8–19 years with moderate/severe TBI were examined with cross sectional scanning at one or two time points after injury: a post-acute assessment 1–5 months post-injury and a chronic assessment 13–19 months post-injury. A battery of cognitive function tests was performed in the same time periods. 56 children were examined in the first phase, 28 TBI patients and 28 healthy controls. In the second phase 34 children were studied, 17 TBI patients and 17 controls (27 participants completed both post-acute and chronic phases. We did not find any significant group differences in the post-acute phase. Chronically, we found extensive group differences, mainly for mean and radial diffusivity (MD and RD. In the chronic phase, we found higher MD and RD across a wide range of WM. Additionally, we found correlations between these WM integrity measures and cognitive deficits. This suggests a distributed pattern of WM disruption that continues over the first year following a TBI in children.

  12. Sevoflurane postconditioning improves long-term learning and memory of neonatal hypoxia-ischemia brain damage rats via the PI3K/Akt-mPTP pathway.

    Science.gov (United States)

    Lai, Zhongmeng; Zhang, Liangcheng; Su, Jiansheng; Cai, Dongmiao; Xu, Qingxiu

    2016-01-01

    Volatile anesthetic postconditioning has been documented to provide neuroprotection in adult animals. Our aim was to investigate whether sevoflurane postconditioning improves long-term learning and memory of neonatal hypoxia-ischemia brain damage (HIBD) rats, and whether the PI3K/Akt pathway and mitochondrial permeability transition pore (mPTP) opening participate in the effect. Seven-day-old Sprague-Dawley rats were subjected to brain HI and randomly allocated to 10 groups (n=24 each group) and treated as follows: (1) Sham, without hypoxia-ischemia; (2) HI/Control, received cerebral hypoxia-ischemia; (3) HI+Atractyloside (Atr), (4) HI+Cyclosporin A (CsA), (5) HI+sevoflurane (Sev), (6) HI+Sev+ LY294002 (LY), (7) HI+Sev+ L-NAME (L-N), (8) HI+Sev+ SB216763 (SB), (9) HI+Sev+Atr, and (10) HI+Sev+CsA. Twelve rats in each group underwent behavioral testing and their brains were harvested for hippocampus neuron count and morphology study. Brains of the other 12 animals were harvested 24h after intervention to examine the expression of Akt, p-Akt, eNOS, p-eNOS, GSK-3β, p-GSK-3β by Western bolting and mPTP opening. Sevoflurane postconditioning significantly improved the long-term cognitive performance of the rats, increased the number of surviving neurons in CA1 and CA3 hippocampal regions, and protected the histomorphology of the left hippocampus. These effects were abolished by inhibitors of PI3K/eNOS/GSK-3β. Although blocking mPTP opening simulated sevoflurane postconditioning-induced neuroprotection, it failed to enhance it. Sevoflurane postconditioning exerts a neuroprotective effect against HIBD in neonatal rats via PI3K/Akt/eNOS and PI3K/Akt/GSK-3β pathways, and blockage of mPTP opening may be involved in attenuation of histomorphological injury. Copyright © 2015 Elsevier B.V. All rights reserved.

  13. WMS-III findings in litigants following moderate to extremely severe brain trauma.

    Science.gov (United States)

    Langeluddecke, Pauline M; Lucas, Sara K

    2005-07-01

    Published information pertaining to the clinical utility of the WMS-III in assessing memory impairment in traumatic brain injury (TBI) remains inadequate. WMS-III findings are reported for 180 litigants with post-acute moderate to extremely severe TBI, classified into three groups according to injury severity, and a healthy control group. A significant "dose-response" relationship was found between memory impairment and TBI severity for most of the WMS-III indexes and subtests. Effect sizes were large for the Immediate and General Memory Indexes and medium for the Working Memory Index. In general, TBI had a greater effect on the Visual than Auditory Indexes. Effect sizes were greatest for Family Pictures and least for the auditory recognition and working memory tasks. Group findings indicate the immediate memory tasks to be clinically useful in relation to a severe or extremely severe TBI, but not for less severe trauma. Delayed memory tasks do not provide information additional to that obtained from immediate memory measures. The revised Tulsky indexes are no more sensitive to the effects of TBI than the original ones. Differences between WMS-III memory indexes are unlikely to be of diagnostic utility although memory-intelligence discrepancies may be.

  14. Self-awareness and neurobehavioral outcomes, 5 years or more after moderate to severe brain injury.

    Science.gov (United States)

    Kelley, Elizabeth; Sullivan, Campbell; Loughlin, Jennifer K; Hutson, Lee; Dahdah, Marie N; Long, Margaret K; Schwab, Karen A; Poole, John H

    2014-01-01

    To examine self-awareness 5 years or more after traumatic brain injury (TBI) and its relation to outcomes. Sixty-two adults with moderate to severe TBI and significant other (SO) informants (family or close friend). Regional veterans medical center. TBI Follow-up Interview, Community Integration Questionnaire, Satisfaction with Life Scale, and Caregiver Burden Inventory. Five to 16 years after acute inpatient rehabilitation, separate staff contacted and interviewed subjects and SOs. Subject awareness was defined as inverse subject-SO discrepancy scores. Subjects significantly underreported neurologic symptoms and overreported their work and home functioning; their self-ratings of emotional distress and social functioning did not differ from SO ratings. Employment was associated with greater self-awareness of cognitive deficits, even after controlling for injury severity. Subjects' life-satisfaction was associated with better self-reported neurologic functioning, which frequently did not agree with SO ratings. Caregiver burden was worse as SOs perceived subjects as having worse symptoms and poorer work and social integration. Impaired self-awareness remains evident more than 5 years after TBI. People with TBI are more likely to gain employment when they are aware of their cognitive deficits and abilities. However, subjective quality of life, for subjects and SOs, was related to their own perception of the TBI outcomes.

  15. HCdc14A is involved in cell cycle regulation of human brain vascular endothelial cells following injury induced by high glucose, free fatty acids and hypoxia.

    Science.gov (United States)

    Su, Jingjing; Zhou, Houguang; Tao, Yinghong; Guo, Zhuangli; Zhang, Shuo; Zhang, Yu; Huang, Yanyan; Tang, Yuping; Hu, Renming; Dong, Qiang

    2015-01-01

    Cell cycle processes play a vital role in vascular endothelial proliferation and dysfunction. Cell division cycle protein 14 (Cdc14) is an important cell cycle regulatory phosphatase. Previous studies in budding yeast demonstrated that Cdc14 could trigger the inactivation of mitotic cyclin-dependent kinases (Cdks), which are required for mitotic exit and cytokinesis. However, the exact function of human Cdc14 (hCdc14) in cell cycle regulation during vascular diseases is yet to be elucidated. There are two HCdc14 homologs: hCdc14A and hCdc14B. In the current study, we investigated the potential role of hCdc14A in high glucose-, free fatty acids (FFAs)-, and hypoxia-induced injury in cultured human brain vascular endothelial cells (HBVECs). Data revealed that high glucose, FFA, and hypoxia down-regulated hCdc14A expression remarkably, and also affected the expression of other cell cycle-related proteins such as cyclin B, cyclin D, cyclin E, and p53. Furthermore, the combined addition of the three stimuli largely blocked cell cycle progression, decreased cell proliferation, and increased apoptosis. We also determined that hCdc14A was localized mainly to centrosomes during interphase and spindles during mitosis using confocal microscopy, and that it could affect the expression of other cycle-related proteins. More importantly, the overexpression of hCdc14A accelerated cell cycle progression, enhanced cell proliferation, and promoted neoplastic transformation, whereas the knockdown of hCdc14A using small interfering RNA produced the opposite effects. Therefore, these findings provide novel evidence that hCdc14A might be involved in cell cycle regulation in cultured HBVECs during high glucose-, FFA-, and hypoxia-induced injury.

  16. Does Apolipoprotein e4 Status Moderate the Association of Family Environment with Long-Term Child Functioning following Early Moderate to Severe Traumatic Brain Injury? A Preliminary Study.

    Science.gov (United States)

    Treble-Barna, Amery; Zang, Huaiyu; Zhang, Nanhua; Martin, Lisa J; Yeates, Keith Owen; Taylor, H Gerry; Wade, Shari L; Kurowski, Brad G

    2016-09-01

    To examine whether apolipoprotein e4 (APOE) status moderates the association of family environment with child functioning following early traumatic brain injury (TBI). Sixty-five children with moderate to severe TBI and 70 children with orthopedic injury (OI) completed assessments 6, 12, 18 months, and 3.5 and 6.8 years post injury. DNA was extracted from saliva samples and genotyped for APOE e4 status. Linear mixed models examined moderating effects of APOE e4 status on associations between two family environment factors (parenting style, home environment) and three child outcomes (executive functioning, behavioral adjustment, adaptive functioning). Children with TBI who were carriers of the e4 allele showed poorer adaptive functioning relative to non-carriers with TBI and children with OI in the context of low authoritarianism. At high levels of authoritarianism, non-carriers with TBI showed the poorest adaptive functioning among groups. There were no main effects or interactions involving APOE and executive functioning or behavioral adjustment. The APOE e4 allele was detrimental for long-term adaptive functioning in the context of positive parenting, whereas in less optimal parenting contexts, being a non-carrier was detrimental. We provide preliminary evidence for an interaction of APOE e4 status and parenting style in predicting long-term outcomes following early TBI. (JINS, 2016, 22, 859-864).

  17. Endogenous hypothermic response to hypoxia reduces brain injury: Implications for modeling hypoxic-ischemic encephalopathy and therapeutic hypothermia in neonatal mice.

    Science.gov (United States)

    Reinboth, Barbara S; Köster, Christian; Abberger, Hanna; Prager, Sebastian; Bendix, Ivo; Felderhoff-Müser, Ursula; Herz, Josephine

    2016-09-01

    Hypothermia treatment (HT) is the only formally endorsed treatment recommended for hypoxic-ischemic encephalopathy (HIE). However, its success in protecting against brain injury is limited with a number to treat of 7-8. The identification of the target mechanisms of HIE in combination with HT will help to explain ineffective therapy outcomes but also requires stable experimental models in order to establish further neuroprotective therapies. Despite clinical and experimental indications for an endogenous thermoregulatory response to HIE, the potential effects on HIE-induced brain injury have largely been neglected in pre-clinical studies. In the present study we analyzed gray and white matter injury and neurobehavioral outcome in neonatal mice considering the endogenous thermoregulatory response during HIE combined with HT. HIE was induced in postnatal day (PND) 9 C57BL/6 mice through occlusion of the right common carotid artery followed by one hour of hypoxia. Hypoxia was performed at 8% or 10% oxygen (O2) at two different temperatures based on the nesting body core temperature. Using the model which mimics the clinical situation most closely, i.e. through maintenance of the nesting temperature during hypoxia we compared two mild HT protocols (rectal temperature difference 3°C for 4h), initiated either immediately after HIE or with delay of 2h. Injury was determined by histology, immunohistochemistry and western blot analyses at PND 16 and PND 51. Functional outcome was evaluated by Rota Rod, Elevated Plus Maze, Open Field and Novel Object Recognition testing at PND 30-PND 36 and PND 44-PND 50. We show that HIE modeling in neonatal mice is associated with a significant endogenous drop in body core temperature by 2°C resulting in profound neuroprotection, expressed by reduced neuropathological injury scores, reduced loss of neurons, axonal structures, myelin and decreased astrogliosis. Immediately applied post-hypoxic HT revealed slight advantages over a delayed

  18. Effect of chronic intermittent hypoxia on the expression of Nip3, cell apoptosis, β-amyloid protein deposit in mice brain cortex

    Institute of Scientific and Technical Information of China (English)

    ZENG Yi-ming; CAI Kai-jin; CHEN Xiao-yong; WU Minx-ia; LIN Xi

    2009-01-01

    Background Chronic intermittent hypoxia (CIH) is the most important pathophysiologic feature of sleep apnea syndrome (SAS). To explore the relationship between SAS and dementia, the effects of CIH on the expression of Nip3, neuron apoptosis andβ-amyloid protein deposit in the brain cortex of the frontal lobe of mice were evaluated in this study. Methods Thirty male ICR mice were divided into four groups: control group (A, n=-10, sham hypoxia/reoxygenation), 2 weeks CIH group (B, n=-5), 4 weeks CIH group (C, n=-5), and 8 weeks CIH group (D, n=10). The ICR mice were placed in a chamber and exposed to intermittent hypoxia (oxygen concentration changed periodically from (21.72±0.55)% to (6.84±0.47)% every two minutes, eight hours per day). Neuron apoptosis of the cortex of the frontal lobe was detected by means of terminal deoxy-nucleotidyl transferase-mediated in situ end labeling (TUNEL). Immunohistochemical staining was performed for measuring expression of Nip3 and β-amyloid protein. The ultrastructure of neurons was observed under a transmission electron microscope. Results TUNEL positive neurons in each square millimeter in the cortex of the frontal lobe were categorized by median or Ri into group A (1,5.5), group B (133, 13), group C (252, 21), and group D (318, 24). There were significant differences among the above four groups (P=0.000). The significance test was performed between the control group and each CIH group respectively: group A and B (P>0.05); group A and C (P 0.05); groups A and C (P<0.005); and groups A and D (P<0.005). There was no significant difference between groups B and C, groups B and D, and groups C and D. The expression of Nip3 was closely correlated with neuron apoptosis in the brain (P <0.05). The expression ofβ-amyloid protein in the brain of mice was negative in all CIH groups and the control group. Ultrastructure observation showed karyopyknosis of nucleus, swelling of chondriosomes, deposit of lipofuscins and degeneration of

  19. Alteration of Plasma Brain Natriuretic Peptide Level After Acute Moderate Exercise in Professional Athletes

    Directory of Open Access Journals (Sweden)

    Homa Sheikhani

    2011-12-01

    Full Text Available Background: Cardiac fatigue or myocardial damage following exercise until complete exhaustion can increase blood levels of brain natriuretic peptide (BNP in athletes. Objectives: The aim of the present study was to investigate the effect of resistance and acute moderate aerobic exercise on alterations in BNP levels in professional athletes. Materials and Methods: Forty professional athletes who had at least 3 years of a championship background in track and field (aerobic group or body building (resistance group volunteered to participate in the present study. Track and field athletes (n = 20 were requested to run 8 km at 60% to 70% of maximum heart rate. Body building athletes (n = 20 performed a resistance training session of 5 exercises in 3 sets of 10 repetitions at 75% of 1 RM (bench press, seated row, leg extension, leg curl, and leg press. Before and immediately after the exercise, plasma BNP levels of both groups of athletes were measured by PATHFASTTM NT-proBNP assay, an immunochemiluminescent assay using two polyclonal antibodies in sandwich test format, on a PATHFASTTM automated analyzer. Results: Plasma BNP levels immediately following exercise increased significantly as compared with baseline values. Plasma BNP concentrations in the aerobic group were significantly higher than in the resistance group before and after exercise. Moreover, the increase in mean BNP concentrations in aerobic athletes was 7 times more than in resistance athletes. Conclusions: BNP levels in athlete who performed distance exercises increased significantly compared with resistance training. Possibly exercise program type, intensity of exercise, volume of exercise program, and field sport can be factors of changes in BNP levels

  20. Predicting emotional well-being following traumatic brain injury: a test of mediated and moderated models.

    Science.gov (United States)

    Kendall, Elizabeth; Terry, Deborah

    2009-09-01

    This study examined two models for predicting emotional well-being following traumatic brain injury (TBI), namely the Lazarus and Folkman (1984) mediated model of stress and coping and the stress-buffer hypothesis (Cohen & Edwards, 1988). The mediated model suggests that antecedent variables (i.e., personal and environmental resources) will predict emotional well-being, but their effect will be mediated through cognitive variables, such as appraisal and coping. In contrast, the moderated (buffer) hypothesis suggests that resources will protect individuals from the effects of stress, so will have different relationships with outcome at different levels of perceived stress. Ninety individuals with TBI were recruited from a major hospital in Brisbane, Australia. They and their relatives completed questionnaires at three time intervals: discharge, one month and nine months post-discharge, discharge being in 1998. Hierarchical regression was used to examine the relationships among the proposed predictors, mediators and outcomes. Support was found for some aspects of both models in the short-term. In the long-term, stress-buffer effects were no longer apparent. However, with the exception of family support, the predictors all influenced long-term adjustment through their impact on short-term adjustment. The role of family support as a direct predictor of emotional well-being in the long-term is highlighted. The findings have the potential to enable the identification of "at risk" individuals prior to discharge and can highlight important foci for rehabilitation. Specifically, the study has identified the importance of early psychological intervention to address appraisal and the need to engage families in rehabilitation.

  1. Age-related carbon dioxide reactivity in children after moderate and severe traumatic brain injury.

    Science.gov (United States)

    Maa, Tensing; Yeates, Keith Owen; Moore-Clingenpeel, Melissa; O'Brien, Nicole F

    2016-07-01

    OBJECTIVE The objective of this study is to assess carbon dioxide reactivity (CO2R) in children following traumatic brain injury (TBI). METHODS This prospective observational study enrolled children younger than 18 years old following moderate and severe TBI. Thirty-eight mechanically ventilated children had daily CO2R testing performed by measuring changes in their bilateral middle cerebral artery flow velocities using transcranial Doppler ultrasonography (TCD) after a transient increase in minute ventilation. The cohort was divided into 3 age groups: younger than 2 years (n = 12); 2 to 5 years old (n = 9); and older than 5 years (n = 17). RESULTS Children younger than 2 years old had a lower mean CO2R over time. The 2-5-year-old age group had higher mean CO2R than younger patients (p = 0.01), and the highest CO2R values compared with either of the other age groups (vs > 5 years old, p = 0.046; vs < 2 years old, p = 0.002). Having a lower minimum CO2R had a statistically significant negative effect on outcome at discharge (p = 0.0413). Impaired CO2R beyond Postinjury Day 4 trended toward having an effect on outcome at discharge (p = 0.0855). CONCLUSIONS Abnormal CO2R is prevalent in children following TBI, and the degree of impairment varies by age. No clinical or laboratory parameters were identified as risk factors for impaired CO2R. Lower minimum CO2R values are associated with worse outcome at discharge.

  2. Expression of c-fos mRNA following moderate lateral fluid percussion brain injury in rats

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    AIM: To study the expression of c-fos mRNA in brain following moderate lateral fluid percussion brain injury in rats, and to observe the temporal patterns of its expression following percussion. METHODS: Male Sprague-Dawley rats were divided into normal control, sham operation control and injury group. The rats of injury group subjected to moderate lateral fluid percussion injury (0.2 mPa). The injury groups were then subdivided into 5 min, 15 min, 30 min, 1h, 2h groups according to the time elapsed after injury. The expression of c-fos mRNA was studied with reverse transcription polymerase chain reaction (RT-PCR) semi-quantitatively.RESULTS: At 5 min after percussion, the induction of c-fos mRNA was increased, and remained elevated up to 2 h after brain injury.CONCLUSION: The induction and expression of the c-fos mRNA in cortex and brain stem after fluid percussion brain injury were increased rapidly.

  3. Vitamin D prevents hypoxia/reoxygenation-induced blood-brain barrier disruption via vitamin D receptor-mediated NF-kB signaling pathways.

    Directory of Open Access Journals (Sweden)

    Soonmi Won

    Full Text Available Maintaining blood-brain barrier integrity and minimizing neuronal injury are critical components of any therapeutic intervention following ischemic stroke. However, a low level of vitamin D hormone is a risk factor for many vascular diseases including stroke. The neuroprotective effects of 1,25(OH2D3 (vitamin D after ischemic stroke have been studied, but it is not known whether it prevents ischemic injury to brain endothelial cells, a key component of the neurovascular unit. We analyzed the effect of 1,25(OH2D3 on brain endothelial cell barrier integrity and tight junction proteins after hypoxia/reoxygenation in a mouse brain endothelial cell culture model that closely mimics many of the features of the blood-brain barrier in vitro. Following hypoxic injury in bEnd.3 cells, 1,25(OH2D3 treatment prevented the decrease in barrier function as measured by transendothelial electrical resistance and permeability of FITC-dextran (40 kDa, the decrease in the expression of the tight junction proteins zonula occludin-1, claudin-5, and occludin, the activation of NF-kB, and the increase in matrix metalloproteinase-9 expression. These responses were blocked when the interaction of 1,25(OH 2D3 with the vitamin D receptor (VDR was inhibited by pyridoxal 5'-phosphate treatment. Our findings show a direct, VDR-mediated, protective effect of 1,25(OH 2D3 against ischemic injury-induced blood-brain barrier dysfunction in cerebral endothelial cells.

  4. Cerebral Hypoxia

    Science.gov (United States)

    ... time, it can cause coma, seizures, and even brain death. In brain death, there is no measurable activity in the brain, ... time, it can cause coma, seizures, and even brain death. In brain death, there is no measurable activity ...

  5. The status of the fourth ventricle and ambient cisterns predict outcome in moderate and severe traumatic brain injury.

    OpenAIRE

    Jacobs, B.; BEEMS, T.; van der Vliet, A M; Borm, G.F.; Vos, P E

    2010-01-01

    Computed tomography (CT) of the head has become the diagnostic tool of choice, particularly for moderate and severe traumatic brain injury (TBI). Various CT characteristics are associated with outcome, and may therefore be used as outcome predictors. One of the most prominent predictors appears to be the status of the basal cisterns. This study describes the prognostic value of the appearance of individual cisterns and ventricles in relation to that of the basal cisterns. Further, we determin...

  6. Mild Concussion, but Not Moderate Traumatic Brain Injury, Is Associated with Long-Term Depression-Like Phenotype in Mice

    OpenAIRE

    Nikita M Bajwa; Shina Halavi; Mary Hamer; Semple, Bridgette D.; Noble-Haeusslein, Linda J; Mohsen Baghchechi; Alex Hiroto; Hartman, Richard E.; André Obenaus

    2016-01-01

    Mild traumatic brain injuries can lead to long-lasting cognitive and motor deficits, increasing the risk of future behavioral, neurological, and affective disorders. Our study focused on long-term behavioral deficits after repeated injury in which mice received either a single mild CHI (mCHI), a repeated mild CHI (rmCHI) consisting of one impact to each hemisphere separated by 3 days, or a moderate controlled cortical impact injury (CCI). Shams received only anesthesia. Behavioral tests were ...

  7. Hyperbaric Oxygen Therapy in the Treatment of Chronic Mild-Moderate Blast-Induced Traumatic Brain Injury PCS and PTSD

    Science.gov (United States)

    2015-10-01

    Award Number: W81XWH-10-1-0962 TITLE: Hyperbaric Oxygen therapy in the Treatment of Chronic Mild-Moderate Blast-Induced Traumatic Brain Injury...Annual 3. DATES COVERED (From – To) 30Sep2014 - 29Sep2015 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER W81XWH-10-1-0962 Hyperbaric Oxygen therapy in...post- hyperbaric oxygen treatment. Four additional subjects have been screened in October 2015 and nine are awaiting first appointment for

  8. Effect of equiosmolar solutions of hypertonic sodium lactate versus mannitol in craniectomy patients with moderate traumatic brain injury

    Directory of Open Access Journals (Sweden)

    Muhammad R. Ahmad

    2014-03-01

    Full Text Available Background: Brain relaxation and prevention from cerebral edema are essential in craniectomy. Osmotherapy with 20% mannitol are generally used to withdraw fluid from the brain parenchyma, however may cause hemodynamic fluctuation, due to increase diuresis. On the other hand 0.5 M hypertonic sodium lactate (HSL appeared as an alternative of osmotherapy. This study  aimed to observe the effect of hypertonic sodium lactate (HSL on brain relaxation, blood glucose level and hemodynamic variables in craniectomy due to moderate brain injury.Methods: A randomized controlled study of 42 cases with moderate brain injury, aged 18 - 65 years, ASA 1 - 3, between September-November 2012, was carried out. The patients were divided into group M (n = 21 that received 2.5 mL/kg 20% mannitol and group HSL that received 2.5 mL/kg 0.5M HSL. Mean arterial pressures (MAP, central venous pressures (CVP and urine output were measured after induction, and at 15, 30, 45, 60 min after infusion. Brain relaxation was assessed at a four-point scale after opening the duramater. Blood glucose levels were measured before induction and at 60 min after the infusion. Appropriate statistical tests were used for comparison. Unpaired t-test was used to compare hemodynamic and blood glucose level, and chi-square was used to compare brain relaxation.Results: MAP at 60 minute was significantly higher in HSL group than M group (81.66 ± 7.85 vs 74.33 ± 6.18 mmHg; p = 0.002. There was no difference in brain relaxation (p = 0.988. A significant increase in blood glucose level was observed in group HSL (17.95 ± 11.46 mg/dL; p = 0.001.Conclusion: Half-molar HSL was as effective as 20% mannitol in producing brain relaxation, with better hemodynamic stability and gave significant increase in blood glucose level.Keywords: brain relaxation, hemodynamic, hypertonic sodium lactate, mannitol, traumatic brain injury

  9. Are moderate degrees of hyperbilirubinemia in healthy term neonates really safe for the brain?

    NARCIS (Netherlands)

    Soorani-Lunsing, [No Value; Woltil, HA; Hadders-Algra, M

    2001-01-01

    In 1994 the American Academy of Pediatrics recommended more liberal rules for the treatment of hyperbilirubinemia in healthy term newborns. Yet, the safety of moderate degrees of hyperbilirubinemia in healthy term newborns is debated. To evaluate the safety of moderate degrees of hyperbilirubinemia,

  10. Growth and survival in a changing environment: Combined effects of moderate hypoxia and low pH on juvenile bivalve Macoma balthica

    Science.gov (United States)

    Jansson, Anna; Norkko, Joanna; Dupont, Sam; Norkko, Alf

    2015-08-01

    Baltic Sea species live in a complex, variable environment characterized by highly fluctuating hydrology, including large seasonal and diel pH variations. For decades, oxygen deficiency caused by anthropogenic eutrophication has affected the Baltic Sea, and large areas of the seafloor are permanently hypoxic resulting in severely degraded benthic communities. Species living in this system are thus potentially tolerant and adapted to this fluctuating environment, but also vulnerable as illustrated by high mortality of benthic species as a result of hypoxia. In the future, the frequency and extent of regularly co-occurring low oxygen and low pH levels will likely increase with on-going climate change. A key species in the Baltic Sea soft-bottom communities, the bivalve Macoma balthica (L.), experiences such conditions throughout its life-cycle, and therefore serves as a good model organism for studying the combined effects of oxygen and pH conditions. To study the response of M. balthica to multiple changes occurring in the benthic environment, we conducted an experiment to investigate the survival and shell growth of newly settled juveniles simultaneously exposed to two pH levels (7.85 and 7.35) and two oxygen levels (8.5 and 3.0 mg/l) for 29 days in a fully factorial design. Survival was high in all treatments (> 60%), but significantly higher in the two low oxygen treatments (> 70%). Although positive growth was observed in all treatments, pH and oxygen as well as their interaction significantly affected relative growth. The highest growth was observed in the "low O2/high pH" treatment, which was 2.4 times higher than in both treatments with high oxygen. Although the mechanism for these differences remains unknown, hypoxia-induced metabolic depression likely plays a role. Our results highlight the need to know more about the occurrence and performance of benthic species regularly exposed to changing conditions, and of the range and conditions encountered in situ

  11. Hypoxia-inducible factor-1α is involved in isoflurane-induced blood-brain barrier disruption in aged rats model of POCD.

    Science.gov (United States)

    Cao, Yiyun; Li, Zhengqian; Li, Hongping; Ni, Cheng; Li, Lunxu; Yang, Ning; Shi, Chengmei; Zhong, Yanfeng; Cui, Dehua; Guo, Xiangyang

    2017-09-05

    Prolonged exposure to inhaled anesthetics may lead to postoperative cognitive dysfunction (POCD). Nevertheless, the underlying mechanisms are not known. Hypoxia-inducible factor-1α (HIF-1α) and its target gene vascular endothelial growth factor (VEGF) were shown to be activated by inhaled anesthetics. The aim of the present study was to determine the role of HIF-1α in isoflurane-induced blood-brain barrier (BBB) disruption and resultant cognitive impairment. After a 4-h exposure to 1.5% isoflurane in 20-month-old rats, increases in vascular permeability, and disrupted BBB ultrastructure were accompanied by the degradation of tight junction proteins occludin and collagen type IV in brain blood vessels. Increases in HIF-1α and VEGF proteins and activation of MMP-2 in the hippocampus were also observed in the hippocamp of isoflurane-exposed rats compared with control rats. Pharmacological inhibition of HIF-1α activation by 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole (YC-1) markedly suppressed the expression of HIF-1α, VEGF and MMP-2, and mitigated the severity of BBB disruption.YC-1 pretreatment also significantly attenuated isoflurane-induced cognitive deficits in the Morris water maze task. Overall, our results demonstrate that hippocampal HIF-1α/VEGF signaling seems to be the upstream mechanism of isoflurane-induced cognitive impairment, and provides apotential preventive and therapeutic target for POCD. Copyright © 2017. Published by Elsevier B.V.

  12. Circulating progenitor cells during exercise, muscle electro-stimulation and intermittent hypobaric hypoxia in patients with traumatic brain injury: a pilot study.

    Science.gov (United States)

    Corral, Luisa; Conde, Laura; Guillamó, Elisabet; Blasi, Juan; Juncadella, Montserrat; Javierre, Casimiro; Viscor, Ginés; Ventura, Josep L

    2014-01-01

    Circulating progenitor cells (CPC) treatments may have great potential for the recovery of neurons and brain function. To increase and maintain CPC with a program of exercise, muscle electro-stimulation (ME) and/or intermittent-hypobaric-hypoxia (IHH), and also to study the possible improvement in physical or psychological functioning of participants with Traumatic Brain Injury (TBI). Twenty-one participants. Four groups: exercise and ME group (EEG), cycling group (CyG), IHH and ME group (HEG) and control group (CG). Psychological and physical stress tests were carried out. CPC were measured in blood several times during the protocol. Psychological tests did not change. In the physical stress tests the VO2 uptake increased in the EEG and the CyG, and the maximal tolerated workload increased in the HEG. CPC levels increased in the last three weeks in EEG, but not in CyG, CG and HEG. CPC levels increased in the last three weeks of the EEG program, but not in the other groups and we did not detect performed psychological test changes in any group. The detected aerobic capacity or workload improvement must be beneficial for the patients who have suffered TBI, but exercise type and the mechanisms involved are not clear.

  13. The nature of the destructive, compensatory and regenerative processes in the brain of rats after experimental moderate traumatic brain injury and the possibility of their pharmacological correction

    Directory of Open Access Journals (Sweden)

    Mamytova E.M.

    2016-06-01

    Full Text Available Background. The most important task of intensive care patients with traumatic brain injury is prevention and treatment of secondary brain injury, including cerebral ischemia secondary, and neuroprotection, which reduces the impact of secondary damaging factors and allows the nerve cells to escape death. One of the most promising ways of neuroprotection in traumatic brain injury can be neurotrophic therapy. Among the drugs used as neuroprotective agents cerebrolysin occupies a special place. Objective. The aim of this work was to study the effect of the drug cerebrolysin on the morphological changes of brain structures in the early posttraumatic period. Methods. To simulate a traumatic brain injury spring drummer was used, it was experimentally calibrated to apply rats moderate injury. At the time of injury animals were briefly pressed to the foam lining, achieved than horizontal arrangement surface of the cranial vault. In the first subgroup of the main group of animals applied injury secondary to severe without further therapy cerebrolysin. In the second subgroup of the main group after the application of the medium-heavy injury in an experimental neuroprotective therapy used Cerebrolysin (0.1 ml once within 10 days. Calculated absolute number or percentage of 100 cells observed in 10 fields of view of the microscope intact pathologically altered neurons and glial cells. Results. Under the recovery and regeneration (day 21 due to the neuroprotective therapy after traumatic brain injury modeling moderate severity in both hemispheres an increase of normal neurons was observed, it was expressed in the absence of significant differences in this indicator when compared with the control. The same trend was observed on the 14th day after the injury, but occurs only in the damaged hemisphere. On day 21 compared to control a decline of the total number of neurons changed, the values of this index approaches the value 1 day after the injury. Morphometric

  14. Persistent dose-dependent changes in brain structure in young adults with low-to-moderate alcohol exposure in utero.

    Science.gov (United States)

    Eckstrand, Kristen L; Ding, Zhaohua; Dodge, Neil C; Cowan, Ronald L; Jacobson, Joseph L; Jacobson, Sandra W; Avison, Malcolm J

    2012-11-01

    Many children with heavy exposure to alcohol in utero display characteristic alterations in brain size and structure. However, the long-term effects of low-to-moderate alcohol exposure on these outcomes are unknown. Using voxel-based morphometry and region-of-interest analyses, we examined the influence of lower doses of alcohol on gray and white matter composition in a prospectively recruited, homogeneous, well-characterized cohort of alcohol-exposed (n = 11, age 19.5 ± 0.3 years) and control (n = 9, age 19.6 ± 0.5 years) young adults. A large proportion of the exposed individuals were born to mothers whose alcohol consumption during pregnancy was in the low-to-moderate range. There were no differences in total brain volume or total gray or white matter volume between the exposed and control groups. However, gray matter volume was reduced in alcohol-exposed individuals in several areas previously reported to be affected by high levels of exposure, including the left cingulate gyrus, bilateral middle frontal gyri, right middle temporal gyrus, and right caudate nucleus. Notably, this gray matter loss was dose dependent, with higher exposure producing more substantial losses. These results indicate that even at low doses, alcohol exposure during pregnancy impacts brain development and that these effects persist into young adulthood. Copyright © 2012 by the Research Society on Alcoholism.

  15. Epidemiology, severity classification, and outcome of moderate and severe traumatic brain injury: a prospective multicenter study

    NARCIS (Netherlands)

    Andriessen, T.M.J.C.; Horn, J.; Franschman, G.; Naalt, J. van der; Haitsma, I.; Jacobs, B.; Steyerberg, E.W.; Vos, P.E.

    2011-01-01

    Changes in the demographics, approach, and treatment of traumatic brain injury (TBI) patients require regular evaluation of epidemiological profiles, injury severity classification, and outcomes. This prospective multicenter study provides detailed information on TBI-related variables of 508 moderat

  16. Epidemiology, Severity Classification, and Outcome of Moderate and Severe Traumatic Brain Injury: A Prospective Multicenter Study

    NARCIS (Netherlands)

    T.M.J.C. Andriessen; J. Horn; G. Franschman; J. van der Naalt; I. Haitsma; B. Jacobs; E.W. Steyerberg; P.E. Vos

    2011-01-01

    Changes in the demographics, approach, and treatment of traumatic brain injury (TBI) patients require regular evaluation of epidemiological profiles, injury severity classification, and outcomes. This prospective multicenter study provides detailed information on TBI-related variables of 508 moderat

  17. Admission criteria to the Danish Brain Cancer Program are moderately associated with magnetic resonance imaging findings

    DEFF Research Database (Denmark)

    Hill, Thomas Winther; Nielsen, Mie Kiszka; Nepper-Rasmussen, Jørgen

    2013-01-01

    The objective of this study was to evaluate the Danish Brain Cancer Program by examining the criteria for admission to the program and the results of magnetic resonance imaging (MRI) of the brain in 359 patients referred to the program at the Odense University Hospital during one year. The admiss......The objective of this study was to evaluate the Danish Brain Cancer Program by examining the criteria for admission to the program and the results of magnetic resonance imaging (MRI) of the brain in 359 patients referred to the program at the Odense University Hospital during one year....... The admission criteria given by the Danish Health and Medicines Authority are as follows: 1. Prior computed tomography or MRI indicating tumour. 2. Progressive focal neurological deficits. 3. Epileptic seizure in adults. 4. Change in behaviour or cognition showing progression. 5. Headache with progression over...

  18. Epidemiology, Severity Classification, and Outcome of Moderate and Severe Traumatic Brain Injury : A Prospective Multicenter Study

    NARCIS (Netherlands)

    Andriessen, Teuntje M. J. C.; Horn, Janneke; Franschman, Gaby; van der Naalt, Joukje; Haitsma, Iain; Jacobs, Bram; Steyerberg, Ewout W.; Vos, Pieter E.

    2011-01-01

    Changes in the demographics, approach, and treatment of traumatic brain injury (TBI) patients require regular evaluation of epidemiological profiles, injury severity classification, and outcomes. This prospective multicenter study provides detailed information on TBI-related variables of 508 moderat

  19. The status of the fourth ventricle and ambient cisterns predict outcome in moderate and severe traumatic brain injury.

    Science.gov (United States)

    Jacobs, Bram; Beems, Tjemme; van der Vliet, Ton M; Borm, George F; Vos, Pieter E

    2010-02-01

    Computed tomography (CT) of the head has become the diagnostic tool of choice, particularly for moderate and severe traumatic brain injury (TBI). Various CT characteristics are associated with outcome, and may therefore be used as outcome predictors. One of the most prominent predictors appears to be the status of the basal cisterns. This study describes the prognostic value of the appearance of individual cisterns and ventricles in relation to that of the basal cisterns. Further, we determine the interrater and intrarater reliability in the evaluation of the cisterns and ventricles. All consecutive moderate and severe adult TBI patients admitted to our hospital were included in this study as part of the prospective Radboud University Brain Injury Cohort Study (RUBICS). Outcome was assessed at 6 months post-trauma using the Glasgow Outcome Scale-Extended (GOS-E). The predictive value of cisterns and ventricles was determined using multivariate binary logistic regression analysis. We included 126 moderate and 574 severe TBI patients. Absence (complete obliteration), but also compression of the ambient cisterns and/or the fourth ventricle were strongly related to unfavorable outcome and death and emerged as the only significant outcome predictors after multivariate analysis. The assessment of the ambient cisterns and the fourth ventricle had a satisfactory inter- and intrarater reliability (kappa coefficients: 0.80-0.95). We conclude that, because obliteration of the ambient cisterns and the fourth ventricle both are better than the status of the basal cisterns as outcome predictors, they might be used in CT prediction models in cases of moderate and severe TBI.

  20. Effects of platelet and plasma transfusion on outcome in traumatic brain injury patients with moderate bleeding diatheses.

    Science.gov (United States)

    Anglin, Catherine O; Spence, Jeffrey S; Warner, Matthew A; Paliotta, Christopher; Harper, Caryn; Moore, Carol; Sarode, Ravi; Madden, Christopher; Diaz-Arrastia, Ramon

    2013-03-01

    Object Coagulopathy and thrombocytopenia are common after traumatic brain injury (TBI), yet transfusion thresholds for mildly to moderately abnormal ranges of international normalized ratio and platelet count remain controversial. This study evaluates associations between fresh frozen plasma (FFP) and platelet transfusions with long-term functional outcome and survival in TBI patients with moderate hemostatic laboratory abnormalities. Methods This study is a retrospective review of prospectively collected data of patients with mild to severe TBI. Data include patient demographics, several initial injury severity metrics, daily laboratory values, Glasgow Outcome Score- Extended (GOSE) scores, Functional Status Examination (FSE) scores, and survival to 6 months. Correlations were evaluated between these variables and transfusion of FFP, platelets, packed red blood cells (RBCs), cryoprecipitate, recombinant factor VIIa, and albumin. Ordinal regression was performed to account for potential confounding variables to further define relationships between transfusion status and long-term outcome. By analyzing collected data, mild to moderate coagulopathy was defined as an international normalized ratio 1.4-2.0, moderate thrombocytopenia as platelet count 50 × 10(9)/L to 107 × 10(9)/L, and moderate anemia as 21%-30% hematocrit. Results In patients with mild to moderate laboratory hematological abnormalities, univariate analysis shows significant correlations between poor outcome scores and FFP, platelet, or packed RBC transfusion; the volume of FFP or packed RBCs transfused also correlated with poor outcome. Several measures of initial injury and laboratory abnormalities also correlated with poor outcome. Patient age, initial Glasgow Coma Scale score, and highest recorded serum sodium were included in the ordinal regression model using backward variable selection. In the moderate coagulopathy subgroup, patients transfused with FFP were more likely to have a lower GOSE

  1. Admission criteria to the Danish Brain Cancer Program are moderately associated with magnetic resonance imaging findings

    DEFF Research Database (Denmark)

    Hill, Thomas Winther; Nielsen, Mie Kiszka; Nepper-Rasmussen, Jørgen

    2013-01-01

    The objective of this study was to evaluate the Danish Brain Cancer Program by examining the criteria for admission to the program and the results of magnetic resonance imaging (MRI) of the brain in 359 patients referred to the program at the Odense University Hospital during one year....... The admission criteria given by the Danish Health and Medicines Authority are as follows: 1. Prior computed tomography or MRI indicating tumour. 2. Progressive focal neurological deficits. 3. Epileptic seizure in adults. 4. Change in behaviour or cognition showing progression. 5. Headache with progression over...

  2. Regulation of Toll-like receptor 1 and -2 in neonatal mice brains after hypoxia-ischemia

    Directory of Open Access Journals (Sweden)

    Naylor Andrew S

    2011-05-01

    Full Text Available Abstract Background Hypoxic-ischemic (HI brain injury remains a major problem in newborns, resulting in increased risk of neurological disorders. Neonatal HI triggers a broad inflammatory reaction in the brain, including activation of the innate immune system. Toll-like receptors (TLRs, which are key components of the innate immune system, are believed to play a role in adult cerebral ischemic injury. The expression of TLRs in the neonatal brain and their regulation after HI is unknown. Methods Wild type C57BL/6, TLR 1 knockout (KO and TLR 2 KO mice were subjected to HI at postnatal day 9 and sacrificed 30 min, 6 h, 24 h or 5 days after HI. TLR mRNA expression was determined by RT-qPCR and protein and cell type localisation by immunohistochemistry (IHC. To evaluate brain injury, infarct volume was measured in the injured hemisphere. Results mRNA expression was detected for all investigated TLRs (TLR1-9, both in normal and HI exposed brains. After HI, TLR-1 was down-regulated at 30 min and up-regulated at 6 h and 24 h. TLR-2 was up-regulated at 6 h and 24 h, and TLR-7 at 24 h. Both TLR-5 and TLR-8 were down-regulated at 24 h and 30 min respectively. IHC showed an increase of TLR-1 in neurons in the ipsilateral hemisphere after HI. TLR-2 was constitutively expressed in astrocytes and in a population of neurons in the paraventricular nucleus in the hypothalamus. No changes in expression were detected following HI. Following HI, TLR-2 KO mice, but not TLR-1 KO, showed a decreased infarct volume compared to wild type (p = 0.0051. Conclusions This study demonstrates that TLRs are regulated after HI in the neonatal brain. TLR-1 protein was up-regulated in injured areas of the brain but TLR-1 KO animals were not protected from HI. In contrast, TLR-2 was constitutively expressed in the brain and TLR-2 deficiency reduced HI injury. These data suggest that TLR-2, but not TLR-1, plays a role in neonatal HI brain injury.

  3. Plasminogen activator inhibitor-1 mitigates brain injury in a rat model of infection-sensitized neonatal hypoxia-ischemia.

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    Yang, Dianer; Sun, Yu-Yo; Nemkul, Niza; Baumann, Jessica M; Shereen, Ahmed; Dunn, R Scott; Wills-Karp, Marsha; Lawrence, Daniel A; Lindquist, Diana M; Kuan, Chia-Yi

    2013-05-01

    Intrauterine infection exacerbates neonatal hypoxic-ischemic (HI) brain injury and impairs the development of cerebral cortex. Here we used low-dose lipopolysaccharide (LPS) pre-exposure followed by unilateral cerebral HI insult in 7-day-old rats to study the pathogenic mechanisms. We found that LPS pre-exposure blocked the HI-induced proteolytic activity of tissue-type plasminogen activator (tPA), but significantly enhanced NF-κB signaling, microglia activation, and the production of pro-inflammatory cytokines in newborn brains. Remarkably, these pathogenic responses were all blocked by intracerebroventricular injection of a stable-mutant form of plasminogen activator protein-1 called CPAI. Similarly, LPS pre-exposure amplified, while CPAI therapy mitigated HI-induced blood-brain-barrier damage and the brain tissue loss with a therapeutic window at 4 h after the LPS/HI insult. The CPAI also blocks microglia activation following a brain injection of LPS, which requires the contribution by tPA, but not the urinary-type plasminogen activator (uPA), as shown by experiments in tPA-null and uPA-null mice. These results implicate the nonproteolytic tPA activity in LPS/HI-induced brain damage and microglia activation. Finally, the CPAI treatment protects near-normal motor and white matter development despite neonatal LPS/HI insult. Together, because CPAI blocks both proteolytic and nonproteolytic tPA neurotoxicity, it is a promising therapeutics of neonatal HI injury either with or without infection.

  4. [Effect of acute hypoxia on the intensity of free radical processes in the basal nuclei of the brain, and the rat behaviour in the open field test under conditions of altered photoperiod].

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    Sopova, I Iu; Zamorskiĭ, I I

    2011-03-01

    The effect of acute hypoxia on the intensity of free radical processes in the basal nuclei (the nucleus caudatus, globus pallidus. nucleus accumbens. amygdaloid complex) of the brain, and the rat behaviour in the open field test has been studied under conditions of altered photoperiod. It has been shown that constant darkness levels the effect of acute hypoxia on the intensity of lipid peroxidation, preserves the activity of superoxide dismutase and catalase at a higher level, lowers the activity of glutathione peroxidase. Under light, the sensitivity of basal nuclei neurons to acute hypoxia is enhanced, the latter being reflected in intensification of lipid peroxidation at the expense of increased formation of dien conjugates. The activity of catalase at that considerably exceeds the level of even intact rats in all the structures. It has been established that an altered photoperiod modulates the effect of acute hypoxia on the parameters of rat's activity in the open field, the character of their change depending on the nature of a photophase change.

  5. Cognitive reserve as a moderator of postconcussive symptoms in children with complicated and uncomplicated mild traumatic brain injury.

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    Fay, Taryn B; Yeates, Keith Owen; Taylor, H Gerry; Bangert, Barbara; Dietrich, Ann; Nuss, Kathryn E; Rusin, Jerome; Wright, Martha

    2010-01-01

    The occurrence of postconcussive symptoms (PCS) following mild traumatic brain injury (TBI) in children may depend on cognitive reserve capacity. This prospective, longitudinal study examined whether the relationship between mild TBI and PCS is moderated by cognitive ability, which served as a proxy for cognitive reserve. Participants included 182 children with mild TBI and 99 children with orthopedic injuries (OI), ranging from 8 to 15 years of age when injured. Mild TBI were classified as complicated (n = 32) or uncomplicated (n = 150) depending on whether they were associated with trauma-related intracranial abnormalities on magnetic resonance imaging. PCS were assessed initially within 3 weeks of injury, and again at 1, 3, and 12 months post injury. The initial assessment also included standardized tests of children's cognitive skills and retrospective parent ratings of pre-injury symptoms. Hierarchical linear modeling indicated that ratings of PCS were moderated jointly by cognitive ability and injury severity. Children of lower cognitive ability with a complicated mild TBI were especially prone to cognitive symptoms across time according to parents and to high acute levels of PCS according to children's self-ratings. Cognitive reserve is an important moderator of the outcomes of mild TBI in children and adolescents.

  6. Autobiographical memory and episodic future thinking after moderate to severe traumatic brain injury

    DEFF Research Database (Denmark)

    Rasmussen, Katrine Willemoes; Berntsen, Dorthe

    2014-01-01

    , participants also completed two modified Autobiographical Memory Questionnaire items to assess self-reported phenomenal qualities associated with remembering and imagining. In addition, TBI patients underwent neuropsychological assessment. Results revealed that TBI patients recalled/imagined proportionally......Converging evidence suggests that autobiographical memory and episodic future thinking share a common neurocognitive basis. Although previous research has shown that traumatic brain injury (TBI) can impair the ability to remember the personal past, episodic future thinking has not previously been...

  7. G-CSF protects human brain vascular endothelial cells injury induced by high glucose, free fatty acids and hypoxia through MAPK and Akt signaling.

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    Jingjing Su

    Full Text Available Granulocyte-colony stimulating factor (G-CSF has been shown to play a neuroprotective role in ischemic stroke by mobilizing bone marrow (BM-derived endothelial progenitor cells (EPCs, promoting angiogenesis, and inhibiting apoptosis. Impairments in mobilization and function of the BM-derived EPCs have previously been reported in animal and human studies of diabetes where there is both reduction in the levels of the BM-derived EPCs and its ability to promote angiogenesis. This is hypothesized to account for the pathogenesis of diabetic vascular complications such as stroke. Here, we sought to investigate the effects of G-CSF on diabetes-associated cerebral vascular defect. We observed that pretreatment of the cultured human brain vascular endothelial cells (HBVECs with G-CSF largely prevented cell death induced by the combination stimulus with high glucose, free fatty acids (FFA and hypoxia by increasing cell viability, decreasing apoptosis and caspase-3 activity. Cell ultrastructure measured by transmission electron microscope (TEM revealed that G-CSF treatment nicely reduced combination stimulus-induced cell apoptosis. The results from fluorescent probe Fluo-3/AM showed that G-CSF greatly suppressed the levels of intracellular calcium ions under combination stimulus. We also found that G-CSF enhanced the expression of cell cycle proteins such as human cell division cycle protein 14A (hCdc14A, cyclinB and cyclinE, inhibited p53 activity, and facilitated cell cycle progression following combination stimulus. In addition, activation of extracellular signal-regulated kinase1/2 (ERK1/2 and Akt, and deactivation of c-Jun N terminal kinase (JNK and p38 were proved to be required for the pro-survival effects of G-CSF on HBVECs exposed to combination stimulus. Overall, G-CSF is capable of alleviating HBVECs injury triggered by the combination administration with high glucose, FFA and hypoxia involving the mitogen-activated protein kinases (MAPK and Akt

  8. G-CSF Protects Human Brain Vascular Endothelial Cells Injury Induced by High Glucose, Free Fatty Acids and Hypoxia through MAPK and Akt Signaling

    Science.gov (United States)

    Tao, Yinghong; Guo, Jingchun; Guo, Zhuangli; Zhang, Shuo; Zhang, Yu; Huang, Yanyan; Tang, Yuping; Dong, Qiang; Hu, Renming

    2015-01-01

    Granulocyte-colony stimulating factor (G-CSF) has been shown to play a neuroprotective role in ischemic stroke by mobilizing bone marrow (BM)-derived endothelial progenitor cells (EPCs), promoting angiogenesis, and inhibiting apoptosis. Impairments in mobilization and function of the BM-derived EPCs have previously been reported in animal and human studies of diabetes where there is both reduction in the levels of the BM-derived EPCs and its ability to promote angiogenesis. This is hypothesized to account for the pathogenesis of diabetic vascular complications such as stroke. Here, we sought to investigate the effects of G-CSF on diabetes-associated cerebral vascular defect. We observed that pretreatment of the cultured human brain vascular endothelial cells (HBVECs) with G-CSF largely prevented cell death induced by the combination stimulus with high glucose, free fatty acids (FFA) and hypoxia by increasing cell viability, decreasing apoptosis and caspase-3 activity. Cell ultrastructure measured by transmission electron microscope (TEM) revealed that G-CSF treatment nicely reduced combination stimulus-induced cell apoptosis. The results from fluorescent probe Fluo-3/AM showed that G-CSF greatly suppressed the levels of intracellular calcium ions under combination stimulus. We also found that G-CSF enhanced the expression of cell cycle proteins such as human cell division cycle protein 14A (hCdc14A), cyclinB and cyclinE, inhibited p53 activity, and facilitated cell cycle progression following combination stimulus. In addition, activation of extracellular signal-regulated kinase1/2 (ERK1/2) and Akt, and deactivation of c-Jun N terminal kinase (JNK) and p38 were proved to be required for the pro-survival effects of G-CSF on HBVECs exposed to combination stimulus. Overall, G-CSF is capable of alleviating HBVECs injury triggered by the combination administration with high glucose, FFA and hypoxia involving the mitogen-activated protein kinases (MAPK) and Akt signaling

  9. The moderating effects of sex and age on the association between traumatic brain injury and harmful psychological correlates among adolescents.

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    Gabriela Ilie

    Full Text Available BACKGROUND: Although it is well established that sex is a risk factor in acquiring a traumatic brain injury (TBI among adolescents, it has not been established whether it also moderates the influence of other TBI psychological health correlates. METHODS AND FINDINGS: Data were derived from a 2011 population-based cross-sectional school survey, which included 9,288 Ontario 7th-12th graders who completed anonymous self-administered questionnaires in classrooms. Response rate was 62%. Preliminary analyses found no evidence of nonresponse bias in the reporting of TBI. TBI was defined as a hit or blow to the head that resulted in a 5 minutes loss of consciousness or at least one overnight hospitalization due to symptoms associated with it. Reports of lifetime TBI were more common among males than females (23.1%, 95% CI: 20.5, 25.8 vs. 17.1%, 95% CI: 14.7, 19.8. Thirteen correlates were examined and included cigarette smoking, elevated psychological distress, suicide ideation, bully victimization (at school, as well as cyber bullying, bullying others, cannabis use, cannabis dependence and drug use problems, physical injuries, daily smoking, drinking alcohol, binge drinking, use of cannabis, and poor academic performance. Among the outcomes examined, sex moderated the relationship between lifetime TBI and cigarette smoking. In addition, sex and age jointly moderated the relationship between lifetime TBI and daily smoking, alcohol use and physical injuries. Late adolescent males who reported lifetime TBI, relative to females, displayed elevated daily smoking and injuries, whereas their females counterparts displayed elevated past year drinking. Possible bias related to self-report procedures and the preclusion of causal inferences due to the cross-sectional nature of the data are limitations of this study. CONCLUSIONS: TBI differences in outcomes need to be assessed for potential moderating effects of sex and age. Results have important implications for

  10. Does self-construal predict activity in the social brain network? A genetic moderation effect

    Science.gov (United States)

    Ma, Yina; Han, Shihui

    2014-01-01

    Neural activity in the social brain network varies across individuals with different cultural traits and different genetic polymorphisms. It remains unknown whether a specific genetic polymorphism may influence the association between cultural traits and neural activity in the social brain network. We tested whether the serotonin transporter promoter polymorphism (5-HTTLPR) affects the association between self-construals and neural activity involved in reflection of personal attributes of oneself and a significant other (i.e., mother). Using functional MRI, we scanned Chinese adults with short/short (s/s) or long/long (l/l) variants of the 5-HTTLPR during reflection of personal attributes of oneself and one’s mother. We found that, while s/s and l/l genotype groups did not differ significantly in self-construals measured by the Self-Construal Scale, the relationship between self-construal scores and neural responses to reflection of oneself and mother was significantly different between the two genotype groups. Specifically, l/l but not s/s genotype group showed significant association between self-construal scores and activity in the medial prefrontal cortex, bilateral middle frontal cortex, temporoparietal junction, insula and hippocampus during reflection on mental attributes of oneself and mother. Our findings suggest that a specific genetic polymorphism may interact with a cultural trait to shape the neural substrates underlying social cognition. PMID:24009354

  11. EFFECTS OF CANNABIDIOL PLUS HYPOTHERMIA ON SHORT-TERM NEWBORN PIG BRAIN DAMAGE AFTER ACUTE HYPOXIA-ISCHEMIA

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    Hector Lafuente

    2016-07-01

    Full Text Available Background: Hypothermia is standard treatment for neonatal encephalopathy, but near 50% of treated infants have adverse outcomes. Pharmacological therapies can act through complementary mechanisms to hypothermia and would improve neuroprotection. Cannabidiol could be a good candidate.Objective: To test whether immediate treatment with cannabidiol and hypothermia act through complementary brain pathways in hypoxic-ischemic newborn piglets.Methods: Hypoxic-ischemic animals were randomized to receive 30 min after the insult: 1 normothermia- and vehicle-treated group; 2 normothermia- and cannabidiol-treated group; 3 hypothermia- and vehicle-treated group; and 4 hypothermia- and cannabidiol-treated group. Six hours after treatment, brains were processed to qualify the number of neurons by Nissl staining. Proton nuclear magnetic resonance spectra were obtained and analyzed for lactate, N-acetyl-aspartate and glutamate. Metabolite ratios were calculated to assess neuronal damage (lactate/N-acetyl-aspartate and excitotoxicity (glutamate/Nacetyl-aspartate. Western blot studies were performed to quantify protein nitrosylation (oxidative stress and expression of caspase-3 (apoptosis and TNFα (inflammation.Results: Individually, the hypothermia and the cannabidiol treatments reduced the glutamate/Nacetyl-aspartate ratio, as well as TNFα and oxidized protein levels. Also, both therapies reduced the number of necrotic neurons and prevented an increase in lactate/N-acetyl-aspartate ratio. The combined effect of hypothermia and cannabidiol on excitotoxicity, inflammation and oxidative stress, and on histological damage, was greater than either hypothermia or cannabidiol alone.Conclusion: Cannabidiol and hypothermia act complementarily and show additive effects on the main factors leading to hypoxic-ischemic brain damage.

  12. Blast-induced moderate neurotrauma (BINT) elicits early complement activation and tumor necrosis factor α (TNFα) release in a rat brain.

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    Dalle Lucca, Jurandir J; Chavko, Mikulas; Dubick, Michael A; Adeeb, Saleena; Falabella, Michael J; Slack, Jessica L; McCarron, Richard; Li, Yansong

    2012-07-15

    Blast-induced neurotrauma (BINT) is a major medical concern yet its etiology is largely undefined. Complement activation may play a role in the development of secondary injury following traumatic brain injury; however, its role in BINT is still undefined. The present study was designed to characterize the complement system and adaptive immune-inflammatory responses in a rat model of moderate BINT. Anesthetized rats were exposed to a moderate blast (120 kPa) using an air-driven shock tube. Brain tissue injury, systemic and local complement, cerebral edema, inflammatory cell infiltration, and pro-inflammatory cytokine production were measured at 0.5, 3, 48, 72, 120, and 168 h. Injury to brain tissue was evaluated by histological evaluation. Systemic complement was measured via ELSIA. The remaining measurements were determined by immunohistoflourescent staining. Moderate blast triggers moderate brain injuries, elevated levels of local brain C3/C5b-9 and systemic C5b-9, increased leukocyte infiltration, unregulated tumor necrosis factor alpha (TNFα), and aquaporin-4 in rat brain cortex at 3- and 48-hour post blast. Early immune-inflammatory response to BINT involves complement and TNFα, which correlates with hippocampus and cerebral cortex damage. Complement and TNFα activation may be a novel therapeutic target for reducing the damaging effects of BINT inflammation.

  13. Moderate alcohol exposure compromises neural tube midline development in prenatal brain.

    Science.gov (United States)

    Zhou, Feng C; Sari, Youssef; Powrozek, Teresa; Goodlett, Charles R; Li, Ting-Kai

    2003-08-12

    We previously reported that fetal alcohol treatment compromised the development of the midline raphe and the serotonin neurons contained in it. In this study, we report that the timely development of midline neural tissue during neural tube formation is sensitive to alcohol exposure. Pregnant dams were treated from embryonic day 7 (E7, prior to neurulation) or E8.5 (at neurulation) with the following diets: (a) alcohol (ALC), given as either a 20% or 25% ethanol-derived calorie (EDC) liquid diet, or (b) isocaloric liquid diet pair-fed (PF), or (c) standard rat chow (Chow). Fetal brains from each group were examined on E13, E15, or E18. Neural tube development was compromised as a result of alcohol exposure in the following ways: (1) approximately 60% of embryos at E13 and 20% at E15 showed perforation of the floor plate in the diencephalic vesicle, (2) although completely closed at E13, 70-80% of embryos failed to complete the formation of neural tissue at the roof as the alcohol exposure continued to E15, and (3) 60-80% of embryos show delayed 'occlusion' of the ventral canal by newly formed nestin-positive neuroepithelial cells and S100beta-positive glia in the brainstem of E15. The compromised (incomplete) neural tube midline (cNTM) occurred near the ventricles at E13 and E15, but was later completed at E18. In all cases, the cNTM was accompanied by an enlarged ventricle, and dose-dependent brain weight reduction. The midline of the neural tube at the roof and floor plates is known to mediate timely trophic induction for neural differentiation. Prenatal midline deficits also have the potential to affect the development of midline neurons such as raphe, septal nuclei, and the timely crossing of commissural fibers. The results of the liquid diet alcohol exposure paradigm suggest it is more a model for Alcohol-Related Neurodevelopmental Disorder (ARND) featuring neuropsychiatric disorders than for full-blown fetal alcohol syndrome (FAS) with noticeable facial

  14. A Novel Preclinical Model of Moderate Primary Blast-Induced Traumatic Brain Injury.

    Science.gov (United States)

    Divani, Afshin A; Murphy, Amanda J; Meints, Joyce; Sadeghi-Bazargani, Homayoun; Nordberg, Jessica; Monga, Manoj; Low, Walter C; Bhatia, Prerana M; Beilman, Greg J; SantaCruz, Karen S

    2015-07-15

    Blast-induced traumatic brain injury (bTBI) is the "signature" injury of the recent Iraq and Afghanistan wars. Here, we present a novel method to induce bTBI using shock wave (SW) lithotripsy. Using a lithotripsy machine, Wistar rats (N = 70; 408.3 ± 93 g) received five SW pulses to the right side of the frontal cortex at 24 kV and a frequency of 60 Hz. Animals were then randomly divided into three study endpoints: 24 h (n = 25), 72 h (n = 19) and 168 h (n = 26). Neurological and behavioral assessments (Garcia's test, beam walking, Rotarod, and elevated plus maze) were performed at the baseline, and further assessments followed at 3, 6, 24, 72, and 168 h post-injury, if applicable. We performed digital subtraction angiography (DSA) to assess presence of cerebral vasospasm due to induced bTBI. Damage to brain tissue was assessed by an overall histological severity (OHS) score based on depth of injury, area of hemorrhage, and extent of axonal injury. Except for beam walking, OHS was significantly correlated with the other three outcome measures with at least one of their assessments during the first 6 h after the experiment. OHS manifested the highest absolute correlation coefficients with anxiety at the baseline and 6 h post-injury (r(baseline) = -0.75, r(6hrs) = 0.85; p<0.05). Median hemispheric differences for contrast peak values (obtained from DSA studies) for 24, 72, and 168 h endpoints were 3.45%, 3.05% and 0.2%, respectively, with statistically significant differences at 1 versus 7 d (p<0.05) and 3 versus 7 d (p<0.01). In this study, we successfully established a preclinical rat model of bTBI with characteristics similar to those observed in clinical cases. This new method may be useful for future investigations aimed at understanding bTBI pathophysiology.

  15. Parent management of the school reintegration needs of children and youth following moderate or severe traumatic brain injury.

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    Roscigno, Cecelia I; Fleig, Denise K; Knafl, Kathleen A

    2015-01-01

    School reintegration following children's traumatic brain injury (TBI) is still poorly understood from families' perspectives. We aimed to understand how both unique and common experiences during children's school reintegration were explained by parents to influence the family. Data came from an investigation using descriptive phenomenology (2005-2007) to understand parents' experiences in the first five years following children's moderate to severe TBI. Parents (N = 42 from 37 families in the United States) participated in two 90-min interviews (first M = 15 months; second M = 27 months). Two investigators independently coded parents' discussions of school reintegration using content analysis to understand the unique and common factors that parents perceived affected the family. Parents' school negotiation themes included the following: (1) legal versus moral basis for helping the child; (2) inappropriate state and local services that did not consider needs specific to TBI; and (3) involvement in planning, implementing and evaluating the child's education plan. Parents perceived that coordinated and collaboration leadership with school personnel lessened families' workload. Families who home-schooled had unique challenges. School reintegration can add to family workload by changing roles and relationships and by adding to parents' perceived stress in managing of the child's condition. Moderate to severe traumatic brain injury is assumed to be the primary cause of children's morbidities post-injury. Despite laws in the United States meant to facilitate children's school reintegration needs, parents often perceived that policies and practices differed from the intentions of laws and added to the family workload and stress. The school environment of the child (physical, cultural or psychological setting) plays an important long-term role in shaping family roles, relationships and management of the child's condition.

  16. Manganese-Enhanced Magnetic Resonance Imaging as a Diagnostic and Dispositional Tool after Mild-Moderate Blast Traumatic Brain Injury.

    Science.gov (United States)

    Rodriguez, Olga; Schaefer, Michele L; Wester, Brock; Lee, Yi-Chien; Boggs, Nathan; Conner, Howard A; Merkle, Andrew C; Fricke, Stanley T; Albanese, Chris; Koliatsos, Vassilis E

    2016-04-01

    Traumatic brain injury (TBI) caused by explosive munitions, known as blast TBI, is the signature injury in recent military conflicts in Iraq and Afghanistan. Diagnostic evaluation of TBI, including blast TBI, is based on clinical history, symptoms, and neuropsychological testing, all of which can result in misdiagnosis or underdiagnosis of this condition, particularly in the case of TBI of mild-to-moderate severity. Prognosis is currently determined by TBI severity, recurrence, and type of pathology, and also may be influenced by promptness of clinical intervention when more effective treatments become available. An important task is prevention of repetitive TBI, particularly when the patient is still symptomatic. For these reasons, the establishment of quantitative biological markers can serve to improve diagnosis and preventative or therapeutic management. In this study, we used a shock-tube model of blast TBI to determine whether manganese-enhanced magnetic resonance imaging (MEMRI) can serve as a tool to accurately and quantitatively diagnose mild-to-moderate blast TBI. Mice were subjected to a 30 psig blast and administered a single dose of MnCl2 intraperitoneally. Longitudinal T1-magnetic resonance imaging (MRI) performed at 6, 24, 48, and 72 h and at 14 and 28 days revealed a marked signal enhancement in the brain of mice exposed to blast, compared with sham controls, at nearly all time-points. Interestingly, when mice were protected with a polycarbonate body shield during blast exposure, the marked increase in contrast was prevented. We conclude that manganese uptake can serve as a quantitative biomarker for TBI and that MEMRI is a minimally-invasive quantitative approach that can aid in the accurate diagnosis and management of blast TBI. In addition, the prevention of the increased uptake of manganese by body protection strongly suggests that the exposure of an individual to blast risk could benefit from the design of improved body armor.

  17. Mild Concussion, but Not Moderate Traumatic Brain Injury, Is Associated with Long-Term Depression-Like Phenotype in Mice.

    Science.gov (United States)

    Bajwa, Nikita M; Halavi, Shina; Hamer, Mary; Semple, Bridgette D; Noble-Haeusslein, Linda J; Baghchechi, Mohsen; Hiroto, Alex; Hartman, Richard E; Obenaus, André

    2016-01-01

    Mild traumatic brain injuries can lead to long-lasting cognitive and motor deficits, increasing the risk of future behavioral, neurological, and affective disorders. Our study focused on long-term behavioral deficits after repeated injury in which mice received either a single mild CHI (mCHI), a repeated mild CHI (rmCHI) consisting of one impact to each hemisphere separated by 3 days, or a moderate controlled cortical impact injury (CCI). Shams received only anesthesia. Behavioral tests were administered at 1, 3, 5, 7, and 90 days post-injury (dpi). CCI animals showed significant motor and sensory deficits in the early (1-7 dpi) and long-term (90 dpi) stages of testing. Interestingly, sensory and subtle motor deficits in rmCHI animals were found at 90 dpi. Most importantly, depression-like behaviors and social passiveness were observed in rmCHI animals at 90 dpi. These data suggest that mild concussive injuries lead to motor and sensory deficits and affective disorders that are not observed after moderate TBI.

  18. Mild Concussion, but Not Moderate Traumatic Brain Injury, Is Associated with Long-Term Depression-Like Phenotype in Mice.

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    Nikita M Bajwa

    Full Text Available Mild traumatic brain injuries can lead to long-lasting cognitive and motor deficits, increasing the risk of future behavioral, neurological, and affective disorders. Our study focused on long-term behavioral deficits after repeated injury in which mice received either a single mild CHI (mCHI, a repeated mild CHI (rmCHI consisting of one impact to each hemisphere separated by 3 days, or a moderate controlled cortical impact injury (CCI. Shams received only anesthesia. Behavioral tests were administered at 1, 3, 5, 7, and 90 days post-injury (dpi. CCI animals showed significant motor and sensory deficits in the early (1-7 dpi and long-term (90 dpi stages of testing. Interestingly, sensory and subtle motor deficits in rmCHI animals were found at 90 dpi. Most importantly, depression-like behaviors and social passiveness were observed in rmCHI animals at 90 dpi. These data suggest that mild concussive injuries lead to motor and sensory deficits and affective disorders that are not observed after moderate TBI.

  19. Brain-derived neurotrophic factor (BDNF) and TrkB in the piglet brainstem after post-natal nicotine and intermittent hypercapnic hypoxia.

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    Tang, Samantha; Machaalani, Rita; Waters, Karen A

    2008-09-26

    Brain-derived neurotrophic factor (BDNF) and its receptor TrkB play a significant role in the regulation of cell growth, survival and death during central nervous system development. The expression of BDNF and TrkB is affected by noxious insults. Two insults during the early post-natal period that are of interest to our laboratory are exposure to nicotine and to intermittent hypercapnic hypoxia (IHH). Piglet models were used to mimic the conditions associated with the risk factors for the sudden infant death syndrome (SIDS) including post-natal cigarette smoke exposure (nicotine model) and prone sleeping where the infant is subjected to re-breathing of expired gases (IHH model). We aimed to determine the effects of nicotine and IHH, alone or in combination, on pro- and rhBDNF and TrkB expression in the developing piglet brainstem. Four piglet groups were studied, with equal gender ratios in each: control (n=14), nicotine (n=14), IHH (n=10) and nic+IHH (n=14). Applying immunohistochemistry, and studying six nuclei of the caudal medulla, we found that compared to controls, TrkB was the only protein significantly decreased after nicotine and nic+IHH exposure regardless of gender. For pro-BDNF and rhBDNF however, observed changes were more evident in males than females exposed to nicotine and nic+IHH. The implications of these findings are that a prior nicotine exposure makes the developing brainstem susceptible to greater changes in the neurotrophic effects of BDNF and its receptor TrkB in the face of a hypoxic insult, and that the effects are greater in males than females.

  20. Deficits in facial emotion recognition indicate behavioral changes and impaired self-awareness after moderate to severe traumatic brain injury.

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    Jacoba M Spikman

    Full Text Available Traumatic brain injury (TBI is a leading cause of disability, specifically among younger adults. Behavioral changes are common after moderate to severe TBI and have adverse consequences for social and vocational functioning. It is hypothesized that deficits in social cognition, including facial affect recognition, might underlie these behavioral changes. Measurement of behavioral deficits is complicated, because the rating scales used rely on subjective judgement, often lack specificity and many patients provide unrealistically positive reports of their functioning due to impaired self-awareness. Accordingly, it is important to find performance based tests that allow objective and early identification of these problems. In the present study 51 moderate to severe TBI patients in the sub-acute and chronic stage were assessed with a test for emotion recognition (FEEST and a questionnaire for behavioral problems (DEX with a self and proxy rated version. Patients performed worse on the total score and on the negative emotion subscores of the FEEST than a matched group of 31 healthy controls. Patients also exhibited significantly more behavioral problems on both the DEX self and proxy rated version, but proxy ratings revealed more severe problems. No significant correlation was found between FEEST scores and DEX self ratings. However, impaired emotion recognition in the patients, and in particular of Sadness and Anger, was significantly correlated with behavioral problems as rated by proxies and with impaired self-awareness. This is the first study to find these associations, strengthening the proposed recognition of social signals as a condition for adequate social functioning. Hence, deficits in emotion recognition can be conceived as markers for behavioral problems and lack of insight in TBI patients. This finding is also of clinical importance since, unlike behavioral problems, emotion recognition can be objectively measured early after injury

  1. Matrix metalloproteinases and their tissue inhibitors in serum and cerebrospinal fluid of patients with moderate and severe traumatic brain injury

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    Kebin Zheng

    2013-01-01

    Full Text Available Objective: In this study, we investigated matrix metalloproteinases (MMPs and tissue inhibitor of metalloproteinase (TIMPs in cerebrospinal fluid (CSF and plasma of traumatic brain injury (TBI patients. Patients and Methods: A total of 30 patients with moderate and severe TBI and 15 age-matched controls were enrolled in this study. Plasma and CSF samples were collected within 24 h (as the initial value, at 72 and 120 h post injury. CSF and plasma MMP-9, MMP-2, TIMP-1 and TIMP-2 were estimated using ELISA. Different levels of these indexes were compared in the two groups and further investigated the correlation between each other. Results: There was a significant elevation in the levels of the initial MMP-9 in the CSF (P < 0.05, which lasted for 72 h post injury. TIMP-1 kept increasing within 120 h post injury and it was different compared with TIMP-1 at 24 and 72 h post injury. Plasma levels of MMP-9, MMP-2, TIMP-1 and TIMP-2 in TBI patients were also significantly different from those in controls. Furthermore the CSF MMP-9 in patients with severe TBI was higher than that in patients with moderate TBI. In addition, there was a positive relationship between the initial MMP-9 and TIMP-1 at 120 h post injury (r = 0.614, P < 0.01. Conclusion: MMPs and TIMPs are increased in both CSF and plasma of TBI patients. TIMP-1 has a positive correlation with MMP-9 and the initial MMP-9 is associated with the neurological outcomes.

  2. Deficits in facial emotion recognition indicate behavioral changes and impaired self-awareness after moderate to severe traumatic brain injury.

    Science.gov (United States)

    Spikman, Jacoba M; Milders, Maarten V; Visser-Keizer, Annemarie C; Westerhof-Evers, Herma J; Herben-Dekker, Meike; van der Naalt, Joukje

    2013-01-01

    Traumatic brain injury (TBI) is a leading cause of disability, specifically among younger adults. Behavioral changes are common after moderate to severe TBI and have adverse consequences for social and vocational functioning. It is hypothesized that deficits in social cognition, including facial affect recognition, might underlie these behavioral changes. Measurement of behavioral deficits is complicated, because the rating scales used rely on subjective judgement, often lack specificity and many patients provide unrealistically positive reports of their functioning due to impaired self-awareness. Accordingly, it is important to find performance based tests that allow objective and early identification of these problems. In the present study 51 moderate to severe TBI patients in the sub-acute and chronic stage were assessed with a test for emotion recognition (FEEST) and a questionnaire for behavioral problems (DEX) with a self and proxy rated version. Patients performed worse on the total score and on the negative emotion subscores of the FEEST than a matched group of 31 healthy controls. Patients also exhibited significantly more behavioral problems on both the DEX self and proxy rated version, but proxy ratings revealed more severe problems. No significant correlation was found between FEEST scores and DEX self ratings. However, impaired emotion recognition in the patients, and in particular of Sadness and Anger, was significantly correlated with behavioral problems as rated by proxies and with impaired self-awareness. This is the first study to find these associations, strengthening the proposed recognition of social signals as a condition for adequate social functioning. Hence, deficits in emotion recognition can be conceived as markers for behavioral problems and lack of insight in TBI patients. This finding is also of clinical importance since, unlike behavioral problems, emotion recognition can be objectively measured early after injury, allowing for early

  3. Facial Emotion Recognition Deficits following Moderate-Severe Traumatic Brain Injury (TBI): Re-examining the Valence Effect and the Role of Emotion Intensity

    NARCIS (Netherlands)

    Rosenberg, H.; McDonald, S.; Dethier, M.; Kessels, R.P.C.; Westbrook, R.F.

    2014-01-01

    Many individuals who sustain moderate-severe traumatic brain injuries (TBI) are poor at recognizing emotional expressions, with a greater impairment in recognizing negative (e.g., fear, disgust, sadness, and anger) than positive emotions (e.g., happiness and surprise). It has been questioned whether

  4. Facial Emotion Recognition Deficits following Moderate-Severe Traumatic Brain Injury (TBI): Re-examining the Valence Effect and the Role of Emotion Intensity

    NARCIS (Netherlands)

    Rosenberg, H.; McDonald, S.; Dethier, M.; Kessels, R.P.C.; Westbrook, R.F.

    2014-01-01

    Many individuals who sustain moderate-severe traumatic brain injuries (TBI) are poor at recognizing emotional expressions, with a greater impairment in recognizing negative (e.g., fear, disgust, sadness, and anger) than positive emotions (e.g., happiness and surprise). It has been questioned whether

  5. The effect of moderate to severe traumatic brain injury (TBI) on different aspects of memory: a selective review.

    Science.gov (United States)

    Vakil, Eli

    2005-11-01

    Deficient learning and memory are frequently reported as a consequence of traumatic brain injury (TBI). Because of the diffuse nature of the injury, patients with TBI are not the ideal group for studying brain-behavior relations. Nevertheless, characterization of the memory breakdown following TBI could contribute to the assessment and rehabilitation of this patient population. It is well documented that memory is not a unitary system. Accordingly, in this article I review studies that have investigated the long-term effect of moderate to severe TBI on different memory aspects, including explicit and implicit tests of memory. This review demonstrates that TBI affects a large range of memory aspects. One of the conclusions is that the memory impairment observed in TBI patients could be viewed, at least to some degree, as a consequence of a more general cognitive deficit. Thus, unlike patients suffering from global amnesia, memory in patients with TBI is not selectively impaired. Nevertheless, it is possible to detect a subgroup of patients that do meet the criteria of amnesia. However, the most common vulnerable memory processes following TBI very much resemble the memory deficits reported in patients following frontal lobe damage, e.g., difficulties in applying active or effortful strategy in the learning or retrieval process. The suggested similarity between patients with TBI and those suffering from frontal lobe injury should be viewed cautiously; considering the nature of TBI, patients suffering from such injuries are not a homogeneous group. In view of this limitation, the future challenge in this field will be to identify subgroups of patients, either a priori according to a range of factors such as severity of injury, or a posteriori based on their specific memory deficit characteristics. Such a research approach has the potential of explaining much of the variability in findings reported in the literature on the effect of TBI on memory.

  6. Apolipoprotein E polymorphism and outcome after mild to moderate traumatic brain injury: A study of patient population in India

    Directory of Open Access Journals (Sweden)

    Pruthi Nupur

    2010-01-01

    Full Text Available Background: The nature and extent of recovery after traumatic brain injury (TBI is heterogeneous. Apolipoprotein E (APOE plays a major role in repair of cell membrane and growth of neurites following injury to cells. Studies done on the western population have shown that the APOE e4 genotype is associated with poor survival following neurotrauma. Aim: To explore the association of APOE polymorphism and outcome following TBI in a patient population from a tertiary care hospital exclusive for neurological diseases in south India. Patients and Methods: Ninety eight patients who sustained mild to moderate TBI (computed tomography (CT scan brain showing traumatic parenchymal contusions were the subjects of the study and the study period was from November 2003 to December 2008. APOE polymorphism status was determined by PCR technique using venous blood. Patients were assessed on follow-up with a battery of four neuropsychological tests as well as Glasgow outcome scale. Results: Of the 98 patients, 20 (20% patients had at least one APOE e4 allele. A follow-up of minimum six months was available for 73 patients. None of the12 patients who had at least one APOE e4 allele had a poor outcome at six-month follow-up whereas 11(18% patients without an APOE e4 allele had a poor outcome (Fisher′s Exact test, P=0.192. On the neuropsychological tests, performance of patients with APOE e4 allele did not differ significantly from those without these alleles. Conclusion: This study does not support the current contention that the presence of APOE e4 allele should have a significant negative effect on the outcome after TBI.

  7. Cardiac Arrest-Induced Global Brain Hypoxia-Ischemia during Development Affects Spontaneous Activity Organization in Rat Sensory and Motor Thalamocortical Circuits during Adulthood.

    Science.gov (United States)

    Shoykhet, Michael; Middleton, Jason W

    2016-01-01

    Normal maturation of sensory information processing in the cortex requires patterned synaptic activity during developmentally regulated critical periods. During early development, spontaneous synaptic activity establishes required patterns of synaptic input, and during later development it influences patterns of sensory experience-dependent neuronal firing. Thalamocortical neurons occupy a critical position in regulating the flow of patterned sensory information from the periphery to the cortex. Abnormal thalamocortical inputs may permanently affect the organization and function of cortical neuronal circuits, especially if they occur during a critical developmental window. We examined the effect of cardiac arrest (CA)-associated global brain hypoxia-ischemia in developing rats on spontaneous and evoked firing of somatosensory thalamocortical neurons and on large-scale correlations in the motor thalamocortical circuit. The mean spontaneous and sensory-evoked firing rate activity and variability were higher in CA injured rats. Furthermore, spontaneous and sensory-evoked activity and variability were correlated in uninjured rats, but not correlated in neurons from CA rats. Abnormal activity patterns of ventroposterior medial nucleus (VPm) neurons persisted into adulthood. Additionally, we found that neurons in the entopeduncular nucleus (EPN) in the basal ganglia had lower firing rates yet had higher variability and higher levels of burst firing after injury. Correlated levels of power in local field potentials (LFPs) between the EPN and the motor cortex (MCx) were also disrupted by injury. Our findings indicate that hypoxic-ischemic injury during development leads to abnormal spontaneous and sensory stimulus-evoked input patterns from thalamus to cortex. Abnormal thalamic inputs likely permanently and detrimentally affect the organization of cortical circuitry and processing of sensory information. Hypoxic-ischemic injury also leads to abnormal single neuron and

  8. DOWN-REGULATION OF THE HYPOTHALAMO-PITUITARY-ADRENAL AXIS REDUCES BRAIN-DAMAGE AND NUMBER OF SEIZURES FOLLOWING HYPOXIA/ISCHAEMIA IN RATS

    NARCIS (Netherlands)

    KRUGERS, HJ; KNOLLEMA, S; KEMPER, RHA; TERHORST, GJ; KORF, J

    1995-01-01

    Several reports suggest that the activity of the hypothalamo-pituitary-adrenal axis (HPA-axis) is increased following hypoxia/ischaemia and that this might be associated with increased neuronal vulnerability. The main goal of this study was to examine the effects of down-regulation of the HPA-axis

  9. Ventilatory long-term facilitation is evident after initial and repeated exposure to intermittent hypoxia in mice genetically depleted of brain serotonin.

    Science.gov (United States)

    Hickner, Stephen; Hussain, Najaah; Angoa-Perez, Mariana; Francescutti, Dina M; Kuhn, Donald M; Mateika, Jason H

    2014-02-01

    Our study was designed to determine if central nervous system (CNS) serotonin is required for the induction of ventilatory long-term facilitation (LTF) in intact, spontaneously breathing mice. Nineteen tryptophan hydroxylase 2-deficient (Tph2(-/-)) mice, devoid of serotonin in the CNS, and their wild-type counterparts (Tph2(+/+)) were exposed to intermittent hypoxia each day for 10 consecutive days. The ventilatory response to intermittent hypoxia was greater in the Tph2(+/+) compared with the Tph2(-/-) mice (1.10 ± 0.10 vs. 0.77 ± 0.01 ml min(-1)·percent(-1) oxygen; P ≤ 0.04). Ventilatory LTF, caused by increases in breathing frequency, was evident in Tph2(+/+) and Tph2(-/-) mice following exposure to intermittent hypoxia each day; however, the magnitude of the response was greater in the Tph2(+/+) compared with the Tph2(-/-) mice (1.11 ± 0.02 vs. 1.05 ± 0.01 normalized to baseline on each day; P ≤ 0.01). The magnitude of ventilatory LTF increased significantly from the initial to the finals days of the protocol in the Tph2(-/-) (1.06 ± 0.02 vs. 1.11 ± 0.03 normalized to baseline on the initial days; P ≤ 0.004) but not in the Tph2(+/+) mice. This enhanced response was mediated by increases in tidal volume. Body temperature and metabolic rate did not account for differences in the magnitude of ventilatory LTF observed between groups after acute and repeated daily exposure to intermittent hypoxia. We conclude that ventilatory LTF, after acute exposure to intermittent hypoxia, is mediated by increases in breathing frequency and occurs in the absence of serotonin, although the magnitude of the response is diminished. This weakened response is enhanced following repeated daily exposure to intermittent hypoxia, via increases in tidal volume, to a similar magnitude evident in Tph2(+/+) mice. Thus the magnitude of ventilatory LTF following repeated daily exposure to intermittent hypoxia is not dependent on the presence of CNS serotonin.

  10. Moderate exercise and chronic stress produce counteractive effects on different areas of the brain by acting through various neurotransmitter receptor subtypes: A hypothesis

    Directory of Open Access Journals (Sweden)

    Saha Asit K

    2006-09-01

    Full Text Available Abstract Background Regular, "moderate", physical exercise is an established non-pharmacological form of treatment for depressive disorders. Brain lateralization has a significant role in the progress of depression. External stimuli such as various stressors or exercise influence the higher functions of the brain (cognition and affect. These effects often do not follow a linear course. Therefore, nonlinear dynamics seem best suited for modeling many of the phenomena, and putative global pathways in the brain, attributable to such external influences. Hypothesis The general hypothesis presented here considers only the nonlinear aspects of the effects produced by "moderate" exercise and "chronic" stressors, but does not preclude the possibility of linear responses. In reality, both linear and nonlinear mechanisms may be involved in the final outcomes. The well-known neurotransmitters serotonin (5-HT, dopamine (D and norepinephrine (NE all have various receptor subtypes. The article hypothesizes that 'Stress' increases the activity/concentration of some particular subtypes of receptors (designated nts for each of the known (and unknown neurotransmitters in the right anterior (RA and left posterior (LP regions (cortical and subcortical of the brain, and has the converse effects on a different set of receptor subtypes (designated nth. In contrast, 'Exercise' increases nth activity/concentration and/or reduces nts activity/concentration in the LA and RP areas of the brain. These effects may be initiated by the activation of Brain Derived Neurotrophic Factor (BDNF (among others in exercise and its suppression in stress. Conclusion On the basis of this hypothesis, a better understanding of brain neurodynamics might be achieved by considering the oscillations caused by single neurotransmitters acting on their different receptor subtypes, and the temporal pattern of recruitment of these subtypes. Further, appropriately designed and planned experiments

  11. Anger Self-Management Training for Chronic Moderate to Severe Traumatic Brain Injury: Results of a Randomized Controlled Trial.

    Science.gov (United States)

    Hart, Tessa; Brockway, Jo Ann; Maiuro, Roland D; Vaccaro, Monica; Fann, Jesse R; Mellick, David; Harrison-Felix, Cindy; Barber, Jason; Temkin, Nancy

    To test efficacy of 8-session, 1:1 treatment, anger self-management training (ASMT), for chronic moderate to severe traumatic brain injury (TBI). Three US outpatient treatment facilities. Ninety people with TBI and elevated self-reported anger; 76 significant others (SOs) provided collateral data. Multicenter randomized controlled trial with 2:1 randomization to ASMT or structurally equivalent comparison treatment, personal readjustment and education (PRE). Primary outcome assessment 1 week posttreatment; 8-week follow-up. Response to treatment defined as 1 or more standard deviation change in self-reported anger. SO-rated anger, emotional and behavioral status, satisfaction with life, timing of treatment response, participant and SO-rated global change, and treatment satisfaction. State-Trait Anger Expression Inventory-Revised Trait Anger (TA) and Anger Expression-Out (AX-O) subscales; Brief Anger-Aggression Questionnaire (BAAQ); Likert-type ratings of treatment satisfaction, global changes in anger and well-being. After treatment, ASMT response rate (68%) exceeded that of PRE (47%) on TA but not AX-O or BAAQ; this finding persisted at 8-week follow-up. No significant between-group differences in SO-reported response rates, emotional/behavioral status, or life satisfaction. ASMT participants were more satisfied with treatment and rated global change in anger as significantly better; SO ratings of global change in both anger and well-being were superior for ASMT. ASMT was efficacious and persistent for some aspects of problematic anger. More research is needed to determine optimal dose and essential ingredients of behavioral treatment for anger after TBI.

  12. Hypoxia-inducible factor-1 (HIF-1) is involved in the regulation of hypoxia-stimulated expression of monocyte chemoattractant protein-1 (MCP-1/CCL2) and MCP-5 (Ccl12) in astrocytes

    OpenAIRE

    Mojsilovic-Petrovic Jelena; Callaghan Debbie; Cui Hong; Dean Clare; Stanimirovic Danica B; Zhang Wandong

    2007-01-01

    Abstract Background Neuroinflammation has been implicated in various brain pathologies characterized by hypoxia and ischemia. Astroglia play an important role in the initiation and propagation of hypoxia/ischemia-induced inflammation by secreting inflammatory chemokines that attract neutrophils and monocytes into the brain. However, triggers of chemokine up-regulation by hypoxia/ischemia in these cells are poorly understood. Hypoxia-inducible factor-1 (HIF-1) is a dimeric transcriptional fact...

  13. Effects of hypoxia-inducible factor 1 on ischemic cerebrovascular disease

    Institute of Scientific and Technical Information of China (English)

    Yongjie Luo; Xiaoping Wang; Hongbin Sun

    2008-01-01

    Hypoxia-inducible factor I, a nuclear transcription factor, is induced by hypoxia. Hypoxia-inducible factor I, a heterodimeric DNA-binding protein, is composed of hypoxia-inducible factor 1α and hypoxia-inducible factor 1 β subunits, which are family members of the basic helix-loop-helix-PER, ARNT, SIM (PAS) protein. O2 concentration regulates hypoxia-inducible factor 1 activity via this subunit. Hypoxia-inducible factor 1α plays a major role in response to hypoxia and transcriptional activation, as well as in the target gene specificity of the DNA enhancer. Hypoxia-inducible factor 1β cannot be induced by hypoxia. This effect may be due to hypoxia-inducible factor 1 stability and activated conformation due to dimerization. Previous studies have shown that hypoxia-inducible factor 1 mRNA expression increases in the penumbra following ischemia/hypoxia. Hypoxia-inducible factor 1 plays an important role in brain tissue injury alter ischemia by affecting a series of target genes, elevating tolerance to hypoxia, and ensuring survival of neural cells. This article summarizes the structure, function, expression, regulatory mechanisms, biological effects, and significance of hypoxia-inducible factor 1 in patients with ischemic cerebrovascular disease. As a transcriptional activator, hypoxia- inducible factor 1 plays a key role in hypoxic responses by stabilizing the internal environment. It also has been shown to regulate the expression of several genes. The regulatory effects of hypoxia-inducible factor 1 in patients with ischemic cerebrovascular disease have been described. The present review re-examined the concept of brain protection at the level of gene regulation.

  14. Visual Fixation in the ICU: A Strong Predictor of Long-Term Recovery After Moderate-to-Severe Traumatic Brain Injury.

    Science.gov (United States)

    Arbour, Caroline; Baril, Andrée-Ann; Westwick, Harrison J; Potvin, Marie-Julie; Gilbert, Danielle; Giguère, Jean-François; Lavigne, Gilles J; Desautels, Alex; Bernard, Francis; Laureys, Steven; Gosselin, Nadia

    2016-12-01

    Posttraumatic amnesia is superior to the initial Glasgow Coma Scale score for predicting traumatic brain injury recovery, but it takes days/weeks to assess. Here, we examined whether return of visual fixation-a potential marker of higher cognitive function-within 24 hours of ICU admission could be used as an early predictor of traumatic brain injury recovery. Two-phase cohort study. Level-I trauma ICU. Moderate-to-severe traumatic brain injury discharged alive between 2010 and 2013. None. Return of visual fixation was assessed through standard behavioral assessments in 181 traumatic brain injury patients who had lost the ability to fixate at ICU admission (phase 1) and compared with posttraumatic amnesia duration and the initial Glasgow Coma Scale score to predict performance on the Glasgow Outcome Scale-Extended 10-40 months after injury (n = 144; phase 2a). A subgroup also completed a visual attention task (n = 35; phase 2b) and a brain MRI after traumatic brain injury (n = 23; phase 2c). With an area under the curve equal to 0.85, presence/absence of visual fixation at 24 hours of ICU admission was found as performant as posttraumatic amnesia (area under the curve, 0.81; difference between area under the curve, 0.04; p = 0.28) for predicting patients' Glasgow Outcome Scale-Extended score. Conversely, the initial Glasgow Coma Scale score was not (area under the curve, 0.63). Even when controlling for age/medication/CT scan findings, fixation remained a significant predictor of Glasgow Outcome Scale-Extended scores (β, -0.29; p brain volume deficits were also observed in patients who could not fixate at 24 hours of ICU admission versus those who could. Visual fixation within 24 hours of ICU admission could be as performant as posttraumatic amnesia for predicting traumatic brain injury recovery, introducing a new variable of interest in traumatic brain injury outcome research.

  15. Chronic Treatment with a Water-Soluble Extract from the Culture Medium of Ganoderma lucidum Mycelia Prevents Apoptosis and Necroptosis in Hypoxia/Ischemia-Induced Injury of Type 2 Diabetic Mouse Brain

    Directory of Open Access Journals (Sweden)

    Meiyan Xuan

    2015-01-01

    Full Text Available Type 2 diabetes mellitus has been known to increase systemic oxidative stress by chronic hyperglycemia and visceral obesity and aggravate cerebral ischemic injury. On the basis of our previous study regarding a water-soluble extract from the culture medium of Ganoderma lucidum mycelia (designed as MAK, which exerts antioxidative and neuroprotective effects, the present study was conducted to evaluate the preventive effects of MAK on apoptosis and necroptosis (a programmed necrosis induced by hypoxia/ischemia (H/I in type 2 diabetic KKAy mice. H/I was induced by a combination of unilateral common carotid artery ligation with hypoxia (8% O2 for 20 min and subsequent reoxygenation. Pretreatment with MAK (1 g/kg, p.o. for a week significantly reduced H/I-induced neurological deficits and brain infarction volume assessed at 24 h of reoxygenation. Histochemical analysis showed that MAK significantly suppressed superoxide production, neuronal cell death, and vacuolation in the ischemic penumbra, which was accompanied by a decrease in the numbers of TUNEL- or cleaved caspase-3-positive cells. Furthermore, MAK decreased the expression of receptor-interacting protein kinase 3 mRNA and protein, a key molecule for necroptosis. These results suggest that MAK confers resistance to apoptotic and necroptotic cell death and relieves H/I-induced cerebral ischemic injury in type 2 diabetic mice.

  16. Cognition and chronic hypoxia in pulmonary diseases

    Directory of Open Access Journals (Sweden)

    Renata Areza-Fegyveres

    Full Text Available Abstract Lung disease with chronic hypoxia has been associated with cognitive impairment of the subcortical type. Objectives: To review the cognitive effects of chronic hypoxia in patients with lung disease and its pathophysiology in brain metabolism. Methods: A literature search of Pubmed data was performed. The words and expressions from the text subitems including "pathophysiology of brain hypoxia", "neuropsychology and hypoxia", "white matter injury and chronic hypoxia", for instance, were key words in a search of reports spanning from 1957 to 2009. Original articles were included. Results: According to national and international literature, patients with chronic obstructive pulmonary disease and sleep obstructive apnea syndrome perform worse on tests of attention, executive functions and mental speed. The severity of pulmonary disease correlates with degree of cognitive impairment. These findings support the diagnosis of subcortical type encephalopathy. Conclusion: Cognitive effects of clinical diseases are given limited importance in congresses and symposia about cognitive impairment and its etiology. Professionals that deal with patients presenting cognitive loss should be aware of the etiologies outlined above as a major cause or potential contributory factors, and of their implications for treatment adherence and quality of life.

  17. Migraine induced by hypoxia

    DEFF Research Database (Denmark)

    Arngrim, Nanna; Schytz, Henrik Winther; Britze, Josefine

    2016-01-01

    Migraine with aura is prevalent in high-altitude populations suggesting an association between migraine aura and hypoxia. We investigated whether experimental hypoxia triggers migraine and aura attacks in patients suffering from migraine with aura. We also investigated the metabolic and vascular...... response to hypoxia. In a randomized double-blind crossover study design, 15 migraine with aura patients were exposed to 180 min of normobaric hypoxia (capillary oxygen saturation 70-75%) or sham on two separate days and 14 healthy controls were exposed to hypoxia. Glutamate and lactate concentrations...... in the visual cortex were measured by proton magnetic resonance spectroscopy. The circumference of cranial arteries was measured by 3 T high-resolution magnetic resonance angiography. Hypoxia induced migraine-like attacks in eight patients compared to one patient after sham (P = 0.039), aura in three...

  18. Therapeutic effects of L-Cysteine in newborn mice subjected to hypoxia-ischemia brain injury via the CBS/H2S system: Role of oxidative stress and endoplasmic reticulum stress.

    Science.gov (United States)

    Liu, Song; Xin, Danqing; Wang, Lingxiao; Zhang, Tiantian; Bai, Xuemei; Li, Tong; Xie, Yunkai; Xue, Hao; Bo, Shishi; Liu, Dexiang; Wang, Zhen

    2017-10-01

    Neonatal hypoxic-ischemic (HI) injury is a major cause of neonatal death and neurological dysfunction. H2S has been shown to protect against hypoxia-induced injury and apoptosis of neurons. L-Cysteine is catalyzed by cystathionine-β-synthase (CBS) in the brain and sequentially produces endogenous H2S. The present study was designed to investigate whether L-Cysteine could attenuate the acute brain injury and improve neurobehavioral outcomes following HI brain injury in neonatal mice by releasing endogenous H2S. L-Cysteine treatment significantly attenuated brain edema and decreased infarct volume and neuronal cell death, as shown by a decrease in the Bax/Bcl-2 ratio, suppression of caspase-3 activation, and reduced phosphorylation of Akt and ERK at 72h after HI. Additionally, L-Cysteine substantially up-regulated NF-E2-related factor 2 and heme oxygenase-1 expression. L-Cysteine also decreased endoplasmic reticulum (ER) stress-associated pro-apoptotic protein expression. Furthermore, L-Cysteine had long-term effects by protecting against the loss of ipsilateral brain tissue and improving neurobehavioral outcomes. Importantly, pre-treatment with a CBS inhibitor significantly attenuated the neuroprotection of L-Cysteine on HI insult. Thus, L-Cysteine exerts neuroprotection against HI-induced injury in neonates via the CBS/H2S pathway, mediated in part by anti-apoptotic effects and reduced oxidative stress and ER stress. Thus, L-Cysteine may be a promising treatment for HI. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  19. Therapeutic effects of L-Cysteine in newborn mice subjected to hypoxia-ischemia brain injury via the CBS/H2S system: Role of oxidative stress and endoplasmic reticulum stress

    Directory of Open Access Journals (Sweden)

    Song Liu

    2017-10-01

    Full Text Available Neonatal hypoxic-ischemic (HI injury is a major cause of neonatal death and neurological dysfunction. H2S has been shown to protect against hypoxia-induced injury and apoptosis of neurons. L-Cysteine is catalyzed by cystathionine-β-synthase (CBS in the brain and sequentially produces endogenous H2S. The present study was designed to investigate whether L-Cysteine could attenuate the acute brain injury and improve neurobehavioral outcomes following HI brain injury in neonatal mice by releasing endogenous H2S. L-Cysteine treatment significantly attenuated brain edema and decreased infarct volume and neuronal cell death, as shown by a decrease in the Bax/Bcl-2 ratio, suppression of caspase-3 activation, and reduced phosphorylation of Akt and ERK at 72 h after HI. Additionally, L-Cysteine substantially up-regulated NF-E2-related factor 2 and heme oxygenase-1 expression. L-Cysteine also decreased endoplasmic reticulum (ER stress-associated pro-apoptotic protein expression. Furthermore, L-Cysteine had long-term effects by protecting against the loss of ipsilateral brain tissue and improving neurobehavioral outcomes. Importantly, pre-treatment with a CBS inhibitor significantly attenuated the neuroprotection of L-Cysteine on HI insult. Thus, L-Cysteine exerts neuroprotection against HI-induced injury in neonates via the CBS/H2S pathway, mediated in part by anti-apoptotic effects and reduced oxidative stress and ER stress. Thus, L-Cysteine may be a promising treatment for HI.

  20. Tumor hypoxia and microscopic diffusion capacity in brain tumors: A comparison of {sup 62}Cu-Diacetyl-Bis (N4-Methylthiosemicarbazone) PET/CT and diffusion-weighted MR imaging

    Energy Technology Data Exchange (ETDEWEB)

    Hino-Shishikura, Ayako; Tateishi, Ukihide; Shibata, Hirofumi; Yoneyama, Tomohiro; Nishii, Toshiaki; Torii, Ikuo; Inoue, Tomio [Graduate School of Medicine, Yokohama City University, Department of Radiology, Yokohama (Japan); Tateishi, Kensuke; Ohtake, Makoto; Kawahara, Nobutaka [Graduate School of Medicine, Yokohama City University, Department of Neurosurgery, Yokohama (Japan)

    2014-07-15

    The aim of this study was to clarify the relationship between tumor hypoxia and microscopic diffusion capacity in primary brain tumors using {sup 62}Cu-Diacetyl-Bis (N4-Methylthiosemicarbazone) ({sup 62}Cu-ATSM) PET/CT and diffusion-weighted MR imaging (DWI). This study was approved by the institutional human research committee and was HIPAA compliant, and informed consent was obtained from all patients. {sup 62}Cu-ATSM PET/CT and DWI were performed in a total of 40 primary brain tumors of 34 patients with low grade glioma (LGG, n = 13), glioblastoma (GBM, n = 20), and primary central nervous system lymphoma (PCNSL, n = 7). {sup 62}Cu-ATSM PET/CT parameters and apparent diffusion coefficient (ADC) obtained by DWI were compared. High intensity signals by {sup 62}Cu-ATSM PET/CT and DWI in patients with GBM and PCNSL, and low intensity signals in LGG patients were observed. An inverse correlation was found between maximum SUV (SUV{sub max}) and minimum ADC (ADC{sub min}) (r = -0.583, p < 0.0001), and between tumor/brain ratio (T/B{sub ratio}) and ADC{sub min} for all tumors (r = -0.532, p < 0.0001). Both SUV{sub max} and T/B{sub ratio} in GBM were higher than LGG (p < 0.0001 and p < 0.0001), and those in PCNSL were also higher than GBM (p = 0.033 and p = 0.044). The ADC{sub min} was lower in GBM (p = 0.011) and PCNSL (p = 0.01) than in LGG, while no significant difference was found between GBM and PCNSL (p = 0.90). Tumor hypoxia assessed by {sup 62}Cu-ATSM PET/CT correlated with microscopic diffusion capacity obtained by DWI in brain tumors. Both {sup 62}Cu-ATSM PET/CT and DWI were considered feasible imaging methods for grading glioma. However, {sup 62}Cu-ATSM PET/CT provided additional diagnostic information to differentiate between GBM and PCNSL. (orig.)

  1. Catechol-O-Methyltransferase Genotypes and Parenting Influence on Long-Term Executive Functioning After Moderate to Severe Early Childhood Traumatic Brain Injury: An Exploratory Study.

    Science.gov (United States)

    Kurowski, Brad G; Treble-Barna, Amery; Zang, Huaiyu; Zhang, Nanhua; Martin, Lisa J; Yeates, Keith Owen; Taylor, H Gerry; Wade, Shari L

    2017-01-05

    To examine catechol-O-methyltransferase (COMT) rs4680 genotypes as moderators of the effects of parenting style on postinjury changes in parent behavior ratings of executive dysfunction following moderate to severe early childhood traumatic brain injury. Research was conducted in an outpatient setting. Participants included children admitted to hospital with moderate to severe traumatic brain injury (n = 55) or orthopedic injuries (n = 70) between ages 3 and 7 years. Prospective cohort followed over 7 years postinjury. Parenting Practices Questionnaire and the Behavior Rating Inventory of Executive Functioning obtained at baseline, 6, 12, and 18 months, and 3.5 and 6.8 years postinjury. DNA was collected from saliva samples, purified using the Oragene (DNA Genotek, Ottawa, Ontario, Canada) OG-500 self-collection tubes, and analyzed using TaqMan (Applied Biosystems, Thermo Fisher Scientific, Waltham, Massachusetts) assay protocols to identify the COMT rs4680 polymorphism. Linear mixed models revealed a significant genotype × parenting style × time interaction (F = 5.72, P = .02), which suggested that the adverse effects of authoritarian parenting on postinjury development of executive functioning were buffered by the presence of the COMT AA genotype (lower enzyme activity, higher dopamine levels). There were no significant associations of executive functioning with the interaction between genotype and authoritative or permissive parenting ratings. The lower activity COMT rs4680 genotype may buffer the negative effect of authoritarian parenting on long-term executive functioning following injury in early childhood. The findings provide preliminary evidence for associations of parenting style with executive dysfunction in children and for a complex interplay of genetic and environmental factors as contributors to decreases in these problems after traumatic injuries in children. Further investigation is warranted to understand the interplay among genetic and

  2. Inverse relationship between brain glucose and ketone metabolism in adults during short-term moderate dietary ketosis: A dual tracer quantitative positron emission tomography study.

    Science.gov (United States)

    Courchesne-Loyer, Alexandre; Croteau, Etienne; Castellano, Christian-Alexandre; St-Pierre, Valérie; Hennebelle, Marie; Cunnane, Stephen C

    2017-07-01

    Ketones (principally β-hydroxybutyrate and acetoacetate (AcAc)) are an important alternative fuel to glucose for the human brain, but their utilisation by the brain remains poorly understood. Our objective was to use positron emission tomography (PET) to assess the impact of diet-induced moderate ketosis on cerebral metabolic rate of acetoacetate (CMRa) and glucose (CMRglc) in healthy adults. Ten participants (35 ± 15 y) received a very high fat ketogenic diet (KD) (4.5:1; lipid:protein plus carbohydrates) for four days. CMRa and CMRglc were quantified by PET before and after the KD with the tracers, (11)C-AcAc and (18)F-fluorodeoxyglucose ((18)F-FDG), respectively. During the KD, plasma ketones increased 8-fold ( p = 0.005) while plasma glucose decreased by 24% ( p = 0.005). CMRa increased 6-fold ( p = 0.005), whereas CMRglc decreased by 20% ( p = 0.014) on the KD. Plasma ketones were positively correlated with CMRa (r = 0.93; p ketones (AcAc and β-hydroxybutyrate combined) while on the KD was estimated to represent about 33% of brain energy requirements or approximately double the CMRa. Whether increased ketone availability raises CMR of ketones to the same extent in older people as observed here or in conditions in which chronic brain glucose hypometabolism is present remains to be determined.

  3. Exercise performed at hypoxia influences mood state and anxiety symptoms

    Directory of Open Access Journals (Sweden)

    Jorge Fernando Tavares de Souza

    2015-06-01

    Full Text Available During hypoxia conditions, psychological states can be worsened. However, little information is available regarding the effect of physical exercise performed in hypoxia conditions on mood state and anxiety symptoms. The aim of the present study was to elucidate the acute effect of moderate physical exercise performed at hypoxia on mood states and anxiety symptoms in healthy young subjects. Ten volunteers were subjected to the following conditions: a normoxic condition (NC and a hypoxic condition (HC. They performed 45 min of physical exercise. Their anxiety symptoms and mood states were evaluated at the initial time point as well as immediately following and 30 and 60 min after the exercise session. Our results showed a significant increase in post-exercise anxiety symptoms and a significant decrease in mood scores immediately after and 30 min after exercise performed in the HC. Moderate physical activity performed at hypoxia condition increased post-exercise anxiety and worsened mood state.

  4. Prognosis in moderate and severe traumatic brain injury : External validation of the IMPACT models and the role of extracranial injuries

    NARCIS (Netherlands)

    Lingsma, Hester; Andriessen, Teuntje M. J. C.; Haitsema, Iain; Horn, Janneke; van der Naalt, Joukje; Franschman, Gaby; Maas, Andrew I. R.; Vos, Pieter E.; Steyerberg, Ewout W.

    BACKGROUND: Several prognostic models to predict outcome in traumatic brain injury (TBI) have been developed, but few are externally validated. We aimed to validate the International Mission on Prognosis and Analysis of Clinical Trials in TBI (IMPACT) prognostic models in a recent unselected patient

  5. Effects of non-traumatogenic cause on rehabilitation in mild and moderate traumatic brain injury patients%非致伤因素对轻中型颅脑损伤恢复期的影响

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    @@Background: It is well know that prognosis of traumatic brain injury (TBI) has direct effected by injury degree. Although obvious injury is not detected by CT or MRI, some patients have bad prognosis. Objective: To discuss no efficient cause on rehabilitation in mild and moderate traumatic brain injury patients. Design: The research and follow-up survey are given to patients who have mild and moderate traumatic brain injury in our hospital (1996.6~ 2001.6). Unit: 251 Hospital of PLA.

  6. Effects of Graded Hypothermia on Hypoxic-ischemic Brain Damage in the Neonatal Rat

    Institute of Scientific and Technical Information of China (English)

    Xiao-yan Xia; Yi-xin Xia

    2011-01-01

    Objective To investigate the effect of graded hypothermia on neuropathologic alteratiors of neonatal rat brain after exposed to hypoxic-ischemic insult at 37℃, 33℃, 31℃, and 28℃, respectively, and to observe the effect of hypothermia on 72-kDa heat shock protein (HSP72) expression after hypoxic-ischemic insult. Methods Seven days old Wistar rats were subjected to unilateral common carotid artery ligation followed by exposure to hypoxia in 8% oxygen for 2 hours at 37℃, 33℃, 31℃, and 28℃, respectively. The brain temperature was monitored indirectly by inserting a mini-thermocouple probe into the temporal muscle during hypoxia. After hypoxia-ischemia their mortality was assessed. Neuronal damage was assessed with HE staining 72 hours after hypoxia. HSP72 expression at 0.5, 24, and 72 hours of recovery was immunohistochemically assessed using a monoclonal antibody to HSP72. Results Hypoxia-ischemia caused 10.5% (2/19) of mortality in rat of 37℃ group, but no death occurred in 33℃, 31℃ or 28℃ groups. HE staining showed neuropathologic damage was extensive in rats exposed to hypoxia-ischemia at 37℃ (more than 80.0%). The incidence of severe brain damage was significantly decreased in 33℃ (53.3%) and 31℃ groups (44.4%), and no histologic injury was seen in the 28℃ group of rats. Expression of HSP72 was manifest and persistent in the rat brain of 37℃ group, but minimum in the rat brain of 28℃ group. Conclusion Mild and moderate hypothermia might prevent cerebral visible neuropathologic damage associated with hypoxic-ischemic injury by decreasing stress response.

  7. A moderate metal-binding hydrazone meets the criteria for a bioinorganic approach towards Parkinson's disease: Therapeutic potential, blood-brain barrier crossing evaluation and preliminary toxicological studies.

    Science.gov (United States)

    Cukierman, Daphne Schneider; Pinheiro, Ana Beatriz; Castiñeiras-Filho, Sergio L P; da Silva, Anastácia Sá P; Miotto, Marco C; De Falco, Anna; de P Ribeiro, Thales; Maisonette, Silvia; da Cunha, Alessandra L M C; Hauser-Davis, Rachel A; Landeira-Fernandez, J; Aucélio, Ricardo Q; Outeiro, Tiago F; Pereira, Marcos D; Fernández, Claudio O; Rey, Nicolás A

    2017-02-22

    Alzheimer's and Parkinson's diseases share similar amyloidogenic mechanisms, in which metal ions might play an important role. In this last neuropathy, misfolding and aggregation of α-synuclein (α-Syn) are crucial pathological events. A moderate metal-binding compound, namely, 8-hydroxyquinoline-2-carboxaldehyde isonicotinoyl hydrazone (INHHQ), which was previously reported as a potential 'Metal-Protein Attenuating Compound' for Alzheimer's treatment, is well-tolerated by healthy Wistar rats and does not alter their major organ weights, as well as the tissues' reduced glutathione and biometal levels, at a concentration of 200mgkg(-1). INHHQ definitively crosses the blood-brain barrier and can be detected in the brain of rats so late as 24h after intraperitoneal administration. After 48h, brain clearance is complete. INHHQ is able to disrupt, in vitro, anomalous copper-α-Syn interactions, through a mechanism probably involving metal ions sequestering. This compound is non-toxic to H4 (human neuroglioma) cells and partially inhibits intracellular α-Syn oligomerization. INHHQ, thus, shows definite potential as a therapeutic agent against Parkinson's as well.

  8. Preconditioning of brain slices against hypoxia induced injury by a Gynostemma pentaphyllum extract--stimulation of anti-oxidative enzyme expression.

    Science.gov (United States)

    Schild, L; Cotte, T; Keilhoff, G; Brödemann, R

    2012-06-15

    A short period of hypoxia/hypoglycaemia (oxygen and glucose deprivation, OGD) induced by perfusion with O(2)/glucose-free medium caused immediate loss and incomplete restoration of evoked field potentials in the CA1 region of transverse hippocampus slices. OGD-dependent decrease in evoked field potentials can be prevented by a proceeding short OGD event (preconditioning). We report about a study investigating the effect of an ethanolic Gynostemma pentaphyllum extract on evoked field potentials when administered before the OGD episode. Using this procedure, the extract completely protected the cells of the slices from functional injury. In an astroglia rich cell culture the ethanolic Gynostemma pentaphyllum extract caused within 48 h of cultivation increased protein and activity levels of the anti-oxidative enzymes manganese superoxide dismutase (Mn-SOD) and glutathione peroxidase (GPx). Consequently, the cellular H(2)O(2) concentration remained at a low level. These data suggest that the Gynostemma pentaphyllum-mediated increase in antioxidative enzyme activities may contribute to the protection of transverse hippocampus slices from OGD induced functional injury. Our results demonstrate that the prophylactic administration of the ethanolic extract from Gynostemma pentaphyllum has a high potential to protect from ischemia/reperfusion injury. Copyright © 2012 Elsevier GmbH. All rights reserved.

  9. The oxygen free radicals originating from mitochondrial complex I contribute to oxidative brain injury following hypoxia-ischemia in neonatal mice

    Science.gov (United States)

    Niatsetskaya, Zoya V.; Sosunov, Sergei A.; Matsiukevich, Dzmitry; Utkina-Sosunova, Irina V.; Ratner, Veniamin I.; Starkov, Anatoly A.; Ten, Vadim S.

    2012-01-01

    Oxidative stress and Ca++ toxicity are mechanisms of hypoxic-ischemic (HI) brain injury. This work investigates if partial inhibition of mitochondrial respiratory chain protects HI-brain by limiting generation of oxidative radicals during reperfusion. HI-insult was produced in p10 mice treated with complex-I (C-I) inhibitor, pyridaben (P), or vehicle. Administration of P significantly decreased extent of HI injury. Mitochondria isolated from the ischemic hemisphere in P-treated animals showed reduced H2O2 emission, less oxidative damage to the mitochondrial matrix, and increased tolerance to Ca++ triggered opening of permeability transition pore. Protective effect of P administration was also observed when the reperfusion-driven oxidative stress was augmented by the exposure to 100% O2 which exacerbated brain injury only in V-treated mice. In vitro, intact brain mitochondria dramatically increased H2O2 emission in response to hyperoxia, resulting in substantial loss of Ca++ buffering capacity. However, in the presence of C-I inhibitor, rotenone, or antioxidant, catalase, these effects of hyperoxia were abolished. Our data suggest that the reperfusion-driven recovery of C-I dependent mitochondrial respiration contributes not only to the cellular survival, but also causes an oxidative damage to the mitochondria, potentiating a loss of Ca++ buffering capacity. This highlights a novel neuroprotective strategy against HI-brain injury where the major therapeutic principle is a pharmacological attenuation, rather than an enhancement of mitochondrial oxidative metabolism during early reperfusion. PMID:22378894

  10. The oxygen free radicals originating from mitochondrial complex I contribute to oxidative brain injury following hypoxia-ischemia in neonatal mice.

    Science.gov (United States)

    Niatsetskaya, Zoya V; Sosunov, Sergei A; Matsiukevich, Dzmitry; Utkina-Sosunova, Irina V; Ratner, Veniamin I; Starkov, Anatoly A; Ten, Vadim S

    2012-02-29

    Oxidative stress and Ca(2+) toxicity are mechanisms of hypoxic-ischemic (HI) brain injury. This work investigates if partial inhibition of mitochondrial respiratory chain protects HI brain by limiting a generation of oxidative radicals during reperfusion. HI insult was produced in p10 mice treated with complex I (C-I) inhibitor, pyridaben, or vehicle. Administration of P significantly decreased the extent of HI injury. Mitochondria isolated from the ischemic hemisphere in pyridaben-treated animals showed reduced H(2)O(2) emission, less oxidative damage to the mitochondrial matrix, and increased tolerance to the Ca(2+)-triggered opening of the permeability transition pore. A protective effect of pyridaben administration was also observed when the reperfusion-driven oxidative stress was augmented by the exposure to 100% O(2) which exacerbated brain injury only in vehicle-treated mice. In vitro, intact brain mitochondria dramatically increased H(2)O(2) emission in response to hyperoxia, resulting in substantial loss of Ca(2+) buffering capacity. However, in the presence of the C-I inhibitor, rotenone, or the antioxidant, catalase, these effects of hyperoxia were abolished. Our data suggest that the reperfusion-driven recovery of C-I-dependent mitochondrial respiration contributes not only to the cellular survival, but also causes oxidative damage to the mitochondria, potentiating a loss of Ca(2+) buffering capacity. This highlights a novel neuroprotective strategy against HI brain injury where the major therapeutic principle is a pharmacological attenuation, rather than an enhancement of mitochondrial oxidative metabolism during early reperfusion.

  11. Regional Brain Volumes Moderate, but Do Not Mediate, the Effects of Group-Based Exercise Training on Reductions in Loneliness in Older Adults

    Directory of Open Access Journals (Sweden)

    Diane K. Ehlers

    2017-04-01

    Full Text Available Introduction: Despite the prevalence of and negative health consequences associated with perceived loneliness in older adults, few studies have examined interactions among behavioral, psychosocial, and neural mechanisms. Research suggests that physical activity and improvements in perceived social support and stress are related to reductions in loneliness. Yet, the influence of brain structure on these changes is unknown. The present study examined whether change in regional brain volume mediated the effects of changes in social support and stress on change in perceived loneliness after an exercise intervention. We also examined the extent to which baseline brain volumes moderated the relationship between changes in social support, stress, and loneliness.Methods: Participants were 247 older adults (65.4 ± 4.6 years-old enrolled in a 6-month randomized controlled trial comprised of four exercise conditions: Dance (n = 69, Strength/Stretching/Stability (n = 70, Walk (n = 54, and Walk Plus (n = 54. All groups met for 1 h, three times weekly. Participants completed questionnaires assessing perceived social support, stress, and loneliness at baseline and post-intervention. Regional brain volumes (amygdala, prefrontal cortex [PFC], hippocampus before and after intervention were measured with automatic segmentation of each participant's T1-weighted structural MRI. Data were analyzed in a latent modeling framework.Results: Perceived social support increased (p = 0.003, while stress (p < 0.001, and loneliness (p = 0.001 decreased over the intervention. Increased social support directly (−0.63, p < 0.01 and indirectly, through decreased stress (−0.10, p = 0.02, predicted decreased loneliness. Changes in amygdala, PFC, and hippocampus volumes were unrelated to change in psychosocial variables (all p ≥ 0.44. However, individuals with larger baseline amygdalae experienced greater decreases in loneliness due to greater reductions in stress (0.35, p = 0

  12. Regional Brain Volumes Moderate, but Do Not Mediate, the Effects of Group-Based Exercise Training on Reductions in Loneliness in Older Adults.

    Science.gov (United States)

    Ehlers, Diane K; Daugherty, Ana M; Burzynska, Agnieszka Z; Fanning, Jason; Awick, Elizabeth A; Chaddock-Heyman, Laura; Kramer, Arthur F; McAuley, Edward

    2017-01-01

    Introduction: Despite the prevalence of and negative health consequences associated with perceived loneliness in older adults, few studies have examined interactions among behavioral, psychosocial, and neural mechanisms. Research suggests that physical activity and improvements in perceived social support and stress are related to reductions in loneliness. Yet, the influence of brain structure on these changes is unknown. The present study examined whether change in regional brain volume mediated the effects of changes in social support and stress on change in perceived loneliness after an exercise intervention. We also examined the extent to which baseline brain volumes moderated the relationship between changes in social support, stress, and loneliness. Methods: Participants were 247 older adults (65.4 ± 4.6 years-old) enrolled in a 6-month randomized controlled trial comprised of four exercise conditions: Dance (n = 69), Strength/Stretching/Stability (n = 70), Walk (n = 54), and Walk Plus (n = 54). All groups met for 1 h, three times weekly. Participants completed questionnaires assessing perceived social support, stress, and loneliness at baseline and post-intervention. Regional brain volumes (amygdala, prefrontal cortex [PFC], hippocampus) before and after intervention were measured with automatic segmentation of each participant's T1-weighted structural MRI. Data were analyzed in a latent modeling framework. Results: Perceived social support increased (p = 0.003), while stress (p < 0.001), and loneliness (p = 0.001) decreased over the intervention. Increased social support directly (-0.63, p < 0.01) and indirectly, through decreased stress (-0.10, p = 0.02), predicted decreased loneliness. Changes in amygdala, PFC, and hippocampus volumes were unrelated to change in psychosocial variables (all p ≥ 0.44). However, individuals with larger baseline amygdalae experienced greater decreases in loneliness due to greater reductions in stress (0.35, p = 0

  13. Neuroprotective effect of melatonin on preterm rat after hypoxia-ischemia brain damage%褪黑素对新生大鼠缺血缺氧后脑损伤的保护作用

    Institute of Scientific and Technical Information of China (English)

    乔丽丽; 沈伟勤; 陈国宏

    2012-01-01

    目的 探讨褪黑素对新生大鼠缺氧缺血性脑损伤 (HIBD) 的保护作用.方法 Wistar大鼠 48 只,5日龄时结扎左侧颈总动脉,吸入氧氮混合气体 50 min 制作成HIBD模型,随机分成生理盐水组,褪黑素组,缺血缺氧 (HI)+生理盐水组,HI+褪黑素组.褪黑素腹腔注射共 3 次,每次 5 mg/kg,第 1 次在结扎动脉前,第 2 次在吸入氧氮混合气体前给予,第 3 次在HIBD模型制作 24 h 后给予.大鼠在HIBD模型制作后 72 h 被处死,取脑作免疫组化染色,判断脑灰质 (microtubule-associatedprotein-2,MAP-2)、脑白质 (myelin basic protein,MBP) 损伤;HIBD模型制作后 7 周作Y迷宫记忆功能测试.结果 褪黑素能明显减轻HIBD大鼠脑灰质MAP-2和脑白质MBP损伤,还可提高大鼠的长期记忆能力和运动协调能力.结论 褪黑素对HIBD大鼠大脑损伤有明显的短期和长期保护作用.%Objective To investigate neuroprotective effect of melatonin on newborn rat brain after hypoxia-ischemia brain damage (HIBD). Methods Forty-eight 5-day-old Wistar rats were randomly divided into physiological saline group, melatonin group, hypoxia-ischemia (HI) + saline group and HI + melatonin group. The HIBD rat models were induced by unilateral ligation of the left common carotid artery followed by 50 min inhalation of mixed oxygen and nitrogen. Melatonin was intraperitoneally injected three times with a dose of 5mg/kg before artery ligation, before ischemia and after 24h HI immediately. The rats were sacrified after 72h HI and the immunohistochemical staining was applied to brain tissue. Microtubule-associated protein-2 (MAP-2) and myelin basic protein (MBP) were evaluated as indicators for damages in grey matter and white matter, respectively. The memory abilities of the rats were measured through Y maze test at 7 weeks after HI. Results Melatonin treatment reduced the injury of grey matter and white matter significantly, and improved the long-term memory ability and motor

  14. Expression and role of factor inhibiting hypoxia-inducible factor-1 in pulmonary arteries of rat with hypoxia-induced hypertension

    Institute of Scientific and Technical Information of China (English)

    Daiyan Fu; Aiguo Dai; Ruicheng Hu; Yunrong Chen; Liming Zhu

    2008-01-01

    Hypoxia-inducible factor-11α subunit (HIF-1α) plays a pivotal role during the development of hypoxia-induced pulmonary hypertension (HPH) by transactivating it's target genes. As an oxygen-sensitive attenuator, factor inhibiting HIF-1 (FIH)hydroxylates a conserved asparagine residue within the C-terminal transactivation domain of HIF-1α under normoxia and moderate hypoxia. FIH protein is downregulated in response to hypoxia, but its dynamic expression and role during the development of HPH remains unclear. In this study,an HPH rat model was established. The mean pulmonary arterial pressure increased significantly after 7 d of hypoxia.The pulmonary artery remodeling index became evident after 7 d of hypoxia, while the right ventricular hypertrophy index became significant after 14 d of hypoxia. The messenger RNA (mRNA) and protein expression of HIF-1α and vascular endothelial growth factor (VEGF), a well-characterized target gene of HIF-1α, were markedly upregulated after exposure to hypoxia in pulmonary arteries. FIH protein in lung tissues declined after 7 d of hypoxia and continued to decline through the duration of hypoxia. FIH mRNA had few changes after exposure to hypoxia compared with after exposure to normoxia.In hypoxic rats, FIH protein showed significant negative correlation with VEGF mRNA and VEGF protein. FIH protein was negatively correlated with mean pulmonary arterial pressure, pulmonary artery remodeling index and right ventricular hypertrophy index. Taken together, our results suggest that, in the pulmonary arteries of rat exposed to moderate hypoxia, a time-dependent decrease in FIH protein may contribute to the development of rat HPH by enhancing the transactivation of HIF-1α target genes such as VEGF.

  15. Symptoms of gonadal dysfunction are more predictive of hypopituitarism than nonspecific symptoms in screening for pituitary dysfunction following moderate or severe traumatic brain injury.

    Science.gov (United States)

    Cuesta, Martín; Hannon, Mark J; Crowley, Rachel K; Behan, Lucy Ann; Tormey, William; Rawluk, Daniel; Delargy, Mark; Agha, Amar; Thompson, Christopher J

    2016-01-01

    The economic and logistic burden of screening for hypopituitarism following moderate/severe traumatic brain injury (TBI) is considerable. A key recommendation in published guidelines is to prioritize for screening those patients with symptoms suggestive of pituitary dysfunction. The purpose of this study was to evaluate the utility of targeted screening for hypopituitarism in long-term survivors after moderate/severe TBI using referrals on the basis of symptoms. In group 1 (G1), consecutive, unselected patients were screened from the Irish National Neurosurgery Centre, whereas in group 2 (G2) patients were targeted based on the presence of symptoms suggestive of pituitary dysfunction. A total of 137 patients (113 male) were systematically screened (G1) and compared to 112 patients (77 male) referred for pituitary evaluation on the basis of suggestive symptoms (G2). The rate of GH, ACTH, gonadotrophin (GT), TSH and ADH deficiency was compared among groups. Patients referred with menstrual dysfunction had more GH (50% vs 11%, P = 0·001), ACTH (60% vs 14%, P < 0·0001), GT (90% vs 16%, P < 0·0001) deficiency and any pituitary hormone deficit (80% vs 33%, P = 0·003) than G1. Men with symptoms of hypogonadism had more GH (33% vs 11%, P = 0·003), GT (58% vs 16%, P < 0·0001) and TSH (16% vs 1%, P = 0·03) deficiency than G1. Patients with nonspecific symptoms were no more likely to have hypopituitarism than those consecutively screened. Symptoms of hypogonadism are sufficiently predictive of hypopituitarism to justify screening for hypopituitarism after moderate/severe TBI. Nonspecific symptoms of hypopituitarism are no more predictive than unselected screening. © 2015 John Wiley & Sons Ltd.

  16. Power of food moderates food craving, perceived control, and brain networks following a short-term post-absorptive state in older adults.

    Science.gov (United States)

    Rejeski, W Jack; Burdette, Jonathan; Burns, Marley; Morgan, Ashley R; Hayasaka, Satoru; Norris, James; Williamson, Donald A; Laurienti, Paul J

    2012-06-01

    The Power of Food Scale (PFS) is a new measure that assesses the drive to consume highly palatable food in an obesogenic food environment. The data reported in this investigation evaluate whether the PFS moderates state cravings, control beliefs, and brain networks of older, obese adults following either a short-term post-absorptive state, in which participants were only allowed to consume water, or a short-term energy surfeit treatment condition, in which they consumed BOOST®. We found that the short-term post-absorptive condition, in which participants consumed water only, was associated with increases in state cravings for desired food, a reduction in participants' confidence related to the control of eating behavior, and shifts in brain networks that parallel what is observed with other addictive behaviors. Furthermore, individuals who scored high on the PFS were at an increased risk for experiencing these effects. Future research is needed to examine the eating behavior of persons who score high on the PFS and to develop interventions that directly target food cravings.

  17. Preliminary guidelines for safe and effective use of repetitive transcranial magnetic stimulation in moderate to severe traumatic brain injury.

    Science.gov (United States)

    Nielson, Dylan M; McKnight, Curtis A; Patel, Riddhi N; Kalnin, Andrew J; Mysiw, Walter J

    2015-04-01

    Transcranial magnetic stimulation has generated extensive interest within the traumatic brain injury (TBI) rehabilitation community, but little work has been done with repetitive protocols, which can produce prolonged changes in behavior. This is partly because of concerns about the safety of repetitive transcranial magnetic stimulation (rTMS) in subjects with TBI, particularly the risk of seizures. These risks can be minimized by careful selection of the rTMS protocol and exclusion criteria. In this article, we identify guidelines for safe use of rTMS in subjects with TBI based on a review of the literature and illustrate their application with a case study. Our subject is a 48-year-old man who sustained a severe TBI 5 years prior to beginning rTMS for the treatment of post-TBI depression. After a 4-week baseline period, we administered daily sessions of low-frequency stimulation to the right dorsolateral prefrontal cortex for 6 weeks. After stimulation, we performed monthly assessments for 3 months. The Hamilton Depression Rating Scale (HAMD) was our primary outcome measure. The stimulation was well tolerated and the patient reported no side effects. After 6 weeks of stimulation, the patient's depression was slightly improved, and these improvements continued through follow-up. At the end of follow-up, the patient's HAMD score was 49% of the average baseline score.

  18. How impulsivity relates to compulsive buying and the burden perceived by caregivers after moderate-to-severe traumatic brain injury.

    Science.gov (United States)

    Rochat, Lucien; Beni, Catia; Billieux, Joël; Annoni, Jean-Marie; Van der Linden, Martial

    2011-01-01

    Impulsivity is a core feature in patients with traumatic brain injury (TBI). The aim of the study is to investigate how a specific dimension of impulsivity, namely urgency (the tendency to act rashly when distressed), might shed new light on the aetiology of compulsive buying proneness in patients with TBI and to explore how urgency and compulsive buying relate to the burden perceived by the caregivers. Caregivers of 74 patients with TBI were given 3 questionnaires in order to assess their subjective burden as well as patients' impulsivity and compulsive buying proneness. Both urgency and compulsive buying tendencies significantly increased after TBI. Furthermore, path analyses revealed that current urgency was both directly and indirectly related to the subjective burden perceived by the caregivers, and this indirect pathway was mediated by compulsive buying. Urgency plays a central role in understanding specific problematic behaviours after TBI and their impact on caregivers. These findings are discussed in light of the cognitive processes underlying the urgency component of impulsivity in relation to the occurrence of compulsive buying behaviours after TBI. Copyright © 2011 S. Karger AG, Basel.

  19. Hypoxia-mediated metastasis.

    Science.gov (United States)

    Chang, Joan; Erler, Janine

    2014-01-01

    Metastasis is responsible for more than 90 % of deaths among cancer patient. It is a highly complex process that involves the interplay between cancer cells, the tumor microenvironment, and even noncancerous host cells. Metastasis can be seen as a step-wise process: acquisition of malignant phenotype, invasion into surrounding tissue, intravasation into blood vessels, survival in circulation, extravasation to distant sites, and colonization of new organs. Before the actual metastatic process, the secondary site is also prepared for the arrival of the cancer cells through formation of "premetastatic niches." Hypoxia (low oxygen tension) is commonly found in solid tumors more than a few millimeters cubed and often is associated with a poor prognosis. Hypoxia increases angiogenesis, cancer cell survival, and metastasis. This chapter described how hypoxia regulates each step of the metastatic process and how blocking hypoxia-driven metastasis through targeting hypoxia-inducible factor 1, or downstream effector molecules such as the lysyl oxidase family may represent highly effective preventive strategies against metastasis in cancer patients.

  20. Sodium hydrosulfide prevents hypoxia-induced behavioral impairment in neonatal mice.

    Science.gov (United States)

    Wang, Zhen; Zhan, Jingmin; Wang, Xueer; Gu, Jianhua; Xie, Kai; Zhang, Qingrui; Liu, Dexiang

    2013-11-13

    Hypoxic encephalopathy is a common cause of neonatal seizures and long-term neurological abnormalities. Endogenous hydrogen sulfide (H2S) may have multiple functions in brain. The aim of this study is to investigate whether sodium hydrosulfide (NaHS), a H2S donor, provides protection against neonatal hypoxia-induced neurobehavioral deficits. Neonatal mice were subjected to hypoxia (5% oxygen for 120min) at postnatal day 1 and received NaHS (5.6mg/kg) once daily for 3d. Neurobehavioral toxicity was examined at 3-30d after hypoxia. Treatment with NaHS significantly attenuated the delayed development of sensory and motor reflexes induced by hypoxia up to two weeks after the insult. Moreover, NaHS improved the learning and memory performance of hypoxic animals as indicated in Morris water maze test at 30d after hypoxia. In mice exposed to hypoxia, treatment with NaHS enhanced expression of brain derived neurotrophic factor (BDNF) in the hippocampus. Furthermore, the protective effects of NaHS were associated with its ability to repress the hypoxia-induced nitric oxide synthase (NOS) activity and nitric oxide production in the hippocampus of mice brain. Taken together, these results suggest that the long-lasting beneficial effects of NaHS on hypoxia-induced neurobehavioral deficits are mediated, at least in part, by inducing BDNF expression and suppressing NOS activity in the brain of mice.

  1. The role of miR-182 in regulating pineal CLOCK expression after hypoxia-ischemia brain injury in neonatal rats.

    Science.gov (United States)

    Ding, Xin; Sun, Bin; Huang, Jian; Xu, Lixiao; Pan, Jian; Fang, Chen; Tao, Yanfang; Hu, Shukun; Li, Ronghu; Han, Xing; Miao, Po; Wang, Ying; Yu, Jian; Feng, Xing

    2015-03-30

    Circadian rhythm disorder is a common neurological deficit caused by neonatal hypoxic-ischemic brain damage (HIBD). However, little is known about its underlying mechanisms. Our previous studies revealed a significant elevation of clock genes at the protein, but not mRNA, levels in the pineal gland after neonatal HIBD. To investigate the mechanisms of post-transcriptional regulation on clock genes, we screened changes of miRNA levels in the pineal gland after neonatal HIBD using high-throughput arrays. Within the miRNAs whose expression was significantly down-regulated, we identified one miRNA (miR182) that targeted the 3'-untranslated region (3'-UTR) of Clock, a key component of clock genes, and played a crucial role in regulating CLOCK expression after oxygen-glucose deprivation in primarily cultured pinealocytes. Our findings therefore provide new insight on studies of therapeutic targets for circadian rhythm disturbance after neonatal HIBD.

  2. BDNF Val 66 Met and 5-HTTLPR genotype moderate the impact of early psychosocial adversity on plasma brain-derived neurotrophic factor and depressive symptoms: a prospective study.

    Science.gov (United States)

    Buchmann, Arlette F; Hellweg, Rainer; Rietschel, Marcella; Treutlein, Jens; Witt, Stephanie H; Zimmermann, Ulrich S; Schmidt, Martin H; Esser, Günter; Banaschewski, Tobias; Laucht, Manfred; Deuschle, Michael

    2013-08-01

    Recent studies have emphasized an important role for neurotrophins, such as brain-derived neurotrophic factor (BDNF), in regulating the plasticity of neural circuits involved in the pathophysiology of stress-related diseases. The aim of the present study was to examine the interplay of the BDNF Val⁶⁶Met and the serotonin transporter promoter (5-HTTLPR) polymorphisms in moderating the impact of early-life adversity on BDNF plasma concentration and depressive symptoms. Participants were taken from an epidemiological cohort study following the long-term outcome of early risk factors from birth into young adulthood. In 259 individuals (119 males, 140 females), genotyped for the BDNF Val⁶⁶Met and the 5-HTTLPR polymorphisms, plasma BDNF was assessed at the age of 19 years. In addition, participants completed the Beck Depression Inventory (BDI). Early adversity was determined according to a family adversity index assessed at 3 months of age. Results indicated that individuals homozygous for both the BDNF Val and the 5-HTTLPR L allele showed significantly reduced BDNF levels following exposure to high adversity. In contrast, BDNF levels appeared to be unaffected by early psychosocial adversity in carriers of the BDNF Met or the 5-HTTLPR S allele. While the former group appeared to be most susceptible to depressive symptoms, the impact of early adversity was less pronounced in the latter group. This is the first preliminary evidence indicating that early-life adverse experiences may have lasting sequelae for plasma BDNF levels in humans, highlighting that the susceptibility to this effect is moderated by BDNF Val⁶⁶Met and 5-HTTLPR genotype.

  3. Ten-Year Employment Patterns of Working Age Individuals After Moderate to Severe Traumatic Brain Injury: A National Institute on Disability and Rehabilitation Research Traumatic Brain Injury Model Systems Study.

    Science.gov (United States)

    Cuthbert, Jeffrey P; Pretz, Christopher R; Bushnik, Tamara; Fraser, Robert T; Hart, Tessa; Kolakowsky-Hayner, Stephanie A; Malec, James F; O'Neil-Pirozzi, Therese M; Sherer, Mark

    2015-12-01

    To describe the 10-year patterns of employment for individuals of working age discharged from a Traumatic Brain Injury Model Systems (TBIMS) center between 1989 and 2009. Secondary data analysis. Inpatient rehabilitation centers. Patients aged 16 to 55 years (N=3618) who were not retired at injury, received inpatient rehabilitation at a TBIMS center, were discharged alive between 1989 and 2009, and had at least 3 completed follow-up interviews at postinjury years 1, 2, 5, and 10. Not applicable. Employment. Patterns of employment were generated using a generalized linear mixed model, where these patterns were transformed into temporal trajectories of probability of employment via random effects modeling. Covariates demonstrating significant relations to growth parameters that govern the trajectory patterns were similar to those noted in previous cross-sectional research and included age, sex, race/ethnicity, education, preinjury substance misuse, preinjury vocational status, and days of posttraumatic amnesia. The calendar year in which the injury occurred also greatly influenced trajectories. An interactive tool was developed to provide visualization of all postemployment trajectories, with many showing decreasing probabilities of employment between 5 and 10 years postinjury. These results highlight that postinjury employment after moderate to severe traumatic brain injury (TBI) is a dynamic process, with varied patterns of employment for individuals with specific characteristics. The overall decline in trajectories of probability of employment between 5 and 10 years postinjury suggests that moderate to severe TBI may have unfavorable chronic effects and that employment outcome is highly influenced by national labor market forces. Additional research targeting the underlying drivers of the decline between 5 and 10 years postinjury is recommended, as are interventions that target influencing factors. Copyright © 2015 American Congress of Rehabilitation Medicine

  4. Process of implementing collaborative care and its impacts on the provision of care and rehabilitation services to patients with a moderate or severe traumatic brain injury

    Directory of Open Access Journals (Sweden)

    Talbot LR

    2014-07-01

    Full Text Available Lise R Talbot,1,2 Annie Lévesque,1 Josée Trottier1 1School of Nursing Sciences, Faculty of Medicine and Health Sciences, University of Sherbrooke, 2Étienne-Le Bel Clinical Research Centre and the Research Centre on Aging, Sherbrooke, QC, Canada Objective: The introduction of new services in a rehabilitation center is a unique opportunity to introduce a new model of care and services between two institutions. A hospital and a rehabilitation center experienced a clinical management model inspired by an American approach – collaborative care. The purpose of this study was to describe the implementation of this approach and to provide a perception of the quality of care and services provided to patients with moderate or severe traumatic brain injury and to their caregivers. Materials and methods: In this qualitative study, individual semistructured interviews were conducted with patients and their caregivers in the hospital and rehabilitation center where the patients were treated. Individual semistructured interviews were conducted with administrators, and two focus groups were held with clinicians before and after the implementation. Results and conclusion: Ten days’ waiting time were saved with the collaborative approach. Implementing the collaborative care approach has been found to have several benefits, including improved communication, coordination of services between institutions, and better preparation, awareness, and involvement of patients and their families. Administrators, clinicians, patients, and caregivers expressed their opinions on the organization of care and services, the needs and expectations of patients and their caregivers, their participation in terms of roles and responsibilities, their perception of continuity of care, their satisfaction with the care process, and their suggestions for improvements. Keywords: traumatic brain injury, collaborative care, rehabilitation, quality of care

  5. Physical activity attenuates intermittent hypoxia-induced spatial learning deficits and oxidative stress

    National Research Council Canada - National Science Library

    Gozal, David; Nair, Deepti; Goldbart, Aviv D

    2010-01-01

    Exposure to intermittent hypoxia (IH), such as occurs in sleep-disordered breathing, is associated with substantial cognitive impairments, oxidative stress and inflammation, and increased neuronal cell losses in brain regions underlying...

  6. Carbohydrate management, anaerobic metabolism, and adenosine levels in the armoured catfish, Liposarcus pardalis (castelnau), during hypoxia.

    Science.gov (United States)

    Maccormack, Tyson James; Lewis, Johanne Mari; Almeida-Val, Vera Maria Fonseca; Val, Adalberto Luis; Driedzic, William Robert

    2006-04-01

    The armoured catfish, Liposarcus pardalis, tolerates severe hypoxia at high temperatures. Although this species can breathe air, it also has a strong anaerobic metabolism. We assessed tissue to plasma glucose ratios and glycogen and lactate in a number of tissues under "natural" pond hypoxia, and severe aquarium hypoxia without aerial respiration. Armour lactate content and adenosine in brain and heart were also investigated. During normoxia, tissue to plasma glucose ratios in gill, brain, and heart were close to one. Hypoxia increased plasma glucose and decreased tissue to plasma ratios to less than one, suggesting glucose phosphorylation is activated more than uptake. High normoxic white muscle glucose relative to plasma suggests gluconeogenesis or active glucose uptake. Excess muscle glucose may serve as a metabolic reserve since hypoxia decreased muscle to plasma glucose ratios. Mild pond hypoxia changed glucose management in the absence of lactate accumulation. Lactate was elevated in all tissues except armour following aquarium hypoxia; however, confinement in aquaria increased armour lactate, even under normoxia. A stress-associated acidosis may contribute to armour lactate sequestration. High plasma lactate levels were associated with brain adenosine accumulation. An increase in heart adenosine was triggered by confinement in aquaria, although not by hypoxia alone.

  7. Cognitive control of conscious error awareness: error awareness and error positivity (Pe) amplitude in moderate-to-severe traumatic brain injury (TBI).

    Science.gov (United States)

    Logan, Dustin M; Hill, Kyle R; Larson, Michael J

    2015-01-01

    Poor awareness has been linked to worse recovery and rehabilitation outcomes following moderate-to-severe traumatic brain injury (M/S TBI). The error positivity (Pe) component of the event-related potential (ERP) is linked to error awareness and cognitive control. Participants included 37 neurologically healthy controls and 24 individuals with M/S TBI who completed a brief neuropsychological battery and the error awareness task (EAT), a modified Stroop go/no-go task that elicits aware and unaware errors. Analyses compared between-group no-go accuracy (including accuracy between the first and second halves of the task to measure attention and fatigue), error awareness performance, and Pe amplitude by level of awareness. The M/S TBI group decreased in accuracy and maintained error awareness over time; control participants improved both accuracy and error awareness during the course of the task. Pe amplitude was larger for aware than unaware errors for both groups; however, consistent with previous research on the Pe and TBI, there were no significant between-group differences for Pe amplitudes. Findings suggest possible attention difficulties and low improvement of performance over time may influence specific aspects of error awareness in M/S TBI.

  8. Hypertonic saline protects brain endothelial cells against hypoxia correlated to the levels of estimated glomerular filtration rate and interleukin-1β

    Science.gov (United States)

    Chen, Sheng-Long; Deng, Yi-Yu; Wang, Qiao-Sheng; Han, Yong-Li; Jiang, Wen-Qiang; Fang, Ming; Hu, Bei; Wu, Zhi-Xin; Huang, Lin-Qiang; Zeng, Hong-Ke

    2017-01-01

    Abstract Objective: The aim of this study was to verify the protective effect of hypertonic saline (HS) on brain endothelial cells under hypoxic conditions and the relevant underlying mechanism. Methods: bEnd.3 cells were treated with oxygen-glucose deprivation (OGD)-induced injury. To measure HS performance, cell viability was determined using the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium salt assay, and cell apoptosis was assessed by flow cytometry and Terminal deoxynucleotidyl transferase UTP nick-end labeling staining. RNA-seq was performed to assess the expression profiles and screen the candidate genes that participated in OGD-induced injury and the HS protective effect. Quantitative real-time polymerase chain reaction (qPCR) and western blot analysis were used to confirm the expression of candidate genes, and enzyme-linked immunosorbent assay was used to measure the level of interleukin (IL)-1β. Overexpression analyses were performed to confirm the functions of the differentially expressed genes. Results: HS with a concentration of 40 mmol/L NaCl had an obvious protective effect on bEnd.3 cells after OGD-induced injury, resulting in increased cell viability and a smaller percentage of apoptotic cells. According to the RNA-seq results, epidermal growth factor receptor (EGFR) was chosen as the differentially expressed gene target in this study. The qPCR and western blot analyses further confirmed that the levels of EGFR/phosphorylated epidermal growth factor receptor and IL-1β were enhanced after OGD-induced injury, but attenuated after treatment with 40 mmol/L of NaCl HS. Overexpressed EGFR reversed the protective effect of HS that caused low viability and high rates of apoptosis in cells. Conclusion: HS can protect endothelial cells against OGD-induced injury, but is affected by the expression of EGFR/p-EGFR and IL-1β. PMID:28072729

  9. Chemoreceptors and cardiovascular control in acute and chronic systemic hypoxia

    Directory of Open Access Journals (Sweden)

    J.M. Marshall

    1998-07-01

    Full Text Available This review describes the ways in which the primary bradycardia and peripheral vasoconstriction evoked by selective stimulation of peripheral chemoreceptors can be modified by the secondary effects of a chemoreceptor-induced increase in ventilation. The evidence that strong stimulation of peripheral chemoreceptors can evoke the behavioural and cardiovascular components of the alerting or defence response which is characteristically evoked by novel or noxious stimuli is considered. The functional significance of all these influences in systemic hypoxia is then discussed with emphasis on the fact that these reflex changes can be overcome by the local effects of hypoxia: central neural hypoxia depresses ventilation, hypoxia acting on the heart causes bradycardia and local hypoxia of skeletal muscle and brain induces vasodilatation. Further, it is proposed that these local influences can become interdependent, so generating a positive feedback loop that may explain sudden infant death syndrome (SIDS. It is also argued that a major contributor to these local influences is adenosine. The role of adenosine in determining the distribution of O2 in skeletal muscle microcirculation in hypoxia is discussed, together with its possible cellular mechanisms of action. Finally, evidence is presented that in chronic systemic hypoxia, the reflex vasoconstrictor influences of the sympathetic nervous system are reduced and/or the local dilator influences of hypoxia are enhanced. In vitro and in vivo findings suggest this is partly explained by upregulation of nitric oxide (NO synthesis by the vascular endothelium which facilitates vasodilatation induced by adenosine and other NO-dependent dilators and attenuates noradrenaline-evoked vasoconstriction.

  10. Intermittent hypoxia protects cerebral mitochondrial function from calcium overload.

    Science.gov (United States)

    Chen, Jian; Liao, Weigong; Gao, Wenxiang; Huang, Jian; Gao, Yuqi

    2013-12-01

    Hypoxia leads to Ca(2+) overload and results in mitochondrial uncoupling, decreased ATP synthesis, and neuronal death. Inhibition of mitochondrial Ca(2+) overload protects mitochondrial function after hypoxia. The present study was aimed to investigate the effect of intermittent hypoxia on mitochondrial function and mitochondrial tolerance to Ca(2+) overload. Wistar rats were divided into control and intermittent hypoxia (IH) groups. The IH group was subject to hypoxia for 4 h daily in a hypobaric cabin (5,000 m) for 7 days. Brain mitochondria were isolated on day 7 following hypoxia. The baseline mitochondrial functions, such as ST3, ST4, and respiratory control ratio (RCR = ST3/ST4), were measured using a Clark-type oxygen electrode. Mitochondrial adenine nucleotide concentrations were measured by HPLC. Mitochondrial membrane potential was determined by measuring rhodamine 123 (Rh-123) fluorescence in the absence and presence of high Ca(2+) concentration (0.1 M), which simulates Ca(2+) overload. Our results revealed that IH did not affect mitochondrial respiratory functions, but led to a reduction in AMP and an increase in ADP concentrations in mitochondria. Both control and IH groups demonstrated decreased mitochondrial membrane potential in the presence of high Ca(2+) (0.1 M), while the IH group showed a relative higher mitochondrial membrane potential. These results indicated that the neuroprotective effect of intermittent hypoxia was resulted partly from preserving mitochondrial membrane potential, and increasing mitochondrial tolerance to high calcium levels. The increased ADP and decreased AMP in mitochondria following intermittent hypoxia may be a mechanism underlying this protection.

  11. Calpain inhibitors reduce retinal hypoxia in ischemic retinopathy by improving neovascular architecture and functional perfusion.

    Science.gov (United States)

    Hoang, Mien V; Smith, Lois E H; Senger, Donald R

    2011-04-01

    In ischemic retinopathies, underlying hypoxia drives abnormal neovascularization that damages retina and causes blindness. The abnormal neovasculature is tortuous and leaky and fails to alleviate hypoxia, resulting in more pathological neovascularization and retinal damage. With an established model of ischemic retinopathy we found that calpain inhibitors, when administered in moderation, reduced architectural abnormalities, reduced vascular leakage, and most importantly reduced retinal hypoxia. Mechanistically, these calpain inhibitors improved stability and organization of the actin cytoskeleton in retinal endothelial cells undergoing capillary morphogenesis in vitro, and they similarly improved organization of actin cables within new blood vessels in vivo. Hypoxia induced calpain activity in retinal endothelial cells and severely disrupted the actin cytoskeleton, whereas calpain inhibitors preserved actin cables under hypoxic conditions. Collectively, these findings support the hypothesis that hyper-activation of calpains by hypoxia contributes to disruption of the retinal endothelial cell cytoskeleton, resulting in formation of neovessels that are defective both architecturally and functionally. Modest suppression of calpain activity with calpain inhibitors restores cytoskeletal architecture and promotes formation of a functional neovasculature, thereby reducing underlying hypoxia. In sharp contrast to "anti-angiogenesis" strategies that cannot restore normoxia and may aggravate hypoxia, the therapeutic strategy described here does not inhibit neovascularization. Instead, by improving the function of neovascularization to reduce underlying hypoxia, moderate calpain inhibition offers a method for alleviating retinal ischemia, thereby suggesting a new treatment paradigm based on improvement rather than inhibition of new blood vessel growth.

  12. Intermittent hypoxia and neurorehabilitation.

    Science.gov (United States)

    Gonzalez-Rothi, Elisa J; Lee, Kun-Ze; Dale, Erica A; Reier, Paul J; Mitchell, Gordon S; Fuller, David D

    2015-12-15

    In recent years, it has become clear that brief, repeated presentations of hypoxia [i.e., acute intermittent hypoxia (AIH)] can boost the efficacy of more traditional therapeutic strategies in certain cases of neurologic dysfunction. This hypothesis derives from a series of studies in animal models and human subjects performed over the past 35 yr. In 1980, Millhorn et al. (Millhorn DE, Eldridge FL, Waldrop TG. Respir Physiol 41: 87-103, 1980) showed that electrical stimulation of carotid chemoafferent neurons produced a persistent, serotonin-dependent increase in phrenic motor output that outlasts the stimulus for more than 90 min (i.e., a "respiratory memory"). AIH elicits similar phrenic "long-term facilitation" (LTF) by a mechanism that requires cervical spinal serotonin receptor activation and de novo protein synthesis. From 2003 to present, a series of studies demonstrated that AIH can induce neuroplasticity in the injured spinal cord, causing functional recovery of breathing capacity after cervical spinal injury. Subsequently, it was demonstrated that repeated AIH (rAIH) can induce recovery of limb function, and the functional benefits of rAIH are greatest when paired with task-specific training. Since uncontrolled and/or prolonged intermittent hypoxia can elicit pathophysiology, a challenge of intermittent hypoxia research is to ensure that therapeutic protocols are well below the threshold for pathogenesis. This is possible since many low dose rAIH protocols have induced functional benefits without evidence of pathology. We propose that carefully controlled rAIH is a safe and noninvasive modality that can be paired with other neurorehabilitative strategies including traditional activity-based physical therapy or cell-based therapies such as intraspinal transplantation of neural progenitors.

  13. Hypoxia and fatty liver.

    Science.gov (United States)

    Suzuki, Tomohiro; Shinjo, Satoko; Arai, Takatomo; Kanai, Mai; Goda, Nobuhito

    2014-11-07

    The liver is a central organ that metabolizes excessive nutrients for storage in the form of glycogen and lipids and supplies energy-producing substrates to the peripheral tissues to maintain their function, even under starved conditions. These processes require a considerable amount of oxygen, which causes a steep oxygen gradient throughout the hepatic lobules. Alcohol consumption and/or excessive food intake can alter the hepatic metabolic balance drastically, which can precipitate fatty liver disease, a major cause of chronic liver diseases worldwide, ranging from simple steatosis, through steatohepatitis and hepatic fibrosis, to liver cirrhosis. Altered hepatic metabolism and tissue remodeling in fatty liver disease further disrupt hepatic oxygen homeostasis, resulting in severe liver hypoxia. As master regulators of adaptive responses to hypoxic stress, hypoxia-inducible factors (HIFs) modulate various cellular and organ functions, including erythropoiesis, angiogenesis, metabolic demand, and cell survival, by activating their target genes during fetal development and also in many disease conditions such as cancer, heart failure, and diabetes. In the past decade, it has become clear that HIFs serve as key factors in the regulation of lipid metabolism and fatty liver formation. This review discusses the molecular mechanisms by which hypoxia and HIFs regulate lipid metabolism in the development and progression of fatty liver disease.

  14. Structural and functional assessment of the brain in European Americans with mild-to-moderate kidney disease: Diabetes Heart Study-MIND

    Science.gov (United States)

    Murea, Mariana; Hsu, Fang-Chi; Cox, Amanda J.; Hugenschmidt, Christina E.; Xu, Jianzhao; Adams, Jeremy N.; Raffield, Laura M.; Whitlow, Christopher T.; Maldjian, Joseph A.; Bowden, Donald W.; Freedman, Barry I.

    2015-01-01

    Background Advanced chronic kidney disease (CKD) is associated with altered cerebral structure and function. Relationships between mild-to-moderate CKD and brain morphology and cognitive performance were evaluated in European Americans (EAs). Methods A total of 478 EAs with estimated glomerular filtration rate (eGFR) >45 mL/min/1.73 m2 and urine albumin:creatinine ratio (UACR) < 300 mg/g, most with type 2 diabetes (T2D), were included. Measures of total intracranial volume (TICV), cerebrospinal fluid volume, total white matter volume (TWMV), total gray matter volume (TGMV), total white matter lesion volume (TWMLV), hippocampal white matter volume (HWMV) and hippocampal gray matter volume (HGMV) were obtained with magnetic resonance imaging. Cognitive testing included memory (Rey Auditory Visual Learning Test), global cognition (Modified Mini-Mental State Examination) and executive function (Stroop Task, Semantic Fluency, Digit Symbol Substitution Test). Associations with CKD were assessed using log-transformed eGFR and UACR, adjusted for age, sex, body mass index, smoking, hemoglobin A1c, blood pressure, diabetes duration, cardiovascular disease and education. Results Participants were 55.2% female, 78.2% had T2D; mean ± SD age 67.6 ± 9.0 years, T2D duration 16.4 ± 6.5 years, eGFR 92.0 ± 22.3 mL/min/1.73 m2 and UACR 23.8 ± 39.6 mg/g. In adjusted models, eGFR was negatively associated with TICV only in participants with T2D [parameter estimate (β): −72.2, P = 0.002]. In non-diabetic participants, inverse relationships were observed between eGFR and HGMV (β: −1.0, P = 0.03) and UACR and normalized TWMLV (β: −0.2, P = 0.03). Kidney function and albuminuria did not correlate with cognitive testing. Conclusions In EAs with mild CKD enriched for T2D, brain structure and cognitive performance were generally not impacted. Longitudinal studies are necessary to determine when cerebral structural changes and cognitive dysfunction develop with progressive CKD in

  15. Effects of hypoxia and ocean acidification on the upper thermal niche boundaries of coral reef fishes.

    Science.gov (United States)

    Ern, Rasmus; Johansen, Jacob L; Rummer, Jodie L; Esbaugh, Andrew J

    2017-07-01

    Rising ocean temperatures are predicted to cause a poleward shift in the distribution of marine fishes occupying the extent of latitudes tolerable within their thermal range boundaries. A prevailing theory suggests that the upper thermal limits of fishes are constrained by hypoxia and ocean acidification. However, some eurythermal fish species do not conform to this theory, and maintain their upper thermal limits in hypoxia. Here we determine if the same is true for stenothermal species. In three coral reef fish species we tested the effect of hypoxia on upper thermal limits, measured as critical thermal maximum (CTmax). In one of these species we also quantified the effect of hypoxia on oxygen supply capacity, measured as aerobic scope (AS). In this species we also tested the effect of elevated CO2 (simulated ocean acidification) on the hypoxia sensitivity of CTmax We found that CTmax was unaffected by progressive hypoxia down to approximately 35 mmHg, despite a substantial hypoxia-induced reduction in AS. Below approximately 35 mmHg, CTmax declined sharply with water oxygen tension (PwO2). Furthermore, the hypoxia sensitivity of CTmax was unaffected by elevated CO2 Our findings show that moderate hypoxia and ocean acidification do not constrain the upper thermal limits of these tropical, stenothermal fishes. © 2017 The Author(s).

  16. The ability of two scoring systems to predict in-hospital mortality of patients with moderate and severe traumatic brain injuries in a Moroccan intensive care unit

    Directory of Open Access Journals (Sweden)

    Hicham Nejmi

    2014-01-01

    Full Text Available Aim of Study: We aim to assess and to compare the predicting power for in-hospital mortality (IHM of the Acute Physiology and Chronic Health Evaluation-II (APACHE-II and the Simplified Acute Physiology Score-II (SAPS-II for traumatic brain injury (TBI. Patients and Methods: This retrospective cohort study was conducted during a period of 2 years and 9 months in a Moroccan intensive care unit. Data were collected during the first 24 h of each admission. The clinical and laboratory parameters were analyzed and used as per each scoring system to calculate the scores. Univariate and multivariate analyses through regression logistic models were performed, to predict IHM after moderate and severe TBIs. Areas under the receiver operating characteristic curves (AUROC, specificities and sensitivities were determined and also compared. Results: A total of 225 patients were enrolled. The observed IHM was 51.5%. The univariate analysis showed that the initial Glasgow coma scale (GCS was lower in nonsurviving patients (mean GCS = 6 than the survivors (mean GCS = 9 with a statistically significant difference (P = 0.0024. The APACHE-II and the SAPS-II of the nonsurviving patients were higher than those of the survivors (respectively 20.4 ± 6.8 and 31.2 ± 13.6 for nonsurvivors vs. 15.7 ± 5.4 and 22.7 ± 10.3 for survivors with a statistically significant difference (P = 0.0032 for APACHE-II and P = 0.0045 for SAPS-II. Multivariate analysis: APACHE-II was superior for predicting IHM (AUROC = 0.92. Conclusion: The APACHE-II is an interesting tool to predict IHM of head injury patients. This is particularly relevant in Morocco, where TBI is a greater public health problem than in many other countries.

  17. Brainstem white matter integrity is related to loss of consciousness and postconcussive symptomatology in veterans with chronic mild to moderate traumatic brain injury.

    Science.gov (United States)

    Delano-Wood, L; Bangen, K J; Sorg, S F; Clark, A L; Schiehser, D M; Luc, N; Bondi, M W; Werhane, M; Kim, R T; Bigler, E D

    2015-09-01

    We investigated associations between DTI indices of three brainstem white matter tracts, traumatic brain injury (TBI) injury characteristics, and postconcussive symptomatology (PCS) in a well-characterized sample of veterans with history of mild to moderate TBI (mTBI). 58 military veterans (mTBI: n = 38, mean age = 33.2, mean time since injury = 90.9 months; military controls [MC]; n = 20; mean age = 29.4) were administered 3T DTI scans as well as a comprehensive neuropsychiatric evaluation including evaluation of TBI injury characteristics and PCS symptoms (e.g., negative mood, dizziness, balance and coordination difficulties). Tractography was employed by seeding ROIs along 3 brainstem white matter tracts (i.e., medial lemniscus-central tegmentum tract [ML-CTT]; corticospinal tracts [CST], and pontine tegmentum [PT]), and mean DTI values were derived from fractional anisotropic (FA) maps. Results showed that there were no significant difference in FA between the MC and TBI groups across the 3 regions of interest; however, among the TBI group, CST FA was significantly negatively associated with LOC duration. Additionally, lower FA of certain tracts-most especially the PT-was significantly associated with increased PCS symptoms (i.e., more severe vestibular symptoms, poorer physical functioning, and greater levels of fatigue), even after adjusting for PTSD symptoms. Our findings show that, in our sample of veterans with mTBI, tractography-based DTI indices of brainstem white matter tracts of interest are related to the presence and severity of PCS symptoms. Findings are promising as they show linkages between brainstem white matter integrity and injury severity (LOC), and they raise the possibility that the pontine tegmentum in particular may be a useful marker of PCS symptoms. Collectively, these data point to important neurobiological substrates of the chronic and complex constellation of symptoms following the 'signature injury' of our

  18. Acetylcholine Esterase Activity and Behavioral Response in Hypoxia Induced Neonatal Rats: Effect of Glucose, Oxygen and Epinephrine Supplementation

    Science.gov (United States)

    Chathu, Finla; Krishnakumar, Amee; Paulose, Cheramadathikudyil S.

    2008-01-01

    Brain damage due to an episode of hypoxia remains a major problem in infants causing deficit in motor and sensory function. Hypoxia leads to neuronal functional failure, cerebral palsy and neuro-developmental delay with characteristic biochemical and molecular alterations resulting in permanent or transitory neurological sequelae or even death.…

  19. Acidosis, hypoxia and bone.

    Science.gov (United States)

    Arnett, Timothy R

    2010-11-01

    Bone homeostasis is profoundly affected by local pH and oxygen tension. It has long been recognised that the skeleton contains a large reserve of alkaline mineral (hydroxyapatite), which is ultimately available to neutralise metabolic H(+) if acid-base balance is not maintained within narrow limits. Bone cells are extremely sensitive to the direct effects of pH: acidosis inhibits mineral deposition by osteoblasts but it activates osteoclasts to resorb bone and other mineralised tissues. These reciprocal responses act to maximise the availability of OH(-) ions from hydroxyapatite in solution, where they can buffer excess H(+). The mechanisms by which bone cells sense small pH changes are likely to be complex, involving ion channels and receptors in the cell membrane, as well as direct intracellular effects. The importance of oxygen tension in the skeleton has also long been known. Recent work shows that hypoxia blocks the growth and differentiation of osteoblasts (and thus bone formation), whilst strongly stimulating osteoclast formation (and thus bone resorption). Surprisingly, the resorptive function of osteoclasts is unimpaired in hypoxia. In vivo, tissue hypoxia is usually accompanied by acidosis due to reduced vascular perfusion and increased glycolytic metabolism. Thus, disruption of the blood supply can engender a multiple negative impact on bone via the direct actions of reduced pO(2) and pH on bone cells. These observations may contribute to our understanding of the bone disturbances that occur in numerous settings, including ageing, inflammation, fractures, tumours, anaemias, kidney disease, diabetes, respiratory disease and smoking.

  20. Alterations in Cortical Thickness and White Matter Integrity in Mild-to-Moderate Communicating Hydrocephalic School-Aged Children Measured by Whole-Brain Cortical Thickness Mapping and DTI

    Science.gov (United States)

    Ye, Xinjian; Bai, Guanghui; Fu, Yuchuan; Mao, Chuanwan; Wu, Aiqin

    2017-01-01

    Follow-up observation is required for mild-to-moderate hydrocephalic patients because of the potential damage to brain. However, effects of mild-to-moderate hydrocephalus on gray and white matter remain unclear in vivo. Using structural MRI and diffusion tensor imaging (DTI), current study compared the cortical thickness and white matter integrity between children with mild-to-moderate communicating hydrocephalus and healthy controls. The relationships between cortical changes and intelligence quota were also examined in patients. We found that cortical thickness in the left middle temporal and left rostral middle frontal gyrus was significantly lower in the hydrocephalus group compared with that of controls. Fractional anisotropy in the right corpus callosum body was significantly lower in the hydrocephalus group compared with that of controls. In addition, there was no association of cortical thinning or white matter fractional anisotropy with intelligence quota in either group. Thus, our findings provide clues to that mild-to-moderate hydrocephalus could lead to structural brain deficits especially in the middle temporal and middle frontal gyrus prior to the behavior changes.

  1. Intermittent hypoxia maintains glycemia in streptozotocin-induced diabetic rats.

    Science.gov (United States)

    Chen, Xiaofei; Zhao, Tong; Huang, Xin; Wu, Liying; Wu, Kuiwu; Fan, Ming; Zhu, Lingling

    2016-05-01

    Increasing studies have shown protective effects of intermittent hypoxia on brain injury and heart ischemia. However, the effect of intermittent hypoxia on blood glucose metabolism, especially in diabetic conditions, is rarely observed. The aim of this study was to investigate whether intermittent hypoxia influences blood glucose metabolism in type 1 diabetic rats. Streptozotocin-induced diabetic adult rats and age-matched control rats were treated with intermittent hypoxia (at an altitude of 3 km, 4 h per day for 3 weeks) or normoxia as control. Fasting blood glucose, body weight, plasma fructosamine, plasma insulin, homeostasis model assessment of insulin resistance (HOMA-IR), pancreas β-cell mass, and hepatic and soleus glycogen were measured. Compared with diabetic rats before treatment, the level of fasting blood glucose in diabetic rats after normoxic treatment was increased (19.88 ± 5.69 mmol/L vs. 14.79 ± 5.84 mmol/L, p  0.05). Meanwhile, fasting blood glucose in diabetic rats after hypoxic treatment was also lower than that in diabetic rats after normoxic treatment (13.14 ± 5.77 mmol/L vs. 19.88 ± 5.69 mmol/L, pintermittent hypoxia was significantly lower than that in diabetic rats receiving normoxia (1.28 ± 0.11 vs. 1.39 ± 0.11, p intermittent hypoxia showed effect on the increase of soleus glycogen but not hepatic glycogen. We conclude that intermittent hypoxia maintains glycemia in streptozotocin-induced diabetic rats and its regulation on muscular glycogenesis may play a role in the underlying mechanism.

  2. Temporal and topographic profiles of tissue hypoxia following transient focal cerebral ischemia in rats.

    Science.gov (United States)

    Noto, Takahisa; Furuichi, Yasuhisa; Ishiye, Masayuki; Matsuoka, Nobuya; Aramori, Ichiro; Mutoh, Seitaro; Yanagihara, Takehiko; Manabe, Noboru

    2006-08-01

    Intravascular accumulation of blood cells after brain ischemia-reperfusion can cause obstruction of cerebral blood flow and tissue hypoxia/ischemia as a consequence. In the present study, we examined temporal and topographic changes of tissue hypoxia/ischemia after occlusion of the middle cerebral artery (MCA) for 60 min in rats with immunohistochemical staining for hypoxia (2-nitroimidazole hypoxia marker: hypoxyprobe-1 adducts). Our results showed that tissue hypoxia expressed as positive staining for hypoxyprobe-1 adducts preceded neuronal degeneration. Platelets and granulocytes were detected close to the hypoxyprobe-1 adducts positive area. These results suggested that the hypoxic environment could persist even after reperfusion of MCA, because of vascular obstruction with accumulation of platelets and granulocytes.

  3. Heat shock response and mammal adaptation to high elevation (hypoxia)

    Institute of Scientific and Technical Information of China (English)

    WANG Xiaolin; XU Cunshuan; WANG Xiujie; WANG Dongjie; WANG Qingshang; ZHANG Baochen

    2006-01-01

    The mammal's high elevation (hypoxia) adaptation was studied by using the immunological and the molecular biological methods to understand the significance of Hsp (hypoxia) adaptation in the organic high elevation, through the mammal heat shock response. (1) From high elevation to low elevation (natural hypoxia): Western blot and conventional RT-PCR and real-time fluorescence quota PCR were adopted. Expression difference of heat shock protein of 70 (Hsp70) and natural expression of brain tissue of Hsp70 gene was determined in the cardiac muscle tissue among the different elevation mammals (yak). (2)From low elevation to high elevation (hypoxia induction):The mammals (domestic rabbits) from the low elevation were sent directly to the areas with different high elevations like 2300, 3300 and 5000 m above sea level to be raised for a period of 3 weeks before being slaughtered and the genetic inductive expression of the brain tissue of Hsp70 was determined with RT-PCR. The result indicated that all of the mammals at different elevations possessed their heat shock response gene. Hsp70 of the high elevation mammal rose abruptly under stress and might be induced to come into being by high elevation (hypoxia). The speedy synthesis of Hsp70 in the process of heat shock response is suitable to maintain the cells' normal physiological functions under stress. The Hsp70 has its threshold value. The altitude of 5000 m above sea level is the best condition for the heat shock response, and it starts to reduce when the altitude is over 6000 m above sea level. The Hsp70 production quantity and the cell hypoxia bearing capacity have their direct ratio.

  4. Occurrence of severe and moderate traumatic brain injury in patients attended in a Brazilian Teaching Hospital: epidemiology and dosage of alcoholemy

    Directory of Open Access Journals (Sweden)

    José Weber Vieira de Faria

    2008-03-01

    Full Text Available This study aimed at observing aspects of epidemiology in order to investigate the use of alcohol in patients older than 18 with severe and moderate traumatic brain injury, which were attended in the Clinics Hospital of the University of Uberlândia. Positive alcoholemy was found in 39.3% of the patients. Of the 33 positive exams alcoholemy was found higher than 60 mg/dL in 28 (84.6%. There was not significant relation between alcoholemy levels and trauma severity. The major prevalence occurred on Saturdays nights. The most frequent types of external causes were transportation accidents (64.74 followed by accidental falls (17.27% and physical aggression (16.55%. 93.9% of the patients with positive alcoholemy were men aged 20-29. 24.2% of the ones with positive alcoholemy died yet no significant difference was found in the study of the ones with negative alcoholemy (n=51 (p=0.93; RR= 0.9; IC95%=0.40-2.08.Os objetivos deste estudo são investigar aspectos da epidemiologia e identificar o uso de álcool em pacientes com traumatismo craniencefálico grave e moderado em maiores de 18 anos atendidos no Hospital de Clínicas da Universidade Federal de Uberlândia. Encontrou-se alcoolemia positiva em 39,3% dos pacientes. Nos 33 exames positivos, foram observadas alcoolemias superiores a 60 mg/dL em 28 (84,6%. Não houve relação significativa entre os níveis de alcoolemia e a gravidade do trauma. Maior prevalência ocorreu aos sábados, no período noturno. Os tipos de causa externa mais frequentes foram os acidentes de transporte (64,74%, seguidos de quedas acidentais (17,27% e de agressões (16,55%. Dos pacientes com alcoolemia positiva, 93,9% eram do sexo masculino, com maior prevalência dos 20 aos 29 anos. Dentre aqueles com alcoolemia positiva, 24,2% vieram a falecer, não havendo diferença significante com os pacientes com alcoolemia negativa (n=51 (p=0,93; RR= 0,9; IC95%=0,40-2,08.

  5. A genetically encoded biosensor for visualising hypoxia responses in vivo

    Science.gov (United States)

    Misra, Tvisha; Baccino-Calace, Martin; Meyenhofer, Felix; Rodriguez-Crespo, David; Akarsu, Hatice; Armenta-Calderón, Ricardo; Gorr, Thomas A.; Frei, Christian; Cantera, Rafael; Egger, Boris

    2017-01-01

    ABSTRACT Cells experience different oxygen concentrations depending on location, organismal developmental stage, and physiological or pathological conditions. Responses to reduced oxygen levels (hypoxia) rely on the conserved hypoxia-inducible factor 1 (HIF-1). Understanding the developmental and tissue-specific responses to changing oxygen levels has been limited by the lack of adequate tools for monitoring HIF-1 in vivo. To visualise and analyse HIF-1 dynamics in Drosophila, we used a hypoxia biosensor consisting of GFP fused to the oxygen-dependent degradation domain (ODD) of the HIF-1 homologue Sima. GFP-ODD responds to changing oxygen levels and to genetic manipulations of the hypoxia pathway, reflecting oxygen-dependent regulation of HIF-1 at the single-cell level. Ratiometric imaging of GFP-ODD and a red-fluorescent reference protein reveals tissue-specific differences in the cellular hypoxic status at ambient normoxia. Strikingly, cells in the larval brain show distinct hypoxic states that correlate with the distribution and relative densities of respiratory tubes. We present a set of genetic and image analysis tools that enable new approaches to map hypoxic microenvironments, to probe effects of perturbations on hypoxic signalling, and to identify new regulators of the hypoxia response. PMID:28011628

  6. Hypoxia impairs visual acuity in snapper (Pagrus auratus).

    Science.gov (United States)

    Robinson, Esme; Jerrett, Alistair; Black, Suzanne; Davison, William

    2013-07-01

    We investigated the effect of environmental hypoxia on vision in snapper (Pagrus auratus). Juvenile snapper inhabit estuarine environments where oxygen conditions fluctuate on a seasonal basis. Optomotor experiments demonstrated that visual acuity is impaired by environmental hypoxia, but not until levels approach the critical oxygen tension (P crit) of this species (around 25% air-saturated seawater). In 100, 80, and 60% air-saturated seawater, a positive optomotor response was present at a minimum separable angle (M SA) of 1°. In 40% air-saturated seawater, vision was partially impaired with positive responses at M SAs of 2° and above. However, in 25% air-saturated seawater, visual acuity was seriously impaired, with positive responses only present at M SAs of 6° and above. Snapper were found to possess a choroid rete, facilitating the maintenance of high ocular oxygen partial pressures (PO2) during normoxia and moderate hypoxia (PO2, between 269 and 290 mmHg). However, at 40 and 25% water oxygen saturation, ocular PO2 was reduced to below 175 mmHg, which is perhaps linked to impairment of visual acuity in these conditions. The ability to preserve visual function during moderate hypoxia is beneficial for the maintenance of a visual lifestyle in the fluctuating oxygen environments of estuaries.

  7. Hypoxic Hypoxia at Moderate Altitudes: State of the Science

    Science.gov (United States)

    2011-05-01

    indicating more O2 unloading, leading to more rapid desaturation of hemoglobin. 6 Conditions such as anemia or high altitude, cause an increase of 2,3...yielded 32 articles, 5 technical reports, 1 master’s thesis , 2 abstracts, and 2 manuals. Excluded from the Dialog search were 17 articles, 2...technical reports, and 2 manuals. Additionally, 52 articles, 1 master’s thesis , and 16 abstracts were obtained for review from references of original

  8. An examination of the Wechsler Adult Intelligence Scales, Fourth Edition (WAIS-IV) in individuals with complicated mild, moderate and Severe traumatic brain injury (TBI).

    Science.gov (United States)

    Carlozzi, Noelle E; Kirsch, Ned L; Kisala, Pamela A; Tulsky, David S

    2015-01-01

    This study examined the clinical utility of the Wechsler Adult Intelligence Scales-Fourth Edition (WAIS-IV) in individuals with complicated mild, moderate or severe TBI. One hundred individuals with TBI (n = 35 complicated mild or moderate TBI; n = 65 severe TBI) and 100 control participants matched on key demographic variables from the WAIS-IV normative dataset completed the WAIS-IV. Univariate analyses indicated that participants with severe TBI had poorer performance than matched controls on all index scores and subtests (except Matrix Reasoning). Individuals with complicated mild/moderate TBI performed more poorly than controls on the Working Memory Index (WMI), Processing Speed Index (PSI), and Full Scale IQ (FSIQ), and on four subtests: the two processing speed subtests (SS, CD), two working memory subtests (AR, LN), and a perceptual reasoning subtest (BD). Participants with severe TBI had significantly lower scores than the complicated mild/moderate TBI on PSI, and on three subtests: the two processing speed subtests (SS and CD), and the new visual puzzles test. Effect sizes for index and subtest scores were generally small-to-moderate for the group with complicated mild/moderate and moderate-to-large for the group with severe TBI. PSI also showed good sensitivity and specificity for classifying individuals with severe TBI versus controls. Findings provide support for the clinical utility of the WAIS-IV in individuals with complicated mild, moderate, and severe TBI.

  9. Coastal hypoxia and sediment biogeochemistry

    Directory of Open Access Journals (Sweden)

    J. J. Middelburg

    2009-07-01

    Full Text Available The intensity, duration and frequency of coastal hypoxia (oxygen concentration <63 μM are increasing due to human alteration of coastal ecosystems and changes in oceanographic conditions due to global warming. Here we provide a concise review of the consequences of coastal hypoxia for sediment biogeochemistry. Changes in bottom-water oxygen levels have consequences for early diagenetic pathways (more anaerobic at expense of aerobic pathways, the efficiency of re-oxidation of reduced metabolites and the nature, direction and magnitude of sediment-water exchange fluxes. Hypoxia may also lead to more organic matter accumulation and burial and the organic matter eventually buried is also of higher quality, i.e. less degraded. Bottom-water oxygen levels also affect the organisms involved in organic matter processing with the contribution of metazoans decreasing as oxygen levels drop. Hypoxia has a significant effect on benthic animals with the consequences that ecosystem functions related to macrofauna such as bio-irrigation and bioturbation are significantly affected by hypoxia as well. Since many microbes and microbial-mediated biogeochemical processes depend on animal-induced transport processes (e.g. re-oxidation of particulate reduced sulphur and denitrification, there are indirect hypoxia effects on biogeochemistry via the benthos. Severe long-lasting hypoxia and anoxia may result in the accumulation of reduced compounds in sediments and elimination of macrobenthic communities with the consequences that biogeochemical properties during trajectories of decreasing and increasing oxygen may be different (hysteresis with consequences for coastal ecosystem dynamics.

  10. The Effects of Hypoxia and Inflammation on Synaptic Signaling in the CNS

    Directory of Open Access Journals (Sweden)

    Gatambwa Mukandala

    2016-02-01

    Full Text Available Normal brain function is highly dependent on oxygen and nutrient supply and when the demand for oxygen exceeds its supply, hypoxia is induced. Acute episodes of hypoxia may cause a depression in synaptic activity in many brain regions, whilst prolonged exposure to hypoxia leads to neuronal cell loss and death. Acute inadequate oxygen supply may cause anaerobic metabolism and increased respiration in an attempt to increase oxygen intake whilst chronic hypoxia may give rise to angiogenesis and erythropoiesis in order to promote oxygen delivery to peripheral tissues. The effects of hypoxia on neuronal tissue are exacerbated by the release of many inflammatory agents from glia and neuronal cells. Cytokines, such as TNF-α, and IL-1β are known to be released during the early stages of hypoxia, causing either local or systemic inflammation, which can result in cell death. Another growing body of evidence suggests that inflammation can result in neuroprotection, such as preconditioning to cerebral ischemia, causing ischemic tolerance. In the following review we discuss the effects of acute and chronic hypoxia and the release of pro-inflammatory cytokines on synaptic transmission and plasticity in the central nervous system. Specifically we discuss the effects of the pro-inflammatory agent TNF-α during a hypoxic event.

  11. A rat pup model of cerebral palsy induced by prenatal inflammation and hypoxia

    Institute of Scientific and Technical Information of China (English)

    Yanrong Hu; Feng Gao; Jianxin Li; Lihui Zhao; Gang Chen; Hong Wan; Zhiyou Zhang; Hong Zhi; Wei Liu; Xinwei Qian; Mingzhao Chen; Linbao Wen

    2013-01-01

    Animal models of cerebral palsy established by simple infection or the hypoxia/ischemia method cannot effectively simulate the brain injury of a premature infant. Healthy 17-day-pregnant Wistar rats were intraperitoneally injected with lipopolysaccharide then subjected to hypoxia. The pups were used for this study at 4 weeks of age. Simultaneously, a hypoxia/ischemia group and a control group were used for comparison. The results of the footprint test, the balance beam test, the water maze test, neuroelectrophysiological examination and neuropathological examination demonstrated that, at 4 weeks after birth, footprint repeat space became larger between the forelimbs and hindlimbs of the rats, the latency period on the balance beam and in the Morris water maze was longer, place navigation and ability were poorer, and the stimulus intensity that induced the maximal wave amplitude of the compound muscle action potential was greater in the lipopolysaccharide/hypoxia and hypoxia/ischemia groups than in the control group. We observed irregular cells around the periventricular area, periventricular leukomalacia and breakage of the nuclear membrane in the lipopolysaccharide/hypoxia and hypoxia/ischemia groups. These results indicate that we successfully established a Wistar rat pup model of cerebral palsy by intraperitoneal injection of lipopolysaccharide and hypoxia.

  12. Effects of Acute Exposure to Mild or Moderate Hypoxia on Human Psychomotor Performance and Visual-reaction Time%急性轻、中度缺氧暴露对心理运动及反应时的影响

    Institute of Scientific and Technical Information of China (English)

    李学义; 吴兴裕; 付川; 沈小凤; 杨长斌; 吴燕红

    2000-01-01

    Objective The aim of this study was to determine whether psychomotor performance and visual reaction time were affected by acute exposure to mild or moderate hypoxia. Method Eighteen healthy male volunteers performed finger tapping, simple reaction time(SRT) and 4-choice reaction time(CRT) tests at simulated altitude of 300 m (control),2800 m, 3600 m and 4400 m for 1 h in a hypobaric chamber. Result SaO2 decreased from 98%(control) to 90%,82% and 74% respectively at the various altitudes. All the performance parameters showed no significant change after exposure to 2800 m for 1 h relative to ground level(P>0.05). However the mean reaction time of 4-CRT under 3600 m prolonged and performance decreased as compared with baseline value(P0.05). Conclusion The results from this study demonstrated that there were no measurable impairment of visual reaction time and psychomotor performance under exposure to an altitude of 2800 m for 1 h. However, adverse effects on psychomotor performance were observed under 3600 m and over.%目的研究急性轻、中度缺氧暴露对人的心理运动及视觉反应时的影响. 方法利用低压舱模拟300 m (对照高度)、2800 m、3600 m、4400 m高度缺氧暴露1 h,考察了18 名健康男性青年被试者指叩测验、简单反应时和选择反应时的变化. 结果血氧饱和度(SaO2)由地面对照值98%分别降至90%、82%和74%.2800 m 缺氧暴露1 h心理运动绩效的各个参数并无显著改变(P>0.05).3600 m缺氧暴露时选择反应时的平均反应时明显延长,运动绩效下降(P0.05). 结论本研究的结果提示,急性缺氧暴露于2800 m高度1 h并未对心理运动产生严重影响,而暴露于3600 m以上高度时会对选择反应时等复杂反应产生负面影响,且随着高度的增加而加重.

  13. Transcriptome analysis of the spalax hypoxia survival response includes suppression of apoptosis and tight control of angiogenesis

    Directory of Open Access Journals (Sweden)

    Malik Assaf

    2012-11-01

    Full Text Available Abstract Background The development of complex responses to hypoxia has played a key role in the evolution of mammals, as inadequate response to this condition is frequently associated with cardiovascular diseases, developmental disorders, and cancers. Though numerous studies have used mice and rats in order to explore mechanisms that contribute to hypoxia tolerance, these studies are limited due to the high sensitivity of most rodents to severe hypoxia. The blind subterranean mole rat Spalax is a hypoxia tolerant rodent, which exhibits unique longevity and therefore has invaluable potential in hypoxia and cancer research. Results Using microarrays, transcript abundance was measured in brain and muscle tissues from Spalax and rat individuals exposed to acute and chronic hypoxia for varying durations. We found that Spalax global gene expression response to hypoxia differs from that of rat and is characterized by the activation of functional groups of genes that have not been strongly associated with the response to hypoxia in hypoxia sensitive mammals. Using functional enrichment analysis of Spalax hypoxia induced genes we found highly significant overrepresentation of groups of genes involved in anti apoptosis, cancer, embryonic/sexual development, epidermal growth factor receptor binding, coordinated suppression and activation of distinct groups of transcription factors and membrane receptors, in addition to angiogenic related processes. We also detected hypoxia induced increases of different critical Spalax hub gene transcripts, including antiangiogenic genes associated with cancer tolerance in Down syndrome human individuals. Conclusions This is the most comprehensive study of Spalax large scale gene expression response to hypoxia to date, and the first to use custom Spalax microarrays. Our work presents novel patterns that may underlie mechanisms with critical importance to the evolution of hypoxia tolerance, with special relevance to

  14. Hypoxia, Monitoring, and Mitigation System

    Science.gov (United States)

    2014-05-01

    al., (2012). Short-term exposure to hypoxia for work and leisure activities in health and disease: which level of hypoxia is safe? Sleep Breath, 16...Altitude Illness. Emergency Medical Clinics of North America. (2):329-55, viii. Travel to a high altitude requires that the human body acclimatize to...preventable. Practitioners working in or advising those traveling to a high altitude must be familiar with the early recognition of symptoms, prompt

  15. Hypoxia, Oxidative Stress and Fat

    Directory of Open Access Journals (Sweden)

    Nikolaus Netzer

    2015-06-01

    Full Text Available Metabolic disturbances in white adipose tissue in obese individuals contribute to the pathogenesis of insulin resistance and the development of type 2 diabetes mellitus. Impaired insulin action in adipocytes is associated with elevated lipolysis and increased free fatty acids leading to ectopic fat deposition in liver and skeletal muscle. Chronic adipose tissue hypoxia has been suggested to be part of pathomechanisms causing dysfunction of adipocytes. Hypoxia can provoke oxidative stress in human and animal adipocytes and reduce the production of beneficial adipokines, such as adiponectin. However, time-dose responses to hypoxia relativize the effects of hypoxic stress. Long-term exposure of fat cells to hypoxia can lead to the production of beneficial substances such as leptin. Knowledge of time-dose responses of hypoxia on white adipose tissue and the time course of generation of oxidative stress in adipocytes is still scarce. This paper reviews the potential links between adipose tissue hypoxia, oxidative stress, mitochondrial dysfunction, and low-grade inflammation caused by adipocyte hypertrophy, macrophage infiltration and production of inflammatory mediators.

  16. A combined gene signature of hypoxia and notch pathway in human glioblastoma and its prognostic relevance.

    Science.gov (United States)

    Irshad, Khushboo; Mohapatra, Saroj Kant; Srivastava, Chitrangda; Garg, Harshit; Mishra, Seema; Dikshit, Bhawana; Sarkar, Chitra; Gupta, Deepak; Chandra, Poodipedi Sarat; Chattopadhyay, Parthaprasad; Sinha, Subrata; Chosdol, Kunzang

    2015-01-01

    Hypoxia is a hallmark of solid tumors including glioblastoma (GBM). Its synergism with Notch signaling promotes progression in different cancers. However, Notch signaling exhibits pleiotropic roles and the existing literature lacks a comprehensive understanding of its perturbations under hypoxia in GBM with respect to all components of the pathway. We identified the key molecular cluster(s) characteristic of the Notch pathway response in hypoxic GBM tumors and gliomaspheres. Expression of Notch and hypoxia genes was evaluated in primary human GBM tissues by q-PCR. Clustering and statistical analyses were applied to identify the combination of hypoxia markers correlated with upregulated Notch pathway components. We found well-segregated tumor-clusters representing high and low HIF-1α/PGK1-expressors which accounted for differential expression of Notch signaling genes. In combination, a five-hypoxia marker set (HIF-1α/PGK1/VEGF/CA9/OPN) was determined as the best predictor for induction of Notch1/Dll1/Hes1/Hes6/Hey1/Hey2. Similar Notch-axis genes were activated in gliomaspheres, but not monolayer cultures, under moderate/severe hypoxia (2%/0.2% O2). Preliminary evidence suggested inverse correlation between patient survival and increased expression of constituents of the hypoxia-Notch gene signature. Together, our findings delineated the Notch-axis maximally associated with hypoxia in resected GBM, which might be prognostically relevant. Its upregulation in hypoxia-exposed gliomaspheres signify them as a better in-vitro model for studying hypoxia-Notch interactions than monolayer cultures.

  17. A combined gene signature of hypoxia and notch pathway in human glioblastoma and its prognostic relevance.

    Directory of Open Access Journals (Sweden)

    Khushboo Irshad

    Full Text Available Hypoxia is a hallmark of solid tumors including glioblastoma (GBM. Its synergism with Notch signaling promotes progression in different cancers. However, Notch signaling exhibits pleiotropic roles and the existing literature lacks a comprehensive understanding of its perturbations under hypoxia in GBM with respect to all components of the pathway. We identified the key molecular cluster(s characteristic of the Notch pathway response in hypoxic GBM tumors and gliomaspheres. Expression of Notch and hypoxia genes was evaluated in primary human GBM tissues by q-PCR. Clustering and statistical analyses were applied to identify the combination of hypoxia markers correlated with upregulated Notch pathway components. We found well-segregated tumor-clusters representing high and low HIF-1α/PGK1-expressors which accounted for differential expression of Notch signaling genes. In combination, a five-hypoxia marker set (HIF-1α/PGK1/VEGF/CA9/OPN was determined as the best predictor for induction of Notch1/Dll1/Hes1/Hes6/Hey1/Hey2. Similar Notch-axis genes were activated in gliomaspheres, but not monolayer cultures, under moderate/severe hypoxia (2%/0.2% O2. Preliminary evidence suggested inverse correlation between patient survival and increased expression of constituents of the hypoxia-Notch gene signature. Together, our findings delineated the Notch-axis maximally associated with hypoxia in resected GBM, which might be prognostically relevant. Its upregulation in hypoxia-exposed gliomaspheres signify them as a better in-vitro model for studying hypoxia-Notch interactions than monolayer cultures.

  18. Expression and activation of hypoxiu inducible factor-1α and iNOS in the brain of rats with chronic intermittent hypoxia%慢性间歇低氧大鼠脑组织内缺氧诱导因子-1α和诱导型一氧化氮合酶的表达

    Institute of Scientific and Technical Information of China (English)

    王赞峰; 康健; 代冰

    2009-01-01

    目的 观察慢性间歇低氧状态下大鼠脑内缺氧诱导因子-1α(HIF-1α)和诱导型一氧化氮合酶(iNOS)的表达情况,结合HIF-1转录活性的测定,研究以HIF-1为核心的神经系统缺氧应答反应的分子机制.方法 3组雄性Wistar大鼠,每组8只,分别在常氧、慢性低氧及间歇低氧状态下30d,免疫组织化学和Westernblot检测HIF-1α和iNOS,逆转录PCR检测二者mRNA的表达,电泳迁移率分析(EMSA)测定HIF-1的DNA结合活性.结果 Westernblot检测结果显示3组iNOS灰度值分别为508±77、1118±106和1937±119,HIF-1α灰度值分别为673±82、1325±139和2088±130,间歇低氧组HIF-1α和iNOS的含量增加最为明显(F=394.5,362.6,P<0.01);间歇低氧组iNOSmRNA增加最为显著,但HIF-1αmRNA无明显增加;间歇低氧组HIF-1的DNA结合活性较常氧对照组明显升高.结论 间歇低氧更易诱导HIF-1α和iNOS的表达;HIF-1可能是间歇低氧状态下促进iNOS转录的主要调控因子;HIF-1通过增强的转录活性来促进iNOS的转录合成.%Objective To study the expression of iNOS and hypoxia inducible factor-1 (HIF-1) α in the brain of rats under chronic intermittent hypoxia, and therefore to explore the molecular mechanisms of hypoxia induced reactions in the nervous system according to the measure of HIF-1 transcription activity. Methods Male Wistar rats were divided into 3 groups: a chronic hypoxia group (n = 8, breathing 10% O_2 for 8 h per day), an intermittent hypoxia group (n =8, breathing 10% O_2 and air altered per 90 sec for 8 h per day) and a control group (n =8, breathing air). Thirty days later, the expression of HIF-1α and iNOS was assessed by using immunohistochemical methods and Western blot, and HIF-1α and iNOS mRNA was assessed by RT-PCR. The detection of binding activity of HIF-1 to the iNOS promoter gene was assessed by electrophoretic mobility shift assay. Results The productions of HIF-1α (508±77,1118±106 and 1937±119) and iNOS (673±82,1325

  19. Hypoxia and hypoxia-inducible factors in leukaemias

    Directory of Open Access Journals (Sweden)

    Margaux eDeynoux

    2016-02-01

    Full Text Available Despite huge improvements in the treatment of leukaemia, the percentage of patients suffering relapse still remains significant. Relapse most often results from a small number of leukaemic stem cells (LSCs within the bone marrow, which are able to self-renew and therefore re-establish the full tumour. The marrow microenvironment contributes considerably in supporting the protection and development of leukaemic cells. LSCs share specific niches with normal haematopoietic stem cells with the niche itself being composed of a variety of cell types including mesenchymal stem/stromal cells, bone cells, immune cells, neuronal cells and vascular cells. A hallmark of the haematopoietic niche is low oxygen partial pressure, indeed this hypoxia is necessary for the long-term maintenance of HSCs. Hypoxia is a strong signal, principally maintained by members of the hypoxia-inducible factor family. In solid tumours, it has been well-established that hypoxia triggers intrinsic metabolic changes and microenvironmental modifications, such as the stimulation of angiogenesis, through activation of HIFs. As leukaemia is not considered a solid tumour, the role of oxygen in the disease was presumed to be inconsequential and remained long overlooked. This view has now been revised since hypoxia has been shown to influence leukaemic cell proliferation, differentiation and resistance to chemotherapy. However, the role of HIF proteins remains controversial with HIFs being considered as either oncogenes or tumour suppressor genes, depending on the study and model. The purpose of this review is to highlight our knowledge of hypoxia and HIFs in leukaemic development and therapeutic resistance, and to discuss the recent hypoxia-based strategies proposed to eradicate leukaemias.

  20. Hypobaric intermittent hypoxia attenuates hypoxia-induced depressor response.

    Directory of Open Access Journals (Sweden)

    Fang Cui

    Full Text Available BACKGROUND: Hypobaric intermittent hypoxia (HIH produces many favorable effects in the cardiovascular system such as anti-hypertensive effect. In this study, we showed that HIH significantly attenuated a depressor response induced by acute hypoxia. METHODOLOGY/PRINCIPAL FINDINGS: Sprague-Dawley rats received HIH in a hypobaric chamber simulating an altitude of 5000 m. The artery blood pressure (ABP, heart rate (HR and renal sympathetic nerve activity (RSNA were recorded in anesthetized control rats and rats received HIH. The baseline ABP, HR and RSNA were not different between HIH and control rats. Acute hypoxia-induced decrease in ABP was significantly attenuated in HIH rat compared with control rats. However, acute hypoxia-induced increases in HR and RSNA were greater in HIH rat than in control rats. After removal of bilateral ascending depressor nerves, acute hypoxia-induced depressor and sympathoexcitatory responses were comparable in control and HIH rats. Furthermore, acute hypoxia-induced depressor and sympathoexcitatory responses did not differ between control and HIH groups after blocking ATP-dependent K(+ channels by glibenclamide. The baroreflex function evaluated by intravenous injection of phenylephrine and sodium nitroprusside was markedly augmented in HIH rats compared with control rats. The pressor and sympathoexcitatory responses evoked by intravenous injection of cyanide potassium were also significantly greater in HIH rats than in control rats. CONCLUSIONS/SIGNIFICANCE: Our findings suggest that HIH suppresses acute hypoxia-induced depressor response through enhancement of baroreflex and chemoreflex function, which involves activation of ATP-dependent K(+ channels. This study provides new information and underlying mechanism on the beneficiary effect of HIH on maintaining cardiovascular homeostasis.

  1. Ischemic injury suppresses hypoxia-induced electrographic seizures and the background EEG in a rat model of perinatal hypoxic-ischemic encephalopathy

    OpenAIRE

    2015-01-01

    The relationship among neonatal seizures, abnormalities of the electroencephalogram (EEG), brain injury, and long-term neurological outcome (e.g., epilepsy) remains controversial. The effects of hypoxia alone (Ha) and hypoxia-ischemia (HI) were studied in neonatal rats at postnatal day 7; both models generate EEG seizures during the 2-h hypoxia treatment, but only HI causes an infarct with severe neuronal degeneration. Single-channel, differential recordings of acute EEG seizures and backgrou...

  2. Moderate and late preterm infants exhibit widespread brain white matter microstructure alterations at term-equivalent age relative to term-born controls

    NARCIS (Netherlands)

    Kelly, Claire E.; Cheong, Jeanie L Y; Gabra Fam, Lillian; Leemans, Alexander; Seal, Marc L.; Doyle, Lex W.; Anderson, Peter J.; Spittle, Alicia J.; Thompson, Deanne K.

    2016-01-01

    Despite the many studies documenting cerebral white matter microstructural alterations associated with very preterm birth (<32 weeks’ gestation), there is a dearth of similar research in moderate and late preterm infants (born 32–36 weeks’ gestation), who experience higher rates of neurodevelopmenta

  3. INTRAUTERINE HYPOXIA OF FETUS - INFLUENCE OF ULTRA-LOW DOSES OF ANTIOXIDANT (EXPERIMENTAL RESEARCH

    Directory of Open Access Journals (Sweden)

    ZARINA KHAYBULLINA

    2011-08-01

    Full Text Available Oxygensensing mechanisms have been developed to maintain cell and tissue homeostasis, as well as to adapt to the chronic lowoxygen condition, but intensive production of reactive oxygen species (ROS can cause cell destruction. Previous studies revealed that the hypoxia induces oxidative stress and neurodegeneration, which is associated with memory, behavioral, and learningeducation impairment in children. In the view of the abovestated concept, the study of influence of ultra low doses of antioxidant on ROS generation and activity of enzymes of antioxidant protection in a brain and blood at intrauterine hypoxia of a fetus appears appealing. The effect of Fenozan in ultra low doses was evaluated in the rats underwent intrauterine hypoxia. Research was made on white rats, 66 pregnant females and 279 infant rats (021 days. It was established, that chronic prenatal hypoxia is accompanied by accumulation of malondialdehyde in brain tissue, blood and subcellular fractions of a liver, with the subsequent spontaneous normalization of its maintenance by 21st day in a brain and blood.Fenozan injection in ultra low doses leads to appreciable decrease in MDA level and increase of the ROSscavenging enzymes at first in a brain and peripheral blood, and then in microsomal and mitochondrial fractions of the liver, that is the precondition for normalization of pathological process in earlier terms. Significance of this data argues that ultra low doses of Fenozan can be less invasive and effective in the treatment of chronic intrauterine hypoxia and suggest the directions for further research.

  4. Brain Basics

    Medline Plus

    Full Text Available ... with symptoms of mental illness every day. They can be moderate, or serious and cause severe disability. ... disorders are brain disorders. Evidence shows that they can be related to changes in the anatomy, physiology, ...

  5. Redox homeostasis protects mitochondria through accelerating ROS conversion to enhance hypoxia resistance in cancer cells.

    Science.gov (United States)

    Li, Pengying; Zhang, Dongyang; Shen, Lingxiao; Dong, Kelei; Wu, Meiling; Ou, Zhouluo; Shi, Dongyun

    2016-03-09

    Mitochondria are the powerhouses of eukaryotic cells and the main source of reactive oxygen species (ROS) in hypoxic cells, participating in regulating redox homeostasis. The mechanism of tumor hypoxia tolerance, especially the role of mitochondria in tumor hypoxia resistance remains largely unknown. This study aimed to explore the role of mitochondria in tumor hypoxia resistance. We observed that glycolysis in hypoxic cancer cells was up-regulated more rapidly, with far lesser attenuation in aerobic oxidation, thus contributing to a more stable ATP/ADP ratio. In hypoxia, cancer cells rapidly convert hypoxia-induced O(2˙)(-) into H2O2. H2O2 is further decomposed by a relatively stronger antioxidant system, causing ROS levels to increase lesser compared to normal cells. The moderate ROS leads to an appropriate degree of autophagy, eliminating the damaged mitochondria and offering nutrients to promote mitochondria fusion, thus protects mitochondria and improves hypoxia tolerance in cancer. The functional mitochondria could enable tumor cells to flexibly switch between glycolysis and oxidative phosphorylation to meet the different physiological requirements during the hypoxia/re-oxygenation cycling of tumor growth.

  6. Lack of protracted behavioral abnormalities following intermittent or continuous chronic mild hypoxia in perinatal C57BL/6 mice.

    Science.gov (United States)

    Lima-Ojeda, Juan M; Vogt, Miriam A; Richter, S Helene; Dormann, Christof; Schneider, Miriam; Gass, Peter; Inta, Dragos

    2014-08-08

    Several prospective studies indicated perinatal hypoxia as risk factor for psychiatric disorders like schizophrenia. It is thought that hypoxia prior to or during birth may contribute to alterations leading to the protracted clinical manifestation during young adulthood. However, only a small fraction of children with a history of perinatal hypoxia develop later psychotic symptoms, therefore it is not known if hypoxia alone is sufficient to trigger long-term behavioral changes. Here we exposed C57BL/6 mice from postnatal day 3-7 (P3-P7) to two established paradigms of chronic mild hypoxia (10% ambient O2), intermittent and continuous. Subsequently, mice were analysed during young adult stages using several basic behavioral tests. Previous studies demonstrated severe, but only transient, cortical damage in these paradigms; it is not clear, if these reversible morphological changes are accompanied by long-term behavioral effects. We found that neither intermittent nor continuous perinatal hypoxia induced long-term behavioral alterations. This may be due to the high regenerative capacity of the perinatal brain. Other possibilities include a potential resistance to perinatal hypoxia of the mouse strain used here or a level of hypoxia that was insufficient to trigger significant behavioral changes. Therefore, our data do not exclude a role of perinatal hypoxia as risk factor for psychiatric disorders. They rather suggest that either other, more severe hypoxic conditions like anoxia, or the presence of additional factors (as genetic risk factors) are necessary for generating long-term behavioral abnormalities.

  7. Moderate whisky consumption in combination with an evening meal reduces tryptophan availability to the brain but does not influence performance in healthy volunteers

    NARCIS (Netherlands)

    Markus, C.R.; Sierksma, A.; Verbeek, C.; Rooijen, J.J.M. van; Patel, H.J.; Brand, A.N.; Hendriks, H.F.J.

    2004-01-01

    Brain serotonin (5-HT) synthesis is controlled by nutrients that influence the availability of plasma tryptophan (Trp) as compared with the sum of the other large neutral amino acids (LNAA; Trp:LNAA). Alcohol consumption is found to change mood and performance and this might well be due to

  8. Moderate whisky consumption in combination with an evening meal reduces tryptophan availability to the brain but does not influence performance in healthy volunteers

    NARCIS (Netherlands)

    Markus, C.R.; Sierksma, A.; Verbeek, C.; Rooijen, J.J.M. van; Patel, H.J.; Brand, A.N.; Hendriks, H.F.J.

    2004-01-01

    Brain serotonin (5-HT) synthesis is controlled by nutrients that influence the availability of plasma tryptophan (Trp) as compared with the sum of the other large neutral amino acids (LNAA; Trp:LNAA). Alcohol consumption is found to change mood and performance and this might well be due to alteratio

  9. The impact of childhood abuse and recent stress on serum brain-derived neurotrophic factor and the moderating role of BDNF Val(66)Met

    NARCIS (Netherlands)

    Elzinga, Bernet M.; Molendijk, Marc L.; Voshaar, Richard C. Oude; Bus, Boudewijn A. A.; Prickaerts, Jos; Spinhoven, Philip; Penninx, Brenda J. W. H.

    2011-01-01

    Recent findings show lowered brain-derived neurotrophic factor (BDNF) levels in major depressive disorder (MDD). Exposure to stressful life events may (partly) underlie these BDNF reductions, but little is known about the effects of early or recent life stress on BDNF levels. Moreover, the effects o

  10. The impact of childhood abuse and recent stress on serum brain-derived neurotrophic factor and the moderating role of BDNF Val66Met

    NARCIS (Netherlands)

    Elzinga, B.M.; Molendijk, M.L.; Oude Voshaar, R.C.; Bus, B.A.A.; Prickaerts, J.; Spinhoven, P.; Penninx, B.J.

    2011-01-01

    RATIONALE: Recent findings show lowered brain-derived neurotrophic factor (BDNF) levels in major depressive disorder (MDD). Exposure to stressful life events may (partly) underlie these BDNF reductions, but little is known about the effects of early or recent life stress on BDNF levels. Moreover, th

  11. Moderate Bravery

    DEFF Research Database (Denmark)

    Majgaard, Klaus

    2016-01-01

    Purpose: The ability to act in a purposeful and effective way amid institutional tensions and paradoxes is, right now, a highly prized quality in public leadership. The purpose of this chapter is to qualify moderately brave acts as a learning format that combines the analytical and performative...... skills implied in this kind of agency. Design/methodology/approach: The chapter explores the engagement with paradoxes as a narrative praxis. From existing literature, it sums up an understanding of agency as a social process of mediating paradoxes in order to make action possible. Drawing on Northrop...

  12. Lung Oxidative Damage by Hypoxia

    Directory of Open Access Journals (Sweden)

    O. F. Araneda

    2012-01-01

    Full Text Available One of the most important functions of lungs is to maintain an adequate oxygenation in the organism. This organ can be affected by hypoxia facing both physiological and pathological situations. Exposure to this condition favors the increase of reactive oxygen species from mitochondria, as from NADPH oxidase, xanthine oxidase/reductase, and nitric oxide synthase enzymes, as well as establishing an inflammatory process. In lungs, hypoxia also modifies the levels of antioxidant substances causing pulmonary oxidative damage. Imbalance of redox state in lungs induced by hypoxia has been suggested as a participant in the changes observed in lung function in the hypoxic context, such as hypoxic vasoconstriction and pulmonary edema, in addition to vascular remodeling and chronic pulmonary hypertension. In this work, experimental evidence that shows the implied mechanisms in pulmonary redox state by hypoxia is reviewed. Herein, studies of cultures of different lung cells and complete isolated lung and tests conducted in vivo in the different forms of hypoxia, conducted in both animal models and humans, are described.

  13. Lung Oxidative Damage by Hypoxia

    Science.gov (United States)

    Araneda, O. F.; Tuesta, M.

    2012-01-01

    One of the most important functions of lungs is to maintain an adequate oxygenation in the organism. This organ can be affected by hypoxia facing both physiological and pathological situations. Exposure to this condition favors the increase of reactive oxygen species from mitochondria, as from NADPH oxidase, xanthine oxidase/reductase, and nitric oxide synthase enzymes, as well as establishing an inflammatory process. In lungs, hypoxia also modifies the levels of antioxidant substances causing pulmonary oxidative damage. Imbalance of redox state in lungs induced by hypoxia has been suggested as a participant in the changes observed in lung function in the hypoxic context, such as hypoxic vasoconstriction and pulmonary edema, in addition to vascular remodeling and chronic pulmonary hypertension. In this work, experimental evidence that shows the implied mechanisms in pulmonary redox state by hypoxia is reviewed. Herein, studies of cultures of different lung cells and complete isolated lung and tests conducted in vivo in the different forms of hypoxia, conducted in both animal models and humans, are described. PMID:22966417

  14. Hypoxia in the changing marine environment

    Digital Repository Service at National Institute of Oceanography (India)

    Zhang, J.; Cowie, G.; Naqvi, S.W.A.

    of ecosystems from tropics to high latitudes. Among the various associated phenomena of ecosystem deterioration, hypoxia can cause serious problems in coastal areas as well as oxygen minimum zones in the open ocean. The negative impacts of hypoxia include...

  15. Hypoxia alters cell cycle regulatory protein expression and induces premature maturation of oligodendrocyte precursor cells.

    Directory of Open Access Journals (Sweden)

    Ravi Shankar Akundi

    Full Text Available BACKGROUND: Periventricular white matter injury (PWMI is a common form of brain injury sustained by preterm infants. A major factor that predisposes to PWMI is hypoxia. Because oligodendrocytes (OLs are responsible for myelination of axons, abnormal OL development or function may affect brain myelination. At present our understanding of the influences of hypoxia on OL development is limited. To examine isolated effects of hypoxia on OLs, we examined the influences of hypoxia on OL development in vitro. METHODOLOGY/FINDINGS: Cultures of oligodendrocyte precursor cells (OPCs were prepared from mixed glial cultures and were 99% pure. OPCs were maintained at 21% O(2 or hypoxia (1% or 4% O(2 for up to 7 days. We observed that 1% O(2 lead to an increase in the proportion of myelin basic protein (MBP-positive OLs after 1 week in culture, and a decrease in the proportion of platelet-derived growth factor receptor alpha (PDGFRalpha-positive cells suggesting premature OL maturation. Increased expression of the cell cycle regulatory proteins p27(Kip1 and phospho-cdc2, which play a role in OL differentiation, was seen as well. CONCLUSIONS: These results show that hypoxia interferes with the normal process of OL differentiation by inducing premature OPC maturation.

  16. Acute Normobaric Hypoxia Increases Post-exercise Lipid Oxidation in Healthy Males.

    Science.gov (United States)

    Kelly, Liam P; Basset, Fabien A

    2017-01-01

    The primary objective of the current study was to determine the effect of moderate normobaric hypoxia exposure during constant load cycling on post-exercise energy metabolism recorded in normoxia. Indirect calorimetry was used to examine whole body substrate oxidation before, during, 40-60 min post, and 22 h after performing 60 min of cycling exercise at two different fractions of inspired oxygen (FIO2): (i) FIO2 = 0.2091 (normoxia) and (ii) FIO2 = 0.15 (hypoxia). Seven active healthy male participants (26 ± 4 years of age) completed both experimental trials in randomized order with a 7-day washout period to avoid carryover effects between conditions. Resting energy expenditure was initially elevated following cycling exercise in normoxia and hypoxia (Δ 0.14 ± 0.05, kcal min(-1), p = 0.037; Δ 0.19 ± 0.03 kcal min(-1), p oxidation occurred after exercise performed in hypoxia while post-exercise measurements were similar to baseline after cycling exercise in normoxia. The additional metabolic stress of hypoxia exposure was sufficient to increase the rate of lipid oxidation (Δ 42 ± 11 mg min(-1), p = 0.019) and tended to suppress carbohydrate oxidation (Δ -55 ± 26 mg min(-1), p = 0.076) 40-60 min post-exercise. This shift in substrate oxidation persisted the next morning, where lipid oxidation remained elevated (Δ 9 ± 3 mg min(-1), p = 0.0357) and carbohydrate oxidation was suppressed (Δ -22 ± 6 mg min(-1), p = 0.019). In conclusion, prior exercise performed under moderate normobaric hypoxia alters post-exercise energy metabolism. This is an important consideration when evaluating the metabolic consequences of hypoxia exposure during prolonged exercise, and future studies should evaluate its role in the beneficial effects of intermittent hypoxia training observed in persons with obesity and insulin resistance.

  17. Assessment of brain tissue injury after moderate hypothermia in neonates with hypoxic–ischaemic encephalopathy: a nested substudy of a randomised controlled trial

    OpenAIRE

    Rutherford, Mary; Ramenghi, Luca A; Edwards, A. David; Brocklehurst, Peter; Halliday, Henry; Levene, Malcolm; Strohm, Brenda; Thoresen, Marianne; Whitelaw, Andrew; Azzopardi, Denis

    2010-01-01

    Summary Background Moderate hypothermia in neonates with hypoxic–ischaemic encephalopathy might improve survival and neurological outcomes at up to 18 months of age, although complete neurological assessment at this age is difficult. To ascertain more precisely the effect of therapeutic hypothermia on neonatal cerebral injury, we assessed cerebral lesions on MRI scans of infants who participated in the Total Body Hypothermia for Neonatal Encephalopathy (TOBY) trial. Methods In the TOBY trial ...

  18. FDG uptake, a surrogate of tumour hypoxia?

    NARCIS (Netherlands)

    Dierckx, Rudi Andre; de Wiele, Christophe Van

    2008-01-01

    Introduction Tumour hyperglycolysis is driven by activation of hypoxia-inducible factor-1 (HIF-1) through tumour hypoxia. Accordingly, the degree of 2-fluro-2-deoxy-D-glucose (FDG) uptake by tumours might indirectly reflect the level of hypoxia, obviating the need for more specific radiopharmaceutic

  19. Moderately delayed post-insult treatment with normobaric hyperoxia reduces excitotoxin-induced neuronal degeneration but increases ischemia-induced brain damage

    Directory of Open Access Journals (Sweden)

    Haelewyn Benoit

    2011-04-01

    Full Text Available Abstract Background The use and benefits of normobaric oxygen (NBO in patients suffering acute ischemic stroke is still controversial. Results Here we show for the first time to the best of our knowledge that NBO reduces both NMDA-induced calcium influxes in vitro and NMDA-induced neuronal degeneration in vivo, but increases oxygen and glucose deprivation-induced cell injury in vitro and ischemia-induced brain damage produced by middle cerebral artery occlusion in vivo. Conclusions Taken together, these results indicate that NBO reduces excitotoxin-induced calcium influx and subsequent neuronal degeneration but favors ischemia-induced brain damage and neuronal death. These findings highlight the complexity of the mechanisms involved by the use of NBO in patients suffering acute ischemic stroke.

  20. Hyperbaric Oxygen Therapy in the Treatment of Chronic Mild-Moderate Blast-Induced Traumatic Brain Injury Post-Concussion Syndrome (PCS) and Post Traumatic Stress Disorder (PTSD)

    Science.gov (United States)

    2016-10-01

    secure funding. There are no study results to report at this time and no significant adverse advents. 15. SUBJECT TERMS HBOT: hyperbaric oxygen...therapy; TBI: traumatic brain injury; PPCS: persistent post-concussion syndrome 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT 18...published 11/2011 in the Journal of Neurotrauma (http://www.liebertonline.com/doi/abs/10.1089/ neu .2011 .1895). The original purpose of the present

  1. Moderate whisky consumption in combination with an evening meal reduces tryptophan availability to the brain but does not influence performance in healthy volunteers.

    Science.gov (United States)

    Markus, C Rob; Sierksma, Aafje; Verbeek, Cees; van Rooijen, Jan J M; Patel, Hamina J; Brand, A Nico; Hendriks, Henk F J

    2004-12-01

    Brain serotonin (5-HT) synthesis is controlled by nutrients that influence the availability of plasma tryptophan (Trp) as compared with the sum of the other large neutral amino acids (LNAA; Trp:LNAA). Alcohol consumption is found to change mood and performance and this might well be due to alterations in the plasma Trp:LNAA ratio and brain 5-HT. In the present study, we tested whether whisky consumption as part of a meal may alter the plasma Trp:LNAA ratio and influence mood and performance in healthy volunteers. Twenty-four healthy male subjects participated in a within-subjects cross-over study. Subjects consumed whisky (125 ml; 40 g alcohol) or water (125 ml) as part of a standard evening meal. Effects of whisky consumption were tested on mood and choice reaction time and blood samples were taken to measure changes in plasma amino acids, glucose and insulin. The plasma Trp:LNAA ratio showed a significant decline 2 h after whisky consumption of alcohol (Pwhisky consumption alters available plasma Trp for uptake into the brain, whereas there were no effects on mood and performance.

  2. Functional and anatomical evidence of cerebral tissue hypoxia in young sickle cell anemia mice.

    Science.gov (United States)

    Cahill, Lindsay S; Gazdzinski, Lisa M; Tsui, Albert Ky; Zhou, Yu-Qing; Portnoy, Sharon; Liu, Elaine; Mazer, C David; Hare, Gregory Mt; Kassner, Andrea; Sled, John G

    2017-03-01

    Cerebral ischemia is a significant source of morbidity in children with sickle cell anemia; however, the mechanism of injury is poorly understood. Increased cerebral blood flow and low hemoglobin levels in children with sickle cell anemia are associated with increased stroke risk, suggesting that anemia-induced tissue hypoxia may be an important factor contributing to subsequent morbidity. To better understand the pathophysiology of brain injury, brain physiology and morphology were characterized in a transgenic mouse model, the Townes sickle cell model. Relative to age-matched controls, sickle cell anemia mice demonstrated: (1) decreased brain tissue pO2 and increased expression of hypoxia signaling protein in the perivascular regions of the cerebral cortex; (2) elevated basal cerebral blood flow , consistent with adaptation to anemia-induced tissue hypoxia; (3) significant reduction in cerebrovascular blood flow reactivity to a hypercapnic challenge; (4) increased diameter of the carotid artery; and (5) significant volume changes in white and gray matter regions in the brain, as assessed by ex vivo magnetic resonance imaging. Collectively, these findings support the hypothesis that brain tissue hypoxia contributes to adaptive physiological and anatomic changes in Townes sickle cell mice. These findings may help define the pathophysiology for stroke in children with sickle cell anemia.

  3. 中重度颅脑损伤后CT影像特点、颅内压与预后的关系%Relationships among CT imaging features, intracranial pressure and prognosis after moderate or severe traumatic brain injury

    Institute of Scientific and Technical Information of China (English)

    李进京; 罗光东; 曹宴宾; 于龙; 李建涛; 于洋

    2013-01-01

    Objective To research the relationships among CT imaging features,intracranial pressure (ICP) and prognosis in patients with moderate or severe traumatic brain injury.Methods ICP monitoring and CT examination were performed in 28 patients with moderate or severe traumatic brain injury.The ICP value and CT imaging features such as the basal cistern compression,midline shift,ventricular compression were recorded,and Rotterdam CT score was calculated.The statistical analyses were performed for these factors.Results The statistical analysis showed:there was a correlation between CT imaging features and ICP level,while the strongest correlation existed between ICP level and Rotterdam CT score.Otherwise,the strongest correlation existed between prognosis and ICP 24 h after injury,while there was not a correlation between both the midline shift and ventricular compression and prognosis.Conclusions Rotterdam CT score is superior to single CT imaging feature for assessing the ICP level and prognosis of patients with moderate or severe traumatic brain injury.There is a negative correlation between ICP level and prognosis after traumatic brain injury,and the ICP monitoring and related treatment can improve the prognosis of patients with moderate or severe traumatic brain injury.%目的研究中、重度颅脑损伤病人颅内压、CT影像特点及预后之间的关系.方法对28例中、重度颅脑损伤病人行颅内压监测和头部CT扫描,记录颅内压值和CT影像特点(基底池受压、中线移位、脑室受压情况),并进行Rotterdam CT评分,对这些因素进行统计学分析.结果经统计学分析:各CT影像特点与颅内压水平存在相关性,Rotterdam CT评分与颅内压水平的相关性最强.伤后24 h颅内压水平与病人预后相关性最强,而中线移位和脑室受压情况与预后无明显相关性.结论在评估中、重度颅脑损伤病人颅内压及预后方面,Rotterdam CT评分优于单个CT影像特征;颅内压与

  4. δ-Opioid receptor (DOR) signaling and reactive oxygen species (ROS) mediate intermittent hypoxia induced protection of canine myocardium.

    Science.gov (United States)

    Estrada, Juan A; Williams, Arthur G; Sun, Jie; Gonzalez, Leticia; Downey, H Fred; Caffrey, James L; Mallet, Robert T

    2016-03-01

    Intermittent, normobaric hypoxia confers robust cardioprotection against ischemia-induced myocardial infarction and lethal ventricular arrhythmias. δ-Opioid receptor (DOR) signaling and reactive oxygen species (ROS) have been implicated in cardioprotective phenomena, but their roles in intermittent hypoxia are unknown. This study examined the contributions of DOR and ROS in mediating intermittent hypoxia-induced cardioprotection. Mongrel dogs completed a 20 day program consisting of 5-8 daily, 5-10 min cycles of moderate, normobaric hypoxia (FIO2 0.095-0.10), with intervening 4 min room air exposures. Subsets of dogs received the DOR antagonist naltrindole (200 μg/kg, sc) or antioxidant N-acetylcysteine (250 mg/kg, po) before each hypoxia session. Twenty-four hours after the last session, the left anterior descending coronary artery was occluded for 60 min and then reperfused for 5 h. Arrhythmias detected by electrocardiography were scored according to the Lambeth II conventions. Left ventricles were sectioned and stained with 2,3,5-triphenyl-tetrazolium-chloride, and infarct sizes were expressed as percentages of the area at risk (IS/AAR). Intermittent hypoxia sharply decreased IS/AAR from 41 ± 5 % (n = 12) to 1.8 ± 0.9 % (n = 9; P intermittent hypoxia). N-acetylcysteine (n = 6) interfered to a similar degree, with IS/AAR 42 ± 3 % and arrhythmia score 4.7 ± 0.3 (P intermittent hypoxia). Without the intervening reoxygenations, hypoxia (n = 4) was not cardioprotective (IS/AAR 50 ± 8 %; arrhythmia score 4.5 ± 0.5; P intermittent hypoxia). Thus DOR, ROS and cyclic reoxygenation were obligatory participants in the gradually evolving cardioprotection produced by intermittent hypoxia.

  5. Molecular response of estuarine fish to hypoxia: a comparative study with ruffe and flounder from field and laboratory.

    Directory of Open Access Journals (Sweden)

    Jessica Tiedke

    Full Text Available On a global scale, the frequencies and magnitudes of hypoxic events in coastal and estuarine waters have increased dramatically over the past 20 years. Fish populations are suitable indicators for the assessment of the quality of aquatic ecosystems, as they are omnipresent and often comprise a variety of different lifestyles and adaption strategies. We have investigated on the molecular level the impact of hypoxia on two fish species typical of European estuaries. We monitored the expression of eleven putatively hypoxia-responsive genes by means of quantitative real-time RT-PCR in brains, gills and hearts of the ruffe (Gymnocephalus cernua and the flounder (Platichthys flesus. We first investigated the effect of naturally occurring hypoxia in the Elbe estuary. In a second approach, expression changes in the response to hypoxia were monitored under controlled laboratory conditions. The genes that showed the strongest effect were two respiratory proteins, myoglobin and neuroglobin, as well as the apoptosis enzyme caspase 3. As previously observed in other fish, myoglobin, which was considered to be muscle-specific, was found in brain and gills as well. Comparison of field and laboratory studies showed that--with the exception of the heart of flounder--that mRNA levels of the selected genes were about the same, suggesting that laboratory conditions reflect natural conditions. Likewise, trends of gene expression changes under hypoxia were the same, although hypoxia response was more pronounced in the Elbe estuary. In general, the flounder displayed a stronger response to hypoxia than the ruffe, suggesting that the flounder is more susceptible to hypoxia. The most pronounced differences were found among tissues within a species, demonstrating that hypoxia response is largely tissue-specific. In summary, our data suggest that laboratory experiments essentially mimic field data, but additional environmental factors enhance hypoxia response in nature.

  6. Blast-Induced Moderate Neurotrauma (BINT) Elicits Early Complement Activation and Tumor Necrosis Factor Alpha (TNFalpha) Release in a Rat Brain

    Science.gov (United States)

    2012-04-25

    for the damaged tissue. Mol Psychiatry 1997;2:133–6. [20] Chavko M, Prusaczyk WK, McCarron RM. Lung injury and recovery after exposure to blast...complement pathways after contusion -induced spinal cord injury. J Neurotrauma2004;21:1831–46. [23] Bellander BM, von Holst H, Fredman P, Svensson M...Activation of the complement cascade and increase of clusterin in the brain following a cortical contusion in the adult rat. J Neurosurg 1996;85:468–75. [24

  7. Plasma volume in acute hypoxia

    DEFF Research Database (Denmark)

    Poulsen, T D; Klausen, T; Richalet, J P

    1998-01-01

    Exposure to acute hypoxia is associated with changes in body fluid homeostasis and plasma volume (PV). This study compared a dye dilution technique using Evans' blue (PV[Evans']) with a carbon monoxide (CO) rebreathing method (PV[CO]) for measurements of PV in ten normal subjects at sea level...

  8. Cerebral hypoxia and ischemia in preterm infants

    Directory of Open Access Journals (Sweden)

    Alberto Ravarino

    2014-06-01

    Full Text Available Premature birth is a major public health issue internationally affecting 13 million babies worldwide. Hypoxia and ischemia is probably the commonest type of acquired brain damage in preterm infants. The clinical manifestations of hypoxic-ischemic injury in survivors of premature birth include a spectrum of cerebral palsy and intellectual disabilities. Until recently, the extensive brain abnormalities in preterm neonates appeared to be related mostly to destructive processes that lead to substantial deletion of neurons, axons, and glia from necrotic lesions in the developing brain. Advances in neonatal care coincide with a growing body of evidence that the preterm gray and white matter frequently sustain less severe insults, where tissue destruction is the minor component. Periventricular leukomalacia (PVL is the major form of white matter injury and consists classically of focal necrotic lesions, with subsequent cyst formation, and a less severe but more diffuse injury to cerebral white mater, with prominent astrogliosis and microgliosis but without overt necrosis. With PVL a concomitant injury occurs to subplate neurons, located in the subcortical white matter. Severe hypoxic-ischemic insults that trigger significant white matter necrosis are accompanied by neuronal degeneration in cerebral gray and white matter. This review aims to illustrate signs of cerebral embryology of the second half of fetal life and correlate hypoxic-ischemic brain injury in the premature infant. This should help us better understand the symptoms early and late and facilitate new therapeutic strategies. Proceedings of the International Course on Perinatal Pathology (part of the 10th International Workshop on Neonatology · October 22nd-25th, 2014 · Cagliari (Italy · October 25th, 2014 · The role of the clinical pathological dialogue in problem solving Guest Editors: Gavino Faa, Vassilios Fanos, Peter Van Eyken

  9. Relaxin protects astrocytes from hypoxia in vitro.

    Directory of Open Access Journals (Sweden)

    Jordan M Willcox

    Full Text Available The peptide relaxin has recently been shown to protect brain tissues from the detrimental effects of ischemia. To date, the mechanisms for this remain unclear. In order to investigate the neuroprotective mechanisms by which relaxin may protect the brain, we investigated the possibility that relaxin protects astrocytes from hypoxia or oxygen/glucose deprivation (OGD. Cultured astrocytes were pre-treated with either relaxin-2 or relaxin-3 and exposed to OGD for 24 or 48 hours. Following OGD exposure, viability assays showed that relaxin-treated cells exhibited a higher viability when compared to astrocytes that experienced OGD-alone. Next, to test whether relaxin reduced the production of reactive oxygen species (ROS astrocytes were exposed to the same conditions as the previous experiment and a commercially available ROS detection kit was used to detect ROS production. Astrocytes that were treated with relaxin-2 and relaxin-3 showed a marked decrease in ROS production when compared to control astrocytes that were exposed only to OGD. Finally, experiments were performed to determine whether or not the mitochondrial membrane potential was affected by relaxin treatment during 24 hour OGD. Mitochondrial membrane potential was higher in astrocytes that were treated with relaxin-2 and relaxin-3 compared to untreated OGD-alone astrocytes. Taken together, these data present novel findings that show relaxin protects astrocytes from ischemic conditions through the reduction of ROS production and the maintenance of mitochondrial membrane potential.

  10. Effects of hypoxic pretreatment on changes in cerebral ultrastructure and free radical content induced by brain hypoxia and ischemia%缺氧预处理对缺血缺氧脑组织超微结构与自由基的影响

    Institute of Scientific and Technical Information of China (English)

    孟凌新; 董有靖; 崔健君; 王忠成

    2001-01-01

    目的观察缺氧预处理对缺血缺氧脑组织超微结构及脑组织自由基的影响.方法将40只小鼠随机分为4组.A组为盐水对照组,B组为缺氧预处理组,IH组为缺血缺氧组,BIH组为缺氧预处理后缺血缺氧组.各组有6只小鼠分别采用黄嘌呤氧化酶法和硫代巴比妥酸法检测脑组织的超氧化物歧化酶(SOD)活性和丙二醛(MDA)含量,另4只小鼠用于透射电镜下脑组织超微结构的观察.结果与A组比较,B组SOD活性增加,IH组MDA含量明显增加,而BIH组SOD活性明显增加的同时,MDA含量较比IH组明显降低.电镜显示B组除部分神经元轻度肿胀外,脑组织超微结构基本同A组,IH组细胞核变形,细胞浆成空泡,严重者满视野几乎找不到正常细胞,无损害的神经元<10%,BIH组细胞结构基本恢复正常,无损伤神经元达63%.结论缺氧预处理对再缺血缺氧引起的神经元损伤有保护作用,内源性抗氧化物质的增加与其有直接关系.%Objective To investigate whether hypoxic pretreatment could ameliorate the cerebral injuries induced by brain hypoxia and ischemia. Methods Forty mice weighting 18-25g were randomly allocated to 4 groups of ten mice each. Group A served as control. In group B animals received hypoxic pretreatment. Mouse was put in a 150ml bottle, then the mouth of the bottle was closed. The mouse was taken out breathing fresh air whenever it developed dyspnea. When it recovered, it was put in the closed bottle again. The process was repeated four times. In group IH animals received ischemia/hypoxia induced by ligation of left common carotid artery and breathing 8% O2 . In group BIH animals received hypoxic pretreatment first and then ischemia/hypoxia. All animals were decapitated at the end of experiment and brain was removed for ultrastrcture examination and determination of superoxide dismutase (SOD) activity and malondialdehyde (MDA) content. Results In group B SOD activity incrreased significantly as

  11. Hypoxia and flight performance of military instructor pilots in a flight simulator.

    Science.gov (United States)

    Temme, Leonard A; Still, David L; Acromite, Michael T

    2010-07-01

    Military aircrew and other operational personnel frequently perform their duties at altitudes posing a significant hypoxia risk, often with limited access to supplemental oxygen. Despite the significant risk hypoxia poses, there are few studies relating it to primary flight performance, which is the purpose of the present study. Objective, quantitative measures of aircraft control were collected from 14 experienced, active duty instructor pilot volunteers as they breathed an air/nitrogen mix that provided an oxygen partial pressure equivalent to the atmosphere at 18,000 ft (5486.4 m) above mean sea level. The flight task required holding a constant airspeed, altitude, and heading at an airspeed significantly slower than the aircraft's minimum drag speed. The simulated aircraft's inherent instability at the target speed challenged the pilot to maintain constant control of the aircraft in order to minimize deviations from the assigned flight parameters. Each pilot's flight performance was evaluated by measuring all deviations from assigned target values. Hypoxia degraded the pilot's precision of altitude and airspeed control by 53%, a statistically significant decrease in flight performance. The effect on heading control effects was not statistically significant. There was no evidence of performance differences when breathing room air pre- and post-hypoxia. Moderate levels of hypoxia degraded the ability of military instructor pilots to perform a precision slow flight task. This is one of a small number of studies to quantify an effect of hypoxia on primary flight performance.

  12. Intermittent hypoxia in childhood: the harmful consequences versus potential benefits of therapeutic uses

    Directory of Open Access Journals (Sweden)

    Tatiana V. Serebrovskaya

    2015-05-01

    Full Text Available Intermittent hypoxia often occurs in early infancy in both preterm and term infants and especially at 36 to 44 weeks postmenstrual age. These episodes of intermittent hypoxia could result from sleep-disordered breathing or may be temporally unrelated to apnea or bradycardia events. There are numerous reports indicating adverse effects of intermittent hypoxia on development, behavior, academic achievement and cognition in children with sleep apnea syndrome. It remains uncertain the exact causative relationship between the neurocognitive and behavioral morbidities and intermittent hypoxia and/or its associated sleep fragmentation. On the other hand, well-controlled and moderate intermittent hypoxia conditioning/training has been used in sick children for treating their various forms of bronchial asthma, allergic dermatoses, autoimmune thyroiditis, cerebral palsy, and obesity. This review article provides an updated and impartial analysis on the currently available evidence in supporting either side of the seemingly contradictory scenarios. We wish to stimulate a comprehensive understanding of such a complex physiological phenomenon as intermittent hypoxia, which may be accompanied by other confounding factors (e.g. hypercapnia, polycythemia, in order to prevent or reduce its harmful consequences, while maximize its potential utility as an effective therapeutic tool in pediatric patients.

  13. Elevated incidence of suicide in people living at altitude, smokers and patients with chronic obstructive pulmonary disease and asthma: possible role of hypoxia causing decreased serotonin synthesis.

    Science.gov (United States)

    Young, Simon N

    2013-11-01

    Recent research indicates that suicide rates are elevated in those living at higher altitudes in both the United States and South Korea. A possible mechanism that was proposed is metabolic stress associated with hypoxia. This commentary discusses these results, and also the association between elevated suicide rates and other conditions associated with hypoxia (smoking, chronic obstructive pulmonary disease and asthma). Tryptophan hydroxylase may not normally be saturated with oxygen, so mild hypoxia would decrease serotonin synthesis. Low brain serotonin is known to be associated with suicide. Thus, the commentary proposes and discusses the hypothesis that decreased brain serotonin synthesis associated with hypoxia is a mechanism that may contribute to suicide in conditions causing hypoxia. Finally the commentary proposes various studies that could test aspects of this hypothesis.

  14. 脑室-腹腔分流术治疗脑外伤后脑积水42例分析%Analysis of Ventricle-peritoneum Shunt on 42 Cases with Hydrocephalus after Moderate and Severe Brain Injury

    Institute of Scientific and Technical Information of China (English)

    陈忠勇

    2009-01-01

    Objective To explore the therapeutic effect of hydrocephalus after moderate and severe brain injury with ventricle-peritoneum shunt(VPS). Methods The clinical data of 42 cases with post-traumatic hydrocephalus admitted in our hospital were analyzed retrospectively.Results The patients' consciousness and nerve function had been improved, including 22 cases (52.4%) of good recovery, 12 cases (28.6%) of moderate deficit, 8 cases(19.0%) medially disabled and severely disabled. There was no operative mortality. Conclusion VPS can improve patients consciousness and nerve function and outcome with hydrocephalus after trauma,and reduce the mortality and disability rate of severe brain injury.%目的 探讨脑室一腹腔分流术治疗脑外伤后脑积水的疗效.方法 回顾性分析我院42例脑外伤后脑积水行脑室一腹腔分流术患者的资料.结果 术后意识及神经功能障碍有不同程度的改善.其中恢复良好22例(52.4%)、中残12例(28.6%)、重残或植物生存8例(19.0%),无手术死亡病例.结论 分流手术能明显改善患者的意识及神经功能障碍,改善患者预后,降低重型脑外伤的死残率.

  15. Postoperative hypoxia and length of intensive care unit stay after cardiac surgery: the underweight paradox?

    Directory of Open Access Journals (Sweden)

    Marco Ranucci

    Full Text Available OBJECTIVE: Cardiac operations with cardiopulmonary bypass can be associated with postoperative lung dysfunction. The present study investigates the incidence of postoperative hypoxia after cardiac surgery, its relationship with the length of intensive care unit stay, and the role of body mass index in determining postoperative hypoxia and intensive care unit length of stay. DESIGN: Single-center, retrospective study. SETTING: University Hospital. Patients. Adult patients (N = 5,023 who underwent cardiac surgery with CPB. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: According to the body mass index, patients were attributed to six classes, and obesity was defined as a body mass index >30. POH was defined as a PaO2/FiO2 ratio <200 at the arrival in the intensive care unit. Postoperative hypoxia was detected in 1,536 patients (30.6%. Obesity was an independent risk factor for postoperative hypoxia (odds ratio 2.4, 95% confidence interval 2.05-2.78, P = 0.001 and postoperative hypoxia was a determinant of intensive care unit length of stay. There is a significant inverse correlation between body mass index and PaO2/FiO2 ratio, with the risk of postoperative hypoxia increasing by 1.7 folds per each incremental body mass index class. The relationship between body mass index and intensive care unit length of stay is U-shaped, with longer intensive care unit stay in underweight patients and moderate-morbid obese patients. CONCLUSIONS: Obese patients are at higher risk for postoperative hypoxia, but this leads to a prolonged intensive care unit stay only for moderate-morbid obese patients. Obese patients are partially protected against the deleterious effects of hemodilution and transfusions. Underweight patients present the "paradox" of a better lung gas exchange but a longer intensive care unit stay. This is probably due to a higher severity of their cardiac disease.

  16. Protection of electroacupuncture at Baihui and Dazhui on neonatal rats with hypoxia-ischemic brain injury%电针刺激百会及大椎穴对新生鼠缺氧缺血性脑损伤的保护

    Institute of Scientific and Technical Information of China (English)

    曲金柱; 李宛青

    2005-01-01

    性细胞的表达.结果:①脑海马区胆碱乙酰转移酶免疫阳性细胞的表达:与假手术组比较,模型对照组明显降低,而电针治疗组则无明显变化[(24.46±8.24),(13.96±7.62),(25.54±5.05)个/视野,P<0.05,P>0.05];电针治疗组高于模型对照组(P<0.05).②脑皮质和海马区脑源性神经生长因子免疫阳性细胞的表达:与假手术组比较,模型对照组和电针治疗组均明显升高[(14.14±6.11),(24.49±8.31),(31.35±9.92)个/视野,P均<0.05;(13.42±5.56),(21.93±5.12),(27.63±7.15)个/视野,P均<0.05];电针治疗组高于模型对照组(P<0.05).结论:电针刺激使缺氧缺血动物中枢胆碱能神经系统处于积极活动状态,使脑源性神经营养因子数量上升增进缺氧缺血动物的神经修复功能.%BACKGROUND: Acupuncture in Chinese traditional medicine improves capacity of brain on resisting injury and accelerates injury repair in treatment of ischemic brain injury.OBJECTIVE: To observe the expressions of cerebral nerve growth factor (NGF) and choline acetyltransferase after simultaneous stimulation with electroacupuncture on Baihui (GV 20) and Dazhui (GV 14) so as to probe into the protection of electroacupuncture on hypoxia-ischemia brain injury.DESIGN: Randomized controlled experiment.SETTING: Department of Life Science in Zhengzhou Normal High Training School.MATERIALS: The experiment was performed in Human Anatomy Department of Basic Medical College of Zhengzhou University, in which, 50 cleangrade neonatal Wistar rats of 7 days old were employed and randomized into sham-operation group (10 rats), model control (20 rats) and electroacupuncture group (20 rats). Hypoxia cabin was self-made with constant pressure, 40 cm ×50 cm×60 cm in size, with two small holes of 2 cm ×2 cm for each to connect with the external. Soda lime was used to absorb moisture and CO2 in the cabin.The model was not prepared in sham-operation group. In model control and electroacupuncture group

  17. Effects of Chronic Intermittent Hypoxia on Rat's Cognition and Expression of cAMP Response Element Binding Protein in Brain%慢性间歇低氧对大鼠认知功能及大脑环磷酸腺苷反应单元结合蛋白表达的影响

    Institute of Scientific and Technical Information of China (English)

    康晶; 王月华; 何静雅; 李清泉; 胡克

    2011-01-01

    Objective: To study the effect of chronic intermittent hypoxia on cognition and expression of cAMP response element binding protein (CREB) in rats. Methods: Chronic intermittent hypoxia rat model was established by a normal pressure and low oxygen cabin. Rats were alternately dealt with 10% and 21% oxygen every 90 seconds for 14 days, and 8 hours each day. Then the spatial reference task learning was assessed by the Morris water maze and the expression of CREB mRNA was determined with RT-PCR. Results: Compared with the normal oxygen control group,rats exposed to normal pressure and chronic intermittent hypoxia showed significant impairment in their cognitive function, such as learning-memory performance in Morris water maze, in which, both the average escape latencies and swim path distances increased. The expressions of CREB mRNA in cortex and hippocampus were lower than those in control group. Conclusion:Chronic intermittent hypoxia can impair rat spatial reference task learning and the chronic brain function damage may be related to the lower expression of CREB mRNA.%目的:探讨慢性间歇低氧对大鼠认知功能及大脑环磷酸腺苷反应单元结合蛋白(CREB)表达的影响.方法:通过常压低氧仓建立间歇低氧大鼠模型,即对成年大鼠每90 s交替给予10%氧和21%氧.每天8 h,连续处理14 d后,以Morris水迷宫观察大鼠空间学习记忆的变化,并采用RT-PCR法观察大鼠皮层区及海马氏环磷酸腺苷反应单元结合蛋白mRNA的表达.结果:与常压对照组比较,常压间歇低氧组大鼠在Morris水迷宫中的空间学习记忆能力明显下降,表现为平均逃避潜伏期延长和游泳总距离增加.同时,大鼠皮层区及海马区CREB mR-NA的表达水平明显降低.结论:慢件间歇低氧可引起大鼠空间学习记忆能力下降.而大鼠这种慢性脑功能损害可能与大脑CREB mRNA的表达下调有关.

  18. Normobaric Intermittent Hypoxia over 8 Months Does Not Reduce Body Weight and Metabolic Risk Factors - a Randomized, Single Blind, Placebo-Controlled Study in Normobaric Hypoxia and Normobaric Sham Hypoxia

    Directory of Open Access Journals (Sweden)

    Hannes Gatterer

    2015-05-01

    Full Text Available Objective: Both a 1- to 4-week continuous or intermittent stay and moderate exercise in hypoxia versus normoxia can lead to weight loss. We examined the reproducibility and durability of added hypoxic exposure in a feasible health program of several months. Methods: 32 obese persons, randomly assigned to either a hypoxia (age 50.3 ± 10.3 years, BMI 37.9 ± 8.1 kg/m² or a normoxia (age 52.4 ± 7.9 years, BMI 36.3 ± 4.0 kg/m² group, completed 52 exercise sessions within 8 months. Participants exercised for 90 min (65-70% HRpeak either at a simulated altitude of 3,500 m or in normoxia, and rested for further 90 min at 4,500 m or normoxia. Before, after 5 weeks, after 3 months, and after the intervention, body composition and exercise capacity were determined. Risk markers (e.g., blood pressure, cholesterol were measured before, after 3 months, and after the intervention period. Results: Body weight, BMI, waist and hip circumference, Ppeak and BPsys improved over time (p Conclusion: Long-term, moderate intensity exercise and rest in hypoxia does not lead to higher reductions in body weight than normoxia alone. Therefore, for weight loss and metabolic markers hypoxic exposure does not add effects at least when stimuli (i.e., hypoxia dose, exercise intensity/duration are unaltered throughout the intervention.

  19. Executive function performance and change in aging is predicted by apolipoprotein E, intensified by catechol-O-methyltransferase and brain-derived neurotrophic factor, and moderated by age and lifestyle.

    Science.gov (United States)

    Sapkota, Shraddha; Bäckman, Lars; Dixon, Roger A

    2017-01-03

    Recent studies have reported several genetic, health, and aging interaction effects in predicting cognitive performance and change. We used an accelerated longitudinal design to examine interactions among genetic, lifestyle, and aging for executive function (EF) in non-demented older adults (n = 634; age range = 53-95 years). The polymorphisms were apolipoprotein E (APOE), catechol-O-methyltransferase (COMT), and brain-derived neurotrophic factor (BDNF). We tested (1) independent and additive effects of APOE, COMT, and BDNF and (2) APOE effect modification for COMT + BDNF, on EF performance and 9-year change as separated by age and lifestyle activities. First, APOE ε4+ carriers had poorer EF performance and steeper 9-year decline. Second, APOE ε4+ carriers with (1) BDNF Met/Met genotype and (2) increasing allelic risk in the COMT + BDNF risk panel had poorer EF performance; these effects were moderated by lifestyle activities (composite of everyday social, physical, and cognitive activities). Examining APOE effect modification for COMT + BDNF risk panel effects with other moderating factors may help identify complex neurobiological and genetic underpinnings of polygenic phenotypes such as EF in aging.

  20. Effects of Hypoxia and Hypercapnic Hypoxia on Oxygen Transport and Acid-Base Status in the Atlantic Blue Crab, Callinectes sapidus, During Exercise.

    Science.gov (United States)

    Lehtonen, Mark P; Burnett, Louis E

    2016-11-01

    The responses of estuarine invertebrates to hypoxic conditions are well established. However, many studies have investigated hypoxia as an isolated condition despite its frequent co-occurrence with hypercapnia (elevated CO2 ). Although many studies suggest deleterious effects, hypercapnia has been observed to improve blue crab walking performance in hypoxia. To investigate the physiological effects of combined hypercapnic hypoxia, we measured Po2 , pH, [l-lactate], Pco2 , and total O2 in pre- and postbranchial hemolymph sampled from blue crabs during walking exercise. Crabs walked at 8 m min(-1) on an aquatic treadmill in normoxic (100% air saturation), moderately hypoxic (50%), and severely hypoxic (20%) seawater with and without the addition of hypercapnia (about 2% CO2 ). Respiration was almost completely aerobic in normoxic conditions, with little buildup of lactate. During exercise under severe hypoxia, lactate increased from 1.4 to 11.0 mM, indicating a heavy reliance on anaerobic respiration. The O2 saturation of arterial hemocyanin was 47% in severe hypoxia after 120 min, significantly lower than in normoxia (80%). However, the addition of hypercapnia significantly increased the percentage saturation of arterial hemocyanin in severe hypoxia to 92% after 120 min of exercise, equivalent to normoxic levels. Hypercapnia in severe hypoxia also caused a marked increase in hemolymph Pco2 (around 1.1 kPa), but caused only a minor decrease in pH of 0.1 units. We suggest that the improved O2 saturation at the gills results from a specific effect of molecular CO2 on hemocyanin oxygen binding affinity, which works independently of and counter to the effects of decreased pH. © 2016 Wiley Periodicals, Inc.

  1. Molecular imaging of tumour hypoxia;Imagerie moleculaire de l'hypoxie tumorale

    Energy Technology Data Exchange (ETDEWEB)

    Huchet, A.; Maire, J.P.; Trouette, R. [Hopital Saint-Andre, CHU de Bordeaux, Service d' Oncologie Medicale et de Radiotherapie, 33 - Bordeaux (France); Fernandez, P.; Allard, M. [CHU de Bordeaux, Service de Medecine Nucleaire, 33 - Bordeaux (France); Belkacemi, Y. [Hopital Henri-Mondor, AP-HP, Oncologie-radiotherapie, 94 - Creteil (France); Eimer, S. [CHU de Bordeaux, Service d' Anatomopathologie, 33 - Bordeaux (France); Tourdias, T. [CHU de Bordeaux, Service de Neuroradiologie, 33 - Bordeaux (France); Loiseau, H. [CHU de Bordeaux, Clinique universitaire de Neurochirurgie, 33 - Bordeaux (France); Huchet, A.; Fernandez, P.; Allard, M.; Maire, J.P.; Eimer, S.; Tourdias, T.; Loiseau, H. [Bordeaux-2 Univ., 33 - Bordeaux (France); Belkacemi, Y. [Paris-12 Univ., 94 - Creteil (France)

    2009-12-15

    By allowing an earlier diagnosis and a more exhaustive assessment of extension of the disease, the tomography by emission of positrons (PET) transforms the care of numerous cancers. At present, {sup 18}F-fluorodeoxyglucose ([{sup 18}F]-F.D.G.) imaging appears as the only one available but new molecular markers are being developed. In the next future they would modify the approach of cancers. In this context, the molecular imaging of the hypoxia and especially the {sup 18}Fluoromisonidazole PET ([{sup 18}F]-MISO PET) can give supplementary information allowing the mapping of hypoxic regions within the tumour. Because of the links, which exist between tumour hypoxia and treatment resistance of very numerous cancers, this information can have an interest, for determination of prognosis as well as for the delineation, volumes to be irradiated. Head and neck tumours are doubtless those for which the literature gives the most elements on the therapeutic impact of tumour hypoxia. Targeted therapies, based on hypoxia, already exist and the contribution of the molecular imaging could be decisive in the evaluation of the impact of such treatment. Molecular imaging of brain tumours remains to be developed. The potential contributions of the [{sup 18}F]-MISO PET for the care of these patients need to be confirmed. In this context, we propose a review of hypoxia molecular imaging taking as examples head and neck tumours and glioblastomas (GB), two tumours for which hypoxia is one of the key factors to overcome in order to increase therapeutics results

  2. Increased cerebral output of free radicals during hypoxia: implications for acute mountain sickness?

    DEFF Research Database (Denmark)

    Bailey, Damian M; Taudorf, Sarah; Berg, Ronan M G

    2009-01-01

    This study examined whether hypoxia causes free radical-mediated disruption of the blood-brain barrier (BBB) and impaired cerebral oxidative metabolism and whether this has any bearing on neurological symptoms ascribed to acute mountain sickness (AMS). Ten men provided internal jugular vein...

  3. Short and Long-Term Analysis and Comparison of Neurodegeneration and Inflammatory Cell Response in the Ipsilateral and Contralateral Hemisphere of the Neonatal Mouse Brain after Hypoxia/Ischemia

    Directory of Open Access Journals (Sweden)

    Kalpana Shrivastava

    2012-01-01

    Full Text Available Understanding the evolution of neonatal hypoxic/ischemic is essential for novel neuroprotective approaches. We describe the neuropathology and glial/inflammatory response, from 3 hours to 100 days, after carotid occlusion and hypoxia (8% O2, 55 minutes to the C57/BL6 P7 mouse. Massive tissue injury and atrophy in the ipsilateral (IL hippocampus, corpus callosum, and caudate-putamen are consistently shown. Astrogliosis peaks at 14 days, but glial scar is still evident at day 100. Microgliosis peaks at 3–7 days and decreases by day 14. Both glial responses start at 3 hours in the corpus callosum and hippocampal fissure, to progressively cover the degenerating CA field. Neutrophils increase in the ventricles and hippocampal vasculature, showing also parenchymal extravasation at 7 days. Remarkably, delayed milder atrophy is also seen in the contralateral (CL hippocampus and corpus callosum, areas showing astrogliosis and microgliosis during the first 72 hours. This detailed and long-term cellular response characterization of the ipsilateral and contralateral hemisphere after H/I may help in the design of better therapeutic strategies.

  4. Evaluation of coping resources and self-esteem as moderators of the relationship between threat appraisals and avoidance of activities after traumatic brain injury.

    Science.gov (United States)

    Riley, Gerard A; Dennis, Rebecca K; Powell, Theresa

    2010-12-01

    It is not uncommon for people after a traumatic brain injury (TBI) to develop anxieties about possible negative outcomes (i.e., threat appraisals) in relation to participating in valued activities. Some respond to this anxiety by avoiding the activities, but others maintain their participation. The present study investigated two factors that may help explain this variation across individuals in their response to threat appraisals - self-esteem and the evaluation of coping resources. Forty-one individuals with a TBI completed the Avoidance and Threat Appraisals Questionnaire, the Rosenberg Self-Esteem Scale and the Coping Resources Questionnaire. The study's hypotheses were supported: Those low in self-esteem, and those with a negative evaluation of their ability to cope with the TBI, were significantly more likely to respond to threat appraisals with avoidance. Those whose injury was more recent and those whose injury was the result of an assault were also more likely to respond with avoidance. The theoretical and therapeutic implications of these results are discussed.

  5. Effect of ovariectomy on inflammation induced by intermittent hypoxia in a mouse model of sleep apnea.

    Science.gov (United States)

    Torres, Marta; Palomer, Xavier; Montserrat, Josep M; Vázquez-Carrera, Manel; Farré, Ramon

    2014-10-01

    Patient data report marked gender and pre-vs-postmenopausal differences in obstructive sleep apnea (OSA). However, no experimental data are available on how sexual hormones modulate OSA consequences. Here we report novel results on estrogen-modulated heart and brain inflammation in female mice subjected to intermittent hypoxia, a major injurious challenge in OSA. C57BL/6J (14-week old) intact and ovariectomized mice (n=6 each) were subjected to intermittent hypoxia (20 s at 5% and 40s at 21%, 60 cycles/h; 6 h/day). Identical intact and ovariectomized groups breathing room air were controls. After 30 days, the gene expressions of interleukins 6 and 8 (IL-6, IL-8) in the brain and heart tissues were measured. Whereas, compared with normoxia, intermittent hypoxia considerably increased IL-6 and IL-8 gene expressions in intact females, no change was found in ovariectomized mice when comparing normoxia and intermittent hypoxia. These data suggest that estrogens modulate the inflammatory effects of intermittent hypoxia and point to further studies on the role played by sex hormones in OSA.

  6. Preconditioning with associated blocking of Ca2+ inflow alleviates hypoxia-induced damage to pancreatic β-cells.

    Directory of Open Access Journals (Sweden)

    Zuheng Ma

    Full Text Available OBJECTIVE: Beta cells of pancreatic islets are susceptible to functional deficits and damage by hypoxia. Here we aimed to characterize such effects and to test for and pharmacological means to alleviate a negative impact of hypoxia. METHODS AND DESIGN: Rat and human pancreatic islets were subjected to 5.5 h of hypoxia after which functional and viability parameters were measured subsequent to the hypoxic period and/or following a 22 h re-oxygenation period. Preconditioning with diazoxide or other agents was usually done during a 22 h period prior to hypoxia. RESULTS: Insulin contents decreased by 23% after 5.5 h of hypoxia and by 61% after a re-oxygenation period. Preconditioning with diazoxide time-dependently alleviated these hypoxia effects in rat and human islets. Hypoxia reduced proinsulin biosynthesis ((3H-leucine incorporation into proinsulin by 35%. Preconditioning counteracted this decrease by 91%. Preconditioning reduced hypoxia-induced necrosis by 40%, attenuated lowering of proteins of mitochondrial complexes I-IV and enhanced stimulation of HIF-1-alpha and phosphorylated AMPK proteins. Preconditioning by diazoxide was abolished by co-exposure to tolbutamide or elevated potassium (i.e. conditions which increase Ca(2+ inflow. Preconditioning with nifedipine, a calcium channel blocker, partly reproduced effects of diazoxide. Both diazoxide and nifedipine moderately reduced basal glucose oxidation whereas glucose-induced oxygen consumption (tested with diazoxide was unaffected. Preconditioning with diaxoxide enhanced insulin contents in transplants of rat islets to non-diabetic rats and lowered hyperglycemia vs. non-preconditioned islets in streptozotocin-diabetic rats. Preconditioning of human islet transplants lowered hyperglycemia in streptozotocin-diabetic nude mice. CONCLUSIONS: 1 Prior blocking of Ca(2+ inflow associates with lesser hypoxia-induced damage, 2 preconditioning affects basal mitochondrial metabolism and accelerates

  7. Musashi mediates translational repression of the Drosophila hypoxia inducible factor

    Science.gov (United States)

    Bertolin, Agustina P.; Katz, Maximiliano J.; Yano, Masato; Pozzi, Berta; Acevedo, Julieta M.; Blanco-Obregón, Dalmiro; Gándara, Lautaro; Sorianello, Eleonora; Kanda, Hiroshi; Okano, Hideyuki; Srebrow, Anabella; Wappner, Pablo

    2016-01-01

    Adaptation to hypoxia depends on a conserved α/β heterodimeric transcription factor called Hypoxia Inducible Factor (HIF), whose α-subunit is regulated by oxygen through different concurrent mechanisms. In this study, we have identified the RNA binding protein dMusashi, as a negative regulator of the fly HIF homologue Sima. Genetic interaction assays suggested that dMusashi participates of the HIF pathway, and molecular studies carried out in Drosophila cell cultures showed that dMusashi recognizes a Musashi Binding Element in the 3′ UTR of the HIFα transcript, thereby mediating its translational repression in normoxia. In hypoxic conditions dMusashi is downregulated, lifting HIFα repression and contributing to trigger HIF-dependent gene expression. Analysis performed in mouse brains revealed that murine Msi1 protein physically interacts with HIF-1α transcript, suggesting that the regulation of HIF by Msi might be conserved in mammalian systems. Thus, Musashi is a novel regulator of HIF that inhibits responses to hypoxia specifically when oxygen is available. PMID:27141964

  8. Hypoxia Impairs Vasodilation in the Lung

    OpenAIRE

    Norbert F Voelkel; McMurtry, Ivan F.; Reeves, John T.

    1981-01-01

    Alveolar hypoxia causes pulmonary vasoconstriction; we investigated whether hypoxia could also impair pulmonary vasodilation. We found in the isolated perfused rat lung a delay in vasodilation following agonist-induced vasoconstriction. The delay was not due to erythrocyte or plasma factors, or to alterations in base-line lung perfusion pressure. Pretreating lungs with arachidonic acid abolished hypoxic vasoconstriction, but did not influence the hypoxia-induced impairment of vasodilation aft...

  9. Role of chronic hypoxia and hypoxia inducible factor in kidney disease

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    @@ Cells are endowed with a defensive mechanism against hypoxia,namely hypoxia-inducible factor (HIF) and hypoxia-responsive element (HRE).Under hypoxic conditions,activation of HIF leads to expression of a variety of adaptive genes with HRE in a coordinated manner.

  10. Mouse intermittent hypoxia mimicking apnoea of prematurity: effects on myelinogenesis and axonal maturation.

    Science.gov (United States)

    Cai, Jun; Tuong, Chi Minh; Zhang, Yiping; Shields, Christopher B; Guo, Gang; Fu, Hui; Gozal, David

    2012-02-01

    Premature babies are at high risk for both infantile apnoea and long-term neurobehavioural deficits. Recent studies suggest that diffuse structural changes in brain white matter are a positive predictor of poor cognitive outcomes. Since oligodendrocyte maturation, myelination, axon development, and synapse formation mainly occur in the third trimester of gestation and first postnatal year, infantile apnoea could lead to and/or exaggerate white matter impairments in preterm neonates. Therefore, we investigated oligodendroglia and axon development in a neonatal mouse model of intermittent hypoxia between postnatal days 2 and 10. During critical phases of central nervous system development, intermittent hypoxia induced hypomyelination in the corpus callosum, striatum, fornix, and cerebellum, but not in the pons or spinal cord. Intermittent hypoxia-elicited alterations in myelin-forming processes were reflected by decreased expression of myelin proteins, including MBP, PLP, MAG, and CNPase, possibly due to arrested maturation of oligodendrocytes. Ultrastructural abnormalities were apparent in the myelin sheath and axon. Immature oligodendrocytes were more vulnerable to neonatal intermittent hypoxia exposures than developing axons, suggesting that hypomyelination may contribute, at least partially, to axonal deficits. Insufficient neurofilament synthesis with anomalous components of neurofilament subunits, β-tubulin, and MAP2 isoforms indicated immaturity of axons in intermittent hypoxia-exposed mouse brains. In addition, down-regulation of synapsin I, synaptophysin, and Gap-43 phosphorylation suggested a potential stunt in axonogenesis and synaptogenesis. The region-selective and complex impairment in brain white matter induced by intermittent hypoxia was further associated with electrophysiological changes that may underlie long-term neurobehavioural sequelae.

  11. Effects of erythropoietin on nestin expression in neural stem cells of neonatal rats with hypoxia-ischemia brain damage%促红细胞生成素干预缺氧缺血性脑损伤新生鼠神经干细胞巢蛋白的表达

    Institute of Scientific and Technical Information of China (English)

    姜红; 许锋; 周春清; 李向红; 舒志荣

    2010-01-01

    背景:巢蛋白是一种存在于神经干细胞的特异性抗原,在神经系统发生病变或损伤引起再生时广泛表达,因此巢蛋白表达常用作判定神经系统发生病变或损伤后能否促进神经再生的一种手段.目的:从神经再生和神经干细胞激活的角度,探讨外源性促红细胞生成素对新生鼠缺氧缺血性脑损伤后神经干细胞巢蛋白表达的影响.方法:结扎大鼠右侧颈总动脉和8%低氧暴露2 h制备新生大鼠缺氧缺血性脑损伤模型.对照组仅游离右侧颈总动脉,不予结扎和缺氧处理.干预组大鼠缺氧缺血后立即腹腔注射重组人促红细胞生成素5 000 IU/kg,1次/d,连用3 d.缺氧缺血性脑损伤组大鼠缺氧缺血后连续腹腔注射等量生理盐水溶液3d.每组随机取8只分别于术后4,7,14d处死.应用免疫组化方法和计算机图像分析技术检测不同时点海马齿状回巢蛋白标记阳性细胞的变化.结果与结论:各时点缺氧缺血性脑损伤组巢蛋白阳性细胞数较对照组增加(P<0.05);各时点干预组巢蛋白阳性细胞较对照组和缺氧缺血性脑损伤组均增加(P<0.05).3组大鼠海马齿状回区巢蛋白阳性细胞数均于术后7 d达高峰.结果提示早期给予重组入促红细胞生成素可促使新生鼠缺氧缺血性脑损伤后海马齿状回区巢蛋白表达增加,促进神经干细胞的增殖再生,在缺氧缺血性脑损伤后神经再生、修复中发挥一定的保护作用.%BACKGROUND: Nestin is a specific antigen of neural stem cells which widely expressed in lesion of nervous system and brain regeneration.Thus,nestin expression is commonly used to assess whether lesion or damage of the nervous system can promote neural regeneration.OBJECTIVE: To investigate the effects of erythropoietin(EPO)on nestin expression in neural stem cells after hypoxia-ischemia brain damage(HIBD)in neonatal rats from the angles of neural regeneration and activation of neural stem cells

  12. Markers of physiological stress during exercise under conditions of normoxia, normobaric hypoxia, hypobaric hypoxia, and genuine high altitude.

    Science.gov (United States)

    Woods, David Richard; O'Hara, John Paul; Boos, Christopher John; Hodkinson, Peter David; Tsakirides, Costas; Hill, Neil Edward; Jose, Darren; Hawkins, Amanda; Phillipson, Kelly; Hazlerigg, Antonia; Arjomandkhah, Nicola; Gallagher, Liam; Holdsworth, David; Cooke, Mark; Green, Nicholas Donald Charles; Mellor, Adrian

    2017-05-01

    To investigate whether there is a differential response at rest and following exercise to conditions of genuine high altitude (GHA), normobaric hypoxia (NH), hypobaric hypoxia (HH), and normobaric normoxia (NN). Markers of sympathoadrenal and adrenocortical function [plasma normetanephrine (PNORMET), metanephrine (PMET), cortisol], myocardial injury [highly sensitive cardiac troponin T (hscTnT)], and function [N-terminal brain natriuretic peptide (NT-proBNP)] were evaluated at rest and with exercise under NN, at 3375 m in the Alps (GHA) and at equivalent simulated altitude under NH and HH. Participants cycled for 2 h [15-min warm-up, 105 min at 55% Wmax (maximal workload)] with venous blood samples taken prior (T0), immediately following (T120) and 2-h post-exercise (T240). Exercise in the three hypoxic environments produced a similar pattern of response with the only difference between environments being in relation to PNORMET. Exercise in NN only induced a rise in PNORMET and PMET. Biochemical markers that reflect sympathoadrenal, adrenocortical, and myocardial responses to physiological stress demonstrate significant differences in the response to exercise under conditions of normoxia versus hypoxia, while NH and HH appear to induce broadly similar responses to GHA and may, therefore, be reasonable surrogates.

  13. Morphological evaluation of the cerebral blood vessels in the late gestation fetal sheep following hypoxia in utero.

    Science.gov (United States)

    Baburamani, Ana A; Lo, Camden; Castillo-Melendez, Margie; Walker, David W

    2013-01-01

    Hypoxia can significantly contribute to the development of permanent brain injury in the term neonate; however the response of cerebral blood vessels is not well understood. This study aimed to quantitatively measure vascular density and morphology using laminin immunohistochemistry as a marker of blood vessels, and determine the effects of a single, severe bout of hypoxia (umbilical cord occlusion, UCO) late in gestation on the developing cerebrovasculature in fetal sheep. At 124-126 days gestation singleton fetal sheep underwent surgery for implantation of catheters and placement of an inflatable cuff around the umbilical cord. A 10 min UCO or sham UCO (n=5) occurred at 132 days gestation. Fetal brains were collected at 24 h (n=5) or 48 h (n=4) after UCO for vascular density and morphology analysis of laminin immunohistochemistry. 48 h following a single, brief bout of severe hypoxia late in gestation decreased vascular density was seen in the caudate nucleus and no changes in vascular morphology occurred. However closer analysis revealed a significant shift in the frequency of smaller (≤10 μm) to larger (≤100 μm) perimeter blood vessels in periventricular and subcortical white matter. Close examination of the frequency distribution of vascular perimeter highlights that alterations in vascular morphology persist in the near term fetal brain for up to 48 h following a brief (10 min) hypoxia in white but not gray matter. These findings suggest that the near term brain may still be vulnerable to white matter injury following in utero hypoxia.

  14. Ets-1 as an early response gene against hypoxia-induced apoptosis in pancreatic β-cells.

    Science.gov (United States)

    Qiao, N; Xu, C; Zhu, Y-X; Cao, Y; Liu, D-C; Han, X

    2015-02-19

    Hypoxia complicates islet isolation for transplantation and may contribute to pancreatic β-cell failure in type 2 diabetes. Pancreatic β-cells are susceptible to hypoxia-induced apoptosis. Severe hypoxic conditions during the immediate post-transplantation period are a main non-immune factor leading to β-cell death and islet graft failure. In this study, we identified the transcription factor Ets-1 (v-ets erythroblastosis virus E26 oncogene homolog 1) as an early response gene against hypoxia-induced apoptosis in pancreatic β-cells. Hypoxia regulates Ets-1 at multiple levels according to the degree of β-cell oxygen deprivation. Moderate hypoxia promotes Ets-1 gene transcription, whereas severe hypoxia promotes its transactivation activity, as well as its ubiquitin-proteasome mediated degradation. This degradation causes a relative insufficiency of Ets-1 activity, and limits the transactivation effect of Ets-1 on downstream hypoxic-inducible genes and its anti-apoptotic function. Overexpression of ectopic Ets-1 in MIN6 and INS-1 cells protects them from severe hypoxia-induced apoptosis in a mitochondria-dependent manner, confirming that a sufficient amount of Ets-1 activity is critical for protection of pancreatic β-cells against hypoxic injury. Targeting Ets-1 expression may be a useful strategy for islet graft protection during the immediate post-transplantation period.

  15. Activation of the Astrocytic Endothelin System in Response to Hypoxia

    Institute of Scientific and Technical Information of China (English)

    An Ding Xua; Kai M.Schmidt-Ott; Scbastian Tuschick; Lutz Liefeldt; Susan Lyons; Helmut Kettcnmann; Martin.Paul

    2000-01-01

    Objcctive:To determine the gene expression patterns of endothelin (ET)system components in cultured astrocytes(AC),and to examine the direct effcct of hypoxia on ET system gene expression in cultured AC.Background:The ET system was considered to be related to the activation of AC. However,how hypoxia affects the ET system in transcriptional levels remains unclear.Methods:AC was prepared form mouse brain,and cultured 4 days.then further incubated under normoxic or hypoxic conditions for 24h. ET peptide levels were determined by RIA.The transcripts of ET system components were measured by Northern Blot RNA hybridization and RT-PCR.Results:In normoxic AC,ET-1,ET converting enzyme(ECE)-2,ETA receptor,and ETB receptor mRNAs were detected by Northern blot hybridization with ETB receptor mRNA appearing to be the predominant receptor transcript.ET-3and ECE-1 were only detected by RT-PCR,indicating low expression levels of these components.Hypoxia induced a 1.7-fold increase in ET peptide level in culture supernatants as comparcd to controls(p<0.001).At the same time,a 3-fold increase of ET-1 mRNA(p<0.001)was determined by Northern blot RNA analysis,indicating a regulation at the transcriptional Ievel.Both ETA and ETB receptor mRNASweredownregulated to approximately 20% of control levels(p<0.001), while ECE-2 mRNA remained unchanged.Conclusions:These results indicate direct effects of hypoxia on astrocytic ET system gene expression.Therefore,similar changes observed in ischemic conditions in vivo are likely to be at least partially independent from the modified cerebral microenvironment.

  16. Restraint Stress Intensifies Interstitial K+ Accumulation during Severe Hypoxia

    Science.gov (United States)

    Schnell, Christian; Janc, Oliwia A.; Kempkes, Belinda; Callis, Carolina Araya; Flügge, Gabriele; Hülsmann, Swen; Müller, Michael

    2012-01-01

    Chronic stress affects neuronal networks by inducing dendritic retraction, modifying neuronal excitability and plasticity, and modulating glial cells. To elucidate the functional consequences of chronic stress for the hippocampal network, we submitted adult rats to daily restraint stress for 3 weeks (6 h/day). In acute hippocampal tissue slices of stressed rats, basal synaptic function and short-term plasticity at Schaffer collateral/CA1 neuron synapses were unchanged while long-term potentiation was markedly impaired. The spatiotemporal propagation pattern of hypoxia-induced spreading depression episodes was indistinguishable among control and stress slices. However, the duration of the extracellular direct current potential shift was shortened after stress. Moreover, K+ fluxes early during hypoxia were more intense, and the postsynaptic recoveries of interstitial K+ levels and synaptic function were slower. Morphometric analysis of immunohistochemically stained sections suggested hippocampal shrinkage in stressed rats, and the number of cells that are immunoreactive for glial fibrillary acidic protein was increased in the CA1 subfield indicating activation of astrocytes. Western blots showed a marked downregulation of the inwardly rectifying K+ channel Kir4.1 in stressed rats. Yet, resting membrane potentials, input resistance, and K+-induced inward currents in CA1 astrocytes were indistinguishable from controls. These data indicate an intensified interstitial K+ accumulation during hypoxia in the hippocampus of chronically stressed rats which seems to arise from a reduced interstitial volume fraction rather than impaired glial K+ buffering. One may speculate that chronic stress aggravates hypoxia-induced pathophysiological processes in the hippocampal network and that this has implications for the ischemic brain. PMID:22470344

  17. Hypoxia-Inducible Factor as an Angiogenic Master Switch

    Science.gov (United States)

    Hashimoto, Takuya; Shibasaki, Futoshi

    2015-01-01

    Hypoxia-inducible factors (HIFs) regulate the transcription of genes that mediate the response to hypoxia. HIFs are constantly expressed and degraded under normoxia, but stabilized under hypoxia. HIFs have been widely studied in physiological and pathological conditions and have been shown to contribute to the pathogenesis of various vascular diseases. In clinical settings, the HIF pathway has been studied for its role in inhibiting carcinogenesis. HIFs might also play a protective role in the pathology of ischemic diseases. Clinical trials of therapeutic angiogenesis after the administration of a single growth factor have yielded unsatisfactory or controversial results, possibly because the coordinated activity of different HIF-induced factors is necessary to induce mature vessel formation. Thus, manipulation of HIF activity to simultaneously induce a spectrum of angiogenic factors offers a superior strategy for therapeutic angiogenesis. Because HIF-2α plays an essential role in vascular remodeling, manipulation of HIF-2α is a promising approach to the treatment of ischemic diseases caused by arterial obstruction, where insufficient development of collateral vessels impedes effective therapy. Eukaryotic initiation factor 3 subunit e (eIF3e)/INT6 interacts specifically with HIF-2α and induces the proteasome inhibitor-sensitive degradation of HIF-2α, independent of hypoxia and von Hippel-Lindau protein. Treatment with eIF3e/INT6 siRNA stabilizes HIF-2α activity even under normoxic conditions and induces the expression of several angiogenic factors, at levels sufficient to produce functional arteries and veins in vivo. We have demonstrated that administration of eIF3e/INT6 siRNA to ischemic limbs or cold-injured brains reduces ischemic damage in animal models. This review summarizes the current understanding of the relationship between HIFs and vascular diseases. We also discuss novel oxygen-independent regulatory proteins that bind HIF-α and the implications

  18. Short Hypoxia Does not Affect Plasma Leptin in Healthy Men under Euglycemic Clamp Conditions

    Directory of Open Access Journals (Sweden)

    Andre Schmoller

    2009-01-01

    Full Text Available Leptin is involved in the endocrine control of energy expenditure and body weight regulation. Previous studies emphasize a relationship between hypoxic states and leptin concentrations. The aim of this study was to investigate the effects of acute hypoxia on leptin concentrations in healthy subjects. We examined 14 healthy men. Hypoxic conditions were induced by decreasing oxygen saturation to 75% for 30 minutes. Plasma leptin concentrations were determined at baseline, after 3 hours of euglycemic clamping, during hypoxia, and repeatedly the following 2.5 hours thereafter. Our results show an increase of plasma leptin concentrations in the course of 6 hours of hyperinsulinemic-euglycemic clamping which may reflect diurnal rhythmicity. Notwithstanding, there was no difference between levels of leptin in the hypoxic and the normoxic condition (=.2. Since we did not find any significant changes in leptin responses upon hypoxia, plasma leptin levels do not seem to be affected by short hypoxic episodes of moderate degree.

  19. Patterns of social-experience-related c-fos and Arc expression in the frontal cortices of rats exposed to saccharin or moderate levels of ethanol during prenatal brain development.

    Science.gov (United States)

    Hamilton, Derek A; Candelaria-Cook, Felicha T; Akers, Katherine G; Rice, James P; Maes, Levi I; Rosenberg, Martina; Valenzuela, C Fernando; Savage, Daniel D

    2010-12-01

    Recent findings from our laboratory indicate that alterations in frontal cortex function, structural plasticity, and related social behaviors are persistent consequences of exposure to moderate levels of ethanol during prenatal brain development [24]. Fetal-ethanol-related reductions in the expression of the immediate early genes (IEGs) c-fos and Arc and alterations in dendritic spine density in ventrolateral and medial aspects of frontal cortex suggest a dissociation reminiscent of that described by Kolb et al. [38] in which these aspects of frontal cortex undergo reciprocal experience-dependent changes. In addition to providing a brief review of the available data on social behavior and frontal cortex function in fetal-ethanol-exposed rats, the present paper presents novel data on social-experience-related IEG expression in four regions of frontal cortex (Zilles LO, VLO, Fr1, Fr2) that are evaluated alongside our prior data from AID and Cg3. Social experience in normal rats was related to a distinct pattern of IEG expression in ventrolateral and medial aspects of frontal cortex, with generally greater expression observed in ventrolateral frontal cortex. In contrast, weaker expression was observed in all aspects of frontal cortex in ethanol-exposed rats, with the exception of an experience-related increase in the medial agranular cortex. Behaviors related to social investigation and wrestling/boxing were differentially correlated with patterns of activity-related IEG expression in the regions under investigation for saccharin- and ethanol-exposed rats. These observations suggest that recruitment and expression of IEGs in frontal cortex following social experience are potentially important for understanding the long-term consequences of moderate prenatal ethanol exposure on frontal cortex function, synaptic plasticity, and related behaviors.

  20. Association between the Osteoporosis Self-Assessment Tool for Asians Score and Mortality in Patients with Isolated Moderate and Severe Traumatic Brain Injury: A Propensity Score-Matched Analysis.

    Science.gov (United States)

    Rau, Cheng-Shyuan; Kuo, Pao-Jen; Wu, Shao-Chun; Chen, Yi-Chun; Hsieh, Hsiao-Yun; Hsieh, Ching-Hua

    2016-12-03

    Background: The purpose of this study was to use a propensity score-matched analysis to investigate the association between the Osteoporosis Self-Assessment Tool for Asians (OSTA) scores and clinical outcomes of patients with isolated moderate and severe traumatic brain injury (TBI). Methods: The study population comprised 7855 patients aged ≥40 years who were hospitalized for treatment of isolated moderate and severe TBI (an Abbreviated Injury Scale (AIS) ≥3 points only in the head and not in other regions of the body) between 1 January 2009 and 31 December 2014. Patients were categorized as high-risk (OSTA score risk (-4 ≤ OSTA score ≤ -1; n = 1647), or low-risk (OSTA score > -1; n = 5359). Two-sided Pearson's chi-squared, or Fisher's exact tests were used to compare categorical data. Unpaired Student's t-test and Mann-Whitney U test were performed to analyze normally and non-normally distributed continuous data, respectively. Propensity score-matching in a 1:1 ratio was performed using NCSS software, with adjustment for covariates. Results: Compared to low-risk patients, high- and medium-risk patients were significantly older and injured more severely. The high- and medium-risk patients had significantly higher mortality rates, longer hospital length of stay, and a higher proportion of admission to the intensive care unit than low-risk patients. Analysis of propensity score-matched patients with adjusted covariates, including gender, co-morbidity, blood alcohol concentration level, Glasgow Coma Scale score, and Injury Severity Score revealed that high- and medium-risk patients still had a 2.4-fold (odds ratio (OR), 2.4; 95% confidence interval (CI), 1.39-4.15; p = 0.001) and 1.8-fold (OR, 1.8; 95% CI, 1.19-2.86; p = 0.005) higher mortality, respectively, than low-risk patients. However, further addition of age as a covariate for the propensity score-matching demonstrated that there was no significant difference between high-risk and low-risk patients or

  1. Association between the Osteoporosis Self-Assessment Tool for Asians Score and Mortality in Patients with Isolated Moderate and Severe Traumatic Brain Injury: A Propensity Score-Matched Analysis

    Directory of Open Access Journals (Sweden)

    Cheng-Shyuan Rau

    2016-12-01

    Full Text Available Background: The purpose of this study was to use a propensity score-matched analysis to investigate the association between the Osteoporosis Self-Assessment Tool for Asians (OSTA scores and clinical outcomes of patients with isolated moderate and severe traumatic brain injury (TBI. Methods: The study population comprised 7855 patients aged ≥40 years who were hospitalized for treatment of isolated moderate and severe TBI (an Abbreviated Injury Scale (AIS ≥3 points only in the head and not in other regions of the body between 1 January 2009 and 31 December 2014. Patients were categorized as high-risk (OSTA score < −4; n = 849, medium-risk (−4 ≤ OSTA score ≤ −1; n = 1647, or low-risk (OSTA score > −1; n = 5359. Two-sided Pearson’s chi-squared, or Fisher’s exact tests were used to compare categorical data. Unpaired Student’s t-test and Mann-Whitney U test were performed to analyze normally and non-normally distributed continuous data, respectively. Propensity score-matching in a 1:1 ratio was performed using NCSS software, with adjustment for covariates. Results: Compared to low-risk patients, high- and medium-risk patients were significantly older and injured more severely. The high- and medium-risk patients had significantly higher mortality rates, longer hospital length of stay, and a higher proportion of admission to the intensive care unit than low-risk patients. Analysis of propensity score-matched patients with adjusted covariates, including gender, co-morbidity, blood alcohol concentration level, Glasgow Coma Scale score, and Injury Severity Score revealed that high- and medium-risk patients still had a 2.4-fold (odds ratio (OR, 2.4; 95% confidence interval (CI, 1.39–4.15; p = 0.001 and 1.8-fold (OR, 1.8; 95% CI, 1.19–2.86; p = 0.005 higher mortality, respectively, than low-risk patients. However, further addition of age as a covariate for the propensity score-matching demonstrated that there was no significant

  2. Hyperplasia and hypertrophy of pulmonary neuroepithelial bodies, presumed airway hypoxia sensors, in hypoxia-inducible factor prolyl hydroxylase-deficient mice.

    Science.gov (United States)

    Pan, Jie; Bishop, Tammie; Ratcliffe, Peter J; Yeger, Herman; Cutz, Ernest

    2016-01-01

    Pulmonary neuroepithelial bodies (NEBs), presumed polymodal airway sensors, consist of innervated clusters of amine (serotonin) and peptide-producing cells. While NEB responses to acute hypoxia are mediated by a membrane-bound O2 sensor complex, responses to sustained and/or chronic hypoxia involve a prolyl hydroxylase (PHD)-hypoxia-inducible factor-dependent mechanism. We have previously reported hyperplasia of NEBs in the lungs of Phd1-/- mice associated with enhanced serotonin secretion. Here we use a novel multilabel immunofluorescence method to assess NEB distribution, frequency, and size, together with the number and size of NEB cell nuclei, and to colocalize multiple cytoplasmic and nuclear epitopes in the lungs of Phd1-/-, Phd2+/-, and Phd3-/- mice and compare them with wild-type controls. To define the mechanisms of NEB cell hyperplasia, we used antibodies against Mash1 and Prox1 (neurogenic genes involved in NEB cell differentiation/maturation), hypoxia-inducible factor-1alpha, and the cell proliferation marker Ki67. Morphometric analysis of (% total lung area) immunostaining for synaptophysin (% synaptophysin), a cytoplasmic marker of NEB cells, was significantly increased in Phd1-/- and Phd3-/- mice compared to wild-type mice. In addition, NEB size and the number and size of NEB nuclei were also significantly increased, indicating that deficiency of Phds is associated with striking hyperplasia and hypertrophy of NEBs. In Phd2+/- mice, while mean % synaptophysin was comparable to wild-type controls, the NEB size was moderately increased, suggesting an effect even in heterozygotes. NEBs in all Phd-deficient mice showed increased expression of Mash1, Prox1, Ki67, and hypoxia-inducible factor-1alpha, in keeping with enhanced differentiation from precursor cells and a minor component of cell proliferation. Since the loss of PHD activity mimics chronic hypoxia, our data provide critical information on the potential role of PHDs in the pathobiology and

  3. [Hypoxia and memory. Specific features of nootropic agents effects and their use].

    Science.gov (United States)

    Voronina, T A

    2000-01-01

    Hypoxia and hypoxic adaptation are powerful factors of controlling memory and behavior processes. Acute hypoxia exerts a differential impact on different deficits of mnestic and cognitive functions. Instrumental reflexes of active and passive avoidance, negative learning, behavior with a change in the stereotype of learning are more greatly damaged. Memory with spatial and visual differentiation and their rearrangement change to a lesser extent and conditional reflexes are not deranged. In this contract, altitude hypoxic adaptation enhances information fixation and increases the degree and duration of retention of temporary relations. Nootropic agents with an antihypoxic action exert a marked effect on hypoxia-induced cognitive and memory disorders and the magnitude of this effect depends on the ration of proper nootropic to antihypoxic components in the spectrum of the drugs' pharmacological activity. The agents that combine a prevailing antiamnestic effect and a marked and moderate antihypoxic action (mexidole, nooglutil, pyracetam, beglymin, etc.) are most effective in eliminating different hypoxia-induced cognitive and memory disorders, nootropic drugs that have a pronounced antiamnestic activity (centrophenoxine, etc.) and no antihypoxic component also restore the main types of mnestic disorders after hypoxia, but to a lesser extent.

  4. Advances of Hypoxia and Lung Cancer

    Directory of Open Access Journals (Sweden)

    Xuebing LI

    2013-04-01

    Full Text Available Lung cancer is one of the malignant tumors with fastest growing rates in incidence and mortality in our country, also with largest threat to human health and life. However, the exact mechanisms underlying lung cancer development remain unclear. The microenvironment of tumor hypoxia was discovered in 1955, but hypoxia in lung cancer tissues had not been successfully detected till 2006. Further studies show that hypoxia not only functions through the resistance to radiotherapy, but also regulates lung cancer development, invasion, metastasis, chemotherapy resistance and prognosis through an important oncogene HIF (hypoxia inducible factor, with its regulators PHD (prolyl hydroxylase domain and pVHL (product of von Hippel-Lindau gene. Therefore, hypoxia, HIF, PHD and pVHL should be considered as potential therapeutic targets for lung cancer pathogenesis and progression.

  5. Analgesics, sedatives, anticonvulsant drugs, and the cooled brain.

    Science.gov (United States)

    Wassink, Guido; Lear, Christopher A; Gunn, Katherine C; Dean, Justin M; Bennet, Laura; Gunn, Alistair J

    2015-04-01

    Multiple randomized controlled trials have shown that prolonged, moderate cerebral hypothermia initiated within a few hours after severe hypoxia-ischemia and continued until resolution of the acute phase of delayed cell death reduces mortality and improves neurodevelopmental outcome in term infants. The challenge is now to find ways to further improve outcomes. In the present review, we critically examine the evidence that conventional analgesic, sedative, or anticonvulsant agents might improve outcomes, in relation to the known window of opportunity for effective protection with hypothermia. This review strongly indicates that there is insufficient evidence to recommend routine use of these agents during therapeutic hypothermia. Further systematic research into the effects of pain and stress on the injured brain, and their treatment during hypothermia, is essential to guide the rational development of clinical treatment protocols. Copyright © 2014 Elsevier Ltd. All rights reserved.

  6. A novel adjustable automated system for inducing chronic intermittent hypoxia in mice

    Science.gov (United States)

    Polšek, Dora; Bago, Marcel; Živaljić, Marija; Rosenzweig, Ivana; Lacza, Zsombor

    2017-01-01

    Background Sleep apnea is a chronic, widely underdiagnosed condition characterized by disruption of sleep architecture and intermittent hypoxia due to short cessations of breathing. It is a major independent risk factor for myocardial infarction, congestive heart failure and stroke as well as one of the rare modifiable risk factors for Alzheimer’s Dementia. Reliable animal disease models are needed to understand the link between sleep apnea and the various clinically linked disorders. New method An automated system for inducing hypoxia was developed, in which the major improvement was the possibility to efficiently adjust the length and intensity of hypoxia in two different periods. The chamber used a small volume of gas allowing for fast exchanges of different oxygen levels. The mice were kept in their cages adapted with the system on the cage lid. As a proof of principle, they were exposed to a three week period of intermittent hypoxia for 8 hours a day, with 90 s intervals of 5, 7% and 21% oxygen to validate the model. Treated (n = 8) and control mice (no hypoxia, n = 7) were handled in the same manner and their hippocampal brain regions compared by histology. Results The chamber provided a fast, reliable and precise intermittent hypoxia, without inducing noticeable side effects to the animals. The validation experiment showed that apoptotic neurons in the hippocampus were more numerous in the mice exposed to intermittent hypoxia than in the control group, in all tested hippocampal regions (cornu ammonis 1 (CA1) P sleep apnea, which was validated by apoptosis of hippocampal neurons. PMID:28362813

  7. 结扎孕鼠双侧子宫动脉复制围产期缺氧缺血性脑损伤动物模型%Reconstructing new animal model of peri-delivery hypoxia-ischemia brain damage by ligaturing bilateral uterine arteries of pregnant mouse

    Institute of Scientific and Technical Information of China (English)

    薄涛; 李巍; 严超英; 霍淑芳

    2001-01-01

    Objective Hypoxia-ischemia brain injury (HIBD) in infants is one of the important factors which induce intelligent defect,cerebral palasy in human beings. Therefore, we produced a new animal model to study HIBD. Method We assigned twenty 19.5-pregnancy-day mice to four groups randomly and had ligated their bilateral uteral arteries for 0,10,20, and 30 minutes respectively before the cesarean sections. Of each group,we observed the mortality,the growth and the brain's pathological changes. Result The longer the uteral arteries were ligated,the higher the mortality was. The slowlier the body weight increased, the more serious the spastic paralysis was .We also found the mice is similar in the brain pathological change to the human beings such as the edema regions,spotted hemorrhage,and local malacosis in the cortex. Conclusion This is a simple and useful model to study HIBD in newborn.%目的 制作一种新型围产期缺氧缺血性脑损伤(HIBD)的动物模型,为进一步深入研究其病理生理机制及治疗方法提供条件。方法 结扎足月妊娠待产(妊娠19.5d)昆明母鼠双侧子宫动脉,不同时间行剖宫产娩出胎鼠,与正常剖宫产娩出的胎鼠相比较,观察实验胎鼠的生长发育及脑部病理改变。结果 随着结扎子宫动脉阻断血供时间的延长,胎鼠的死亡率迅速增高,两者具有直线正相关关系(P<0.05),实验组胎鼠体重增长明显减慢,运动发育迟滞,脑部的病理改变与人类HIBD的改变相一致。结论 通过结扎孕鼠双侧子宫动脉,胎鼠所产生的一系列变化符合人类HIBD的改变,这是一种较理想的、操作较简便的复制HIBD动物模型的方法。

  8. Stem cells to regenerate the newborn brain

    NARCIS (Netherlands)

    van Velthoven, C.T.J.

    2011-01-01

    Perinatal hypoxia-ischemia (HI) is a frequent cause of perinatal morbidity and mortality with limited therapeutic options. In this thesis we investigate whether mesenchymal stem cells (MSC) regenerate the neonatal brain after HI injury. We show that transplantation of MSC after neonatal brain injury

  9. Patterns of fetal lamb regional cerebral blood flow during and after prolonged hypoxia.

    Science.gov (United States)

    Ashwal, S; Majcher, J S; Vain, N; Longo, L D

    1980-10-01

    In an effort to determine to what extent cerebral blood flow (CBF) varies in different parts of the brain during prolonged fetal hypoxia, we measured flow to 34 regions in 12 chronically catheterized fetal lambs 130 to 140 days gestation. Control values of PO2, PCO2 pH, heart rate, and blood pressure were obtained, and CBF was measured by use of radioactive labeled microspheres during a control period, during (15-, 30-, and 90-min) reduction of maternal inspired O2 concentration (fetal arterial PO2 was maintained at 12 to 15 torr), and 60 min after returning the ewe to room air. control blood flow to cortical, subcortical, and brainstem structures equaled 134, 186, and 254 ml x min-1 x 100 g-1, respectively. During hypoxia, CBF increased 92%, and 60 min after fetal oxygenation was restored, it remained 50% above control values. We noted a similar response in regional CBF to the cortex, subcortex, and brainstem during and after hypoxia. Blood flow to smaller areas within the three major regions were quite homogenous and had a similar pattern of response to hypoxia. We conclude that: (1) significant fetal regional CBF differences occurred in utero with brainstem and subcortical flows being substantially greater than flows to other regions of the brain; (2) during prolonged intrauterine hypoxia, total regional CBF increased 92%; (3) 1 hr after fetal oxygenation was restored, CBF still remained 50% above control values; and finally, (4) there was no significant preferential shunting of regional CBF during prolonged hypoxia in utero.

  10. Transgenerational effects of neonatal hypoxia-ischemia in progeny.

    Science.gov (United States)

    Infante, Smitha K; Rea, Harriett C; Perez-Polo, J R

    2013-10-01

    Neonatal hypoxia-ischemia (HI) affects 60% of low birth weight infants and up to 40% of preterm births. Cell death and brain injury after HI have been shown to cause long-lasting behavioral deficits. By using a battery of behavioral tests on second generation 3-week-old rodents, we found that neonatal HI is associated with behavioral outcomes in the progeny of HI-affected parents. Our results suggest an epigenetic transfer mechanism of some of the neurological symptoms associated with neonatal HI. Elucidating the transfer of brain injury to the next generation after HI calls attention to the risks associated with HI injury and the need for proper treatment to reverse these effects. Assessing the devastating extent of HI's reach serves as a cautionary tale to the risks associated with neonatal HI, and provides an incentive to create improved therapeutic measures to treat HI.

  11. CD36 upregulation mediated by intranasal LV-NRF2 treatment mitigates hypoxia-induced progression of Alzheimer's-like pathogenesis.

    Science.gov (United States)

    Wang, Chun-Yan; Wang, Zhan-You; Xie, Jing-Wei; Cai, Jian-Hui; Wang, Tao; Xu, Ye; Wang, Xu; An, Li

    2014-12-01

    There is extensive evidence that oxidative stress induces cellular dysfunction in the brain and plays a critical role in Alzheimer's disease (AD) pathogenesis. Hypoxia increases factors involved in oxidative stress injury and contributes to the onset and progression of AD. Nuclear factor erythroid 2-related factor 2 (NRF2), a major component regulating antioxidant response, is attenuated in the AD brain. Importantly, NRF2 directly regulates the alternative first exons of CD36, an important participant in oxidative and inflammatory processes. To explore the effects of hypoxia-induced deterioration of AD-like pathogenesis and investigate the correlation between hypoxia-induced NRF2 signal alterations and CD36 expression, we examined the NRF2 signaling, CD36, and oxidative stress events in hypoxia-treated APPswe/PSEN1dE9 (APP/PS1) mice brain. We observed that hypoxia treatment increased oxidative stress, exacerbated inflammation, and aggravated learning defects in aged APP/PS1 mice. Microglia from hypoxia-treated mice brain exhibited marked reduction in CD36 expression and inhibition of β-amyloid (Aβ) degradation. Accordingly, hypoxia treatment caused a decrease in transactivation of NRF2 target genes in the aging mouse brain. Intranasal administration with a lentiviral vector encoding human NRF2 increased CD36 expression, ameliorated the weak antioxidant response triggered by hypoxia, diminished Aβ deposition, and improved spatial memory defects. In this study, we demonstrated for the first time that NRF2 intranasal treatment-induced increases of CD36 could enhance Aβ clearance in AD transgenic mouse. These results suggest that targeting NRF2-mediated CD36 expression might provide a beneficial intervention for cognitive impairment and oxidative stress in AD progression.

  12. Distúrbio de coagulação em crianças e adolescentes com traumatismo cranioencefálico moderado e grave Coagulation disorder in children and adolescents with moderate to severe traumatic brain injury

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    Carolina A. Affonseca

    2007-06-01

    diretamente associada à ocorrência de óbito, pode ser considerada um marcador de gravidade.OBJECTIVES: To describe the epidemiological profile of children and adolescents with moderate to severe traumatic brain injury admitted to an intensive care unit; to describe the frequency of coagulation disorders in these patients; to determine the relationship between coagulopathy and trauma severity; to assess the factors associated with coagulopathy; and to assess the effect of coagulopathy on the mortality of these patients. METHODS: Cross-sectional study with 301 patients aged up to 16 years admitted to an intensive care unit due to moderate to severe traumatic brain injury, carried out over a 5-year period. The coagulation profile was associated with clinical, epidemiological and CT findings. Univariate and multivariate analyses were used to check the association between coagulopathy and mortality. RESULTS: Minimum age was 23 days, and maximum age was 16 years (mean of 7.9 years. About 77% of patients had coagulopathy, whose occurrence was directly associated with the severity of the trauma, but not with the rise in mortality. The factors associated with the presence of coagulopathy were the following: severity of the traumatic brain injury (OR = 2.83; 95%CI 1.58-5.07, diagnosis of brain swelling on cranial computed tomography (OR = 2.11; 95%CI 1.13-4.07 and occurrence of chest and/or abdominal injury (OR = 2.07; 95%CI 1.11-4.00. Approximately 35% of patients died. The multivariate analysis showed that the factors associated with an increased risk of death were presence of sodium disorders (OR = 5.56; 95%CI 2.90-10.65, hypotension in the intensive care unit (OR = 12.58; 95%CI 4.40-35.00 and acute respiratory distress syndrome (OR = 13.57; 95%CI 1.51-121.66. CONCLUSION:The development of coagulopathy is a frequent complication in patients with moderate to severe traumatic brain injury. Even though it is not closely associated with death in this study, it may be regarded as a

  13. Metabolic aspects of acute cerebral hypoxia during extracorporeal circulation and their modification induced by acetyl-carnitine treatment.

    Science.gov (United States)

    Corbucci, G G; Menichetti, A; Cogliatti, A; Nicoli, P; Arduini, A; Damonti, W; Marchionni, A; Calvani, M

    1992-01-01

    Following their previous research experiences in human tissue hypoxia, in the present study the authors. investigated the metabolic effects of acute brain hypoxia in a group of patients in course of extracorporeal circulation for aorto-pulmonary bypass. One hundred subjects were treated, half with a placebo and half with acetyl-carnitine to evaluate the effects of oxidative stress in some brain plasmatic metabolites and to verify the effect of acetyl-carnitine on the tissue energy capacity. The levels of lactate, pyruvate, succinate and fumarate showed a significant imbalance due to hypoxia, while the acetyl-carnitine treatment confined the metabolic gradients within physiological limits. This means that during the course of extracorporeal circulation brain hypoxia plays a pathological role assuming the typical picture of cellular oxidative damage and the acetyl-carnitine antagonizes these deleterious effects of hypoxia by a protective mechanism on the energy processes and then on the cellular enzymic activities. In this regard, the d-tyrosine levels, considered as a proteolytic index, confirm the action of acetyl-carnitine on the cell morpho-functional integrity.

  14. Behavioural effects of near-term acute fetal hypoxia in a small precocial animal, the spiny mouse (Acomys cahirinus).

    Science.gov (United States)

    Ireland, Zoe; Dickinson, Hayley; Fleiss, Bobbi; Hutton, Lisa C; Walker, David W

    2010-01-01

    We have previously developed a model of near-term intra-uterine hypoxia producing significant neonatal mortality (37%) in a small laboratory animal - the spiny mouse - which has precocial offspring at birth. The aim of the present study was to determine if this insult resulted in the appearance of behavioural abnormalities in those offspring which survived the hypoxic delivery. Behavioural tests assessed gait (using footprint patterns), motor coordination and balance on an accelerating rotarod, and spontaneous locomotion and exploration in an open field. We found that the near-term acute hypoxic episode produced a mild neurological deficit in the early postnatal period. In comparison to vaginally delivered controls, hypoxia pups were able to remain on the accelerating rotarod for significantly shorter durations on postnatal days 1-2, and in the open field they travelled significantly shorter distances, jumped less, and spent a greater percentage of time stationary on postnatal days 5 and 15. No changes were observed in gait. Unlike some rodent models of cerebral hypoxia-ischaemia, macroscopic examination of the brain on postnatal day 5 showed no gross cystic lesions, oedema or infarct. Future studies should be directed at identifying hypoxia-induced alterations in the function of specific brain regions, and assessing if maternal administration of neuroprotective agents can prevent against hypoxia-induced neurological deficits and brain damage that occur at birth.

  15. Hippocampal mitogen-activated protein kinase activation is associated with intermittent hypoxia in a rat model of obstructive sleep apnea syndrome.

    Science.gov (United States)

    Zhao, Ya-Ning; Wang, Hong-Yang; Li, Jian-Min; Chen, Bao-Yuan; Xia, Guo; Zhang, Pan-Pan; Ge, Yan-Lei

    2016-01-01

    Obstructive sleep apnea syndrome (OSAS), characterized by intermittent hypoxia/re‑oxygenation, may impair the cerebral system. Although mitogen‑activated protein kinase (MAPK) signaling was observed to have a key role in hypoxia‑induced brain injury, the intracellular events and their underlying mechanisms for intermittent hypoxia/re‑oxygenation-associated damage to hippocamal MAPKs, including extracellular signal‑regulated kinase (ERK)1/2, P38MAPK and c‑Jun N‑terminal kinase (JNK) remain to be elucidated and require further investigation. A total of five rats in each sub‑group were exposed to intermittent hypoxia or continued hypoxia for 2, 4, 6 or 8 weeks. Histological, immunohistochemical and biological analyses were performed to assess nerve cell injury in the hippocampus. Surviving CA1 pyramidal cells were identified by hematoxylin and eosin staining. The levels of phosphorylated ERK1/2, P38MAPK and JNK were detected by western blotting. B‑cell lymphoma 2 (Bcl‑2) and Bcl‑2‑associated X protein (Bax) in neural cells were examined by immunohistochemistry. The malondialdehyde (MDA) contents and superoxide dismutase (SOD) activities were measured by thiobarbituric acid and xanthine oxidation methods, respectively. Under continued hypoxia, the levels of phospho‑ERK1/2 peaked at the fourth week and then declined, whereas phospho‑P38MAPK and JNK were detected only in the late stages. By contrast, under intermittent hypoxia, ERK1/2, P38MAPK and JNK were activated at all time-points assessed (2, 4, 6 and 8 weeks). The levels of phospho‑ERK1/2, P38MAPK and JNK were all higher in the intermittent hypoxia groups than those in the corresponding continued hypoxia groups. Bcl‑2 was mainly increased and reached the highest level at six weeks in the continued hypoxia group. Of note, Bcl‑2 rapidly increased to the peak level at four weeks, followed by a decrease to the lowest level at the eighth week in the intermittent hypoxia group. Bax was

  16. Metabolomic analysis of anti-hypoxia and anti-anxiety effects of Fu Fang Jin Jing Oral Liquid.

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    Xia Liu

    Full Text Available BACKGROUND: Herba Rhodiolae is a traditional Chinese medicine used by the Tibetan people for treating hypoxia related diseases such as anxiety. Based on the previous work, we developed and patented an anti-anxiety herbal formula Fu Fang Jin Jing Oral Liquid (FJJOL with Herba Rhodiolae as a chief ingredient. In this study, the anti-hypoxia and anti-anxiety effects of FJJOL in a high altitude forced-swimming mouse model with anxiety symptoms will be elucidated by NMR-based metabolomics. METHODS: In our experiments, the mice were divided randomly into four groups as flatland group, high altitude saline-treated group, high altitude FJJOL-treated group, and high altitude diazepam-treated group. To cause anxiety effects and hypoxic defects, a combination use of oxygen level decreasing (hypobaric cabin and oxygen consumption increasing (exhaustive swimming were applied to mice. After a three-day experimental handling, aqueous metabolites of mouse brain tissues were extracted and then subjected to NMR analysis. The therapeutic effects of FJJOL on the hypobaric hypoxia mice with anxiety symptoms were verified. RESULTS: Upon hypoxic exposure, both energy metabolism defects and disorders of functional metabolites in brain tissues of mice were observed. PCA, PLS-DA and OPLS-DA scatter plots revealed a clear group clustering for metabolic profiles in the hypoxia versus normoxia samples. After a three-day treatment with FJJOL, significant rescue effects on energy metabolism were detected, and levels of ATP, fumarate, malate and lactate in brain tissues of hypoxic mice recovered. Meanwhile, FJJOL also up-regulated the neurotransmitter GABA, and the improvement of anxiety symptoms was highly related to this effect. CONCLUSIONS: FJJOL ameliorated hypobaric hypoxia effects by regulating energy metabolism, choline metabolism, and improving the symptoms of anxiety. The anti-anxiety therapeutic effects of FJJOL were comparable to the conventional anti-anxiety drug

  17. Effect of Ca2EDTA on zinc mediated inflammation and neuronal apoptosis in hippocampus of an in vivo mouse model of hypobaric hypoxia.

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    Udayabanu Malairaman

    Full Text Available BACKGROUND: Calcium overload has been implicated as a critical event in glutamate excitotoxicity associated neurodegeneration. Recently, zinc accumulation and its neurotoxic role similar to calcium has been proposed. Earlier, we reported that free chelatable zinc released during hypobaric hypoxia mediates neuronal damage and memory impairment. The molecular mechanism behind hypobaric hypoxia mediated neuronal damage is obscure. The role of free zinc in such neuropathological condition has not been elucidated. In the present study, we investigated the underlying role of free chelatable zinc in hypobaric hypoxia-induced neuronal inflammation and apoptosis resulting in hippocampal damage. METHODS: Adult male Balb/c mice were exposed to hypobaric hypoxia and treated with saline or Ca2EDTA (1.25 mM/kg i.p daily for four days. The effects of Ca2EDTA on apoptosis (caspases activity and DNA fragmentation, pro-inflammatory markers (iNOS, TNF-α and COX-2, NADPH oxidase activity, poly(ADP ribose polymerase (PARP activity and expressions of Bax, Bcl-2, HIF-1α, metallothionein-3, ZnT-1 and ZIP-6 were examined in the hippocampal region of brain. RESULTS: Hypobaric hypoxia resulted in increased expression of metallothionein-3 and zinc transporters (ZnT-1 and ZIP-6. Hypobaric hypoxia elicited an oxidative stress and inflammatory response characterized by elevated NADPH oxidase activity and up-regulation of iNOS, COX-2 and TNF-α. Furthermore, hypobaric hypoxia induced HIF-1α protein expression, PARP activation and apoptosis in the hippocampus. Administration of Ca2EDTA significantly attenuated the hypobaric hypoxia induced oxidative stress, inflammation and apoptosis in the hippocampus. CONCLUSION: We propose that hypobaric hypoxia/reperfusion instigates free chelatable zinc imbalance in brain associated with neuroinflammation and neuronal apoptosis. Therefore, zinc chelating strategies which block zinc mediated neuronal damage linked with cerebral hypoxia

  18. A Hypoxia-Regulated Adeno-Associated Virus Vector for Cancer-Specific Gene Therapy

    Directory of Open Access Journals (Sweden)

    Hangjun Ruan

    2001-01-01

    Full Text Available The presence of hypoxic cells in human brain tumors is an important factor leading to resistance to radiation therapy. However, this physiological difference between normal tissues and tumors also provides the potential for designing cancer-specific gene therapy. We compared the increase of gene expression under anoxia (<0.01% oxygen produced by 3, 6, and 9 copies of hypoxia-responsive elements (HRE from the erythropoietin gene (Epo, which are activated through the transcriptional complex hypoxia-inducible factor 1 (HIF-1. Under anoxic conditions, nine copies of HIRE (9XHRE yielded 27- to 37-fold of increased gene expression in U-251 MG and U-87 MG human brain tumor cell lines. Under the less hypoxic conditions of 0.3% and 1% oxygen, gene activation by 9XHRE increased expression 11- to 18-fold in these cell lines. To generate a recombinant adeno-associated virus (rAAV in which the transgene can be regulated by hypoxia, we inserted the DNA fragment containing 9XHRE and the LacZ reporter gene into an AAV vector. Under anoxic conditions, this vector produced 79- to 110-fold increase in gene expression. We believe this hypoxia-regulated rAAV vector will provide a useful delivery vehicle for cancer-specific gene therapy.

  19. Hypoxia induces apelin expression in human adipocytes.

    Science.gov (United States)

    Geiger, K; Muendlein, A; Stark, N; Saely, C H; Wabitsch, M; Fraunberger, P; Drexel, H

    2011-06-01

    Adipokines play a central role in the development of diseases associated with insulin resistance and obesity. Hypoxia in adipose tissue leads to a dysregulation of the expression of adipokines. The effect of hypoxia on the more recently identified adipokine apelin in human adipocytes is unclear. Therefore, we aimed at investigating the role of hypoxia on the expression of the adipokine apelin. Differentiated human Simpson-Golabi-Behmel syndrome (SGBS) adipocytes were cultured under hypoxic conditions for varying time periods. A modular incubator chamber was used to create a hypoxic tissue culture environment (defined as 1% O(2), 94% N, and 5% CO(2)). In addition, hypoxic conditions were mimicked by using CoCl(2). The effect of hypoxia on the expression of the investigated adipokines was measured by real-time PCR and the secretion of apelin was quantified by ELISA. Induction of hypoxia significantly induced mRNA expression of leptin and apelin in differentiated SGBS adipocytes compared with the normoxic control condition. Expression of adiponectin was significantly decreased by hypoxia. In addition, the amount of secreted apelin protein in response to hypoxia was elevated compared to untreated cells. Furthermore, we could demonstrate that the observed hypoxia-induced induction of apelin mRNA expression is in the first phase dependent on HIF-1α. In our study, we could demonstrate for the first time that apelin expression and secretion by human adipocytes are strongly induced under hypoxic conditions and that the early response on hypoxia with apelin induction is dependent on HIF-1α. © Georg Thieme Verlag KG Stuttgart · New York.

  20. Midazolam inhibits the hypoxia-induced up-regulation of erythropoietin in the central nervous system.

    Science.gov (United States)

    Matsuyama, Tomonori; Tanaka, Tomoharu; Tatsumi, Kenichiro; Daijo, Hiroki; Kai, Shinichi; Harada, Hiroshi; Fukuda, Kazuhiko

    2015-08-15

    Erythropoietin (EPO), a regulator of red blood cell production, is endogenously expressed in the central nervous system. It is mainly produced by astrocytes under hypoxic conditions and has proven to have neuroprotective and neurotrophic effects. In the present study, we investigated the effect of midazolam on EPO expression in primary cultured astrocytes and the mouse brain. Midazolam was administered to 6-week-old BALB/c male mice under hypoxic conditions and pregnant C57BL/6N mice under normoxic conditions. Primary cultured astrocytes were also treated with midazolam under hypoxic conditions. The expression of EPO mRNA in mice brains and cultured astrocytes was studied. In addition, the expression of hypoxia-inducible factor (HIF), known as the main regulator of EPO, was evaluated. Midazolam significantly reduced the hypoxia-induced up-regulation of EPO in BALB/c mice brains and primary cultured astrocytes and suppressed EPO expression in the fetal brain. Midazolam did not affect the total amount of HIF proteins but significantly inhibited the nuclear expression of HIF-1α and HIF-2α proteins. These results demonstrated the suppressive effects of midazolam on the hypoxia-induced up-regulation of EPO both in vivo and in vitro.

  1. The protective effects of ethanol extract of Trillium tschonoskii Maxim. on hypoxia-ischemia brain damage in neonatal rats%头顶一颗珠醇提物对新生大鼠缺血/缺氧性脑损伤的保护作用

    Institute of Scientific and Technical Information of China (English)

    邱勇; 李人鹏; 刘粟; 谭志鑫; 陈龙全; 刘红; 吴昊

    2016-01-01

    目的探讨头顶一颗珠醇提物对新生大鼠缺血/缺氧性脑损伤( HIBD )的保护作用及可能机制。方法50只7日龄SD大鼠随机分为假手术组( n=10)、模型组( n=20)、头顶一颗珠治疗组(n=20),各组分别予以3 d相应的生理盐水及头顶一颗珠醇提物腹腔注射。分别通过氯化三苯基四氮唑( TTC)和尼氏染色检测脑缺血及神经细胞死亡情况,通过Western blot检测Bcl-2、Bax蛋白的表达。结果 HIBD模型组可见脑组织稍有肿大,且右侧脑部可见缺血的白色坏死区;治疗组可见大脑形态完好,未见明显肿胀及坏死,TTC染色后,模型组可见右侧脑部出现明显缺血区,经治疗后缺血区域减少。尼氏染色结果提示模型组可见神经元细胞减少,而治疗后神经元细胞增加。 Western blot 显示 HIBD 后Bcl-2表达减少(P<0.01),Bax表达增加(P<0.01),而经过头顶一颗珠治疗后,Bcl-2表达增加(P<0.01),Bax表达降低( P<0.01)。结论头顶一颗珠对HIBD具有保护作用,其机制可能与降低神经元细胞凋亡有关。%Aim To investigate the effect of Trillium tschonoskii Maxim ( TTM ) ethanol extract on hypoxia ischemia brain damage ( HIBD ) in neonatal rats and potential mechanisms. Methods Fifty healthy SD rats of 7 day-old were randomly divided into three groups:the sham operation group ( n=10 ) , the model group ( n=20 ) and TTM treatment group ( n=20 ) , which received 3-day intraperitoneal injection of normal saline or ethanol extract of TTM respectively. TTC staining and Nissl staining were performed to detect the cerebral ischemia area and neuronal death. Western blot was used to detect the expression of Bcl-2 and Bax. Re-sults The brain tissue of model group was slightly swollen, and white necrotic zone induced by ischemia occured on the right side of the brain, while the brain morphology of TTM treatment group was good. After TTC staining, ischemia zone was clearly seen on the right side of the

  2. Hypoxia-triggered m-calpain activation evokes endoplasmic reticulum stress and neuropathogenesis in a transgenic mouse model of Alzheimer's disease.

    Science.gov (United States)

    Wang, Chun-Yan; Xie, Jing-Wei; Wang, Tao; Xu, Ye; Cai, Jian-Hui; Wang, Xu; Zhao, Bao-Lu; An, Li; Wang, Zhan-You

    2013-10-01

    Previous studies have demonstrated that endoplasmic reticulum (ER) stress is activated in Alzheimer's disease (AD) brains. ER stress-triggered unfolded protein response (UPR) leads to tau phosphorylation and neuronal death. In this study, we tested the hypothesis that hypoxia-induced m-calpain activation is involved in ER stress-mediated AD pathogenesis. We employed a hypoxic exposure in APP/PS1 transgenic mice and SH-SY5Y cells overexpressing human Swedish mutation APP (APPswe). We observed that hypoxia impaired spatial learning and memory in the APP/PS1 mouse. In the transgenic mouse brain, hypoxia increased the UPR, upregulated apoptotic signaling, enhanced the activation of calpain and glycogen synthase kinase-3β (GSK3β), and increased tau hyperphosphorylation and β-amyloid deposition. In APPswe cells, m-calpain silencing reduced hypoxia-induced cellular dysfunction and resulted in suppression of GSK3β activation, ER stress and tau hyperphosphorylation reduction as well as caspase pathway suppression. These findings demonstrate that hypoxia-induced abnormal calpain activation may increase ER stress-induced apoptosis in AD pathogenesis. In contrast, a reduction in the expression of the m-calpain isoform reduces ER stress-linked apoptosis that is triggered by hypoxia. These findings suggest that hypoxia-triggered m-calpain activation is involved in ER stress-mediated AD pathogenesis. m-calpain is a potential target for AD therapeutics. © 2013 John Wiley & Sons Ltd.

  3. Dopamine transporters are involved in the onset of hypoxia-induced dopamine efflux in striatum as revealed by in vivo microdialysis.

    Science.gov (United States)

    Orset, Cyrille; Parrot, Sandrine; Sauvinet, Valérie; Cottet-Emard, Jean-Marie; Bérod, Anne; Pequignot, Jean-Marc; Denoroy, Luc

    2005-06-01

    Although many studies have revealed alterations in neurotransmission during ischaemia, few works have been devoted to the neurochemical effects of mild hypoxia, a situation encountered during life in altitude or in several pathologies. In that context, the present work was undertaken to determine the in vivo mechanisms underlying the striatal dopamine efflux induced by mild hypoxaemic hypoxia. For that purpose, the extracellular concentrations of dopamine and its metabolite 3,4-dihydroxyphenyl acetic acid were simultaneously measured using brain microdialysis during acute hypoxic exposure (10% O(2), 1h) in awake rats. Hypoxia induced a +80% increase in dopamine. Application of the dopamine transporters inhibitor, nomifensine (10 microM), just before the hypoxia prevented the rise in dopamine during the early part of hypoxia; in contrast the application of nomifensine after the beginning of hypoxia, failed to alter the increase in dopamine. Application of the voltage-dependent Na(+) channel blocker tetrodotoxin abolished the increase in dopamine, whether administered just before or after the beginning of hypoxia. These data show that the neurochemical mechanisms of the dopamine efflux may change over the course of the hypoxic exposure, dopamine transporters being involved only at the beginning of hypoxia.

  4. Kinetic modeling in PET imaging of hypoxia

    DEFF Research Database (Denmark)

    Joergensen, Jesper T; Hansen, Anders E; Kjaer, Andreas

    2014-01-01

    Tumor hypoxia is associated with increased therapeutic resistance leading to poor treatment outcome. Therefore the ability to detect and quantify intratumoral oxygenation could play an important role in future individual personalized treatment strategies. Positron Emission Tomography (PET) can...... be used for non-invasive mapping of tissue oxygenation in vivo and several hypoxia specific PET tracers have been developed. Evaluation of PET data in the clinic is commonly based on visual assessment together with semiquantitative measurements e.g. standard uptake value (SUV). However, dynamic PET...... analysis for PET imaging of hypoxia....

  5. Improvement of oxygen supply by an artificial carrier in combination with normobaric oxygenation decreases the volume of tissue hypoxia and tissue damage from transient focal cerebral ischemia

    NARCIS (Netherlands)

    Seiffge, David J.; Lapina, Natalia E.; Tsagogiorgas, Charalambos; Theisinger, Bastian; Henning, Robert H.; Schilling, Lothar

    2012-01-01

    Tissue hypoxia may play an important role in the development of ischemic brain damage. In the present study we investigated in a rat model of transient focal brain ischemia the neuroprotective effects of increasing the blood oxygen transport capacity by applying a semifluorinated alkane (SFA)-contai

  6. Effect of hypoxia on the activity and binding of glycolytic and associated enzymes in sea scorpion tissues

    Directory of Open Access Journals (Sweden)

    Lushchak V.I.

    1998-01-01

    Full Text Available The effect of hypoxia on the levels of glycogen, glucose and lactate as well as the activities and binding of glycolytic and associated enzymes to subcellular structures was studied in brain, liver and white muscle of the teleost fish, Scorpaena porcus. Hypoxia exposure decreased glucose levels in liver from 2.53 to 1.70 µmol/g wet weight and in muscle led to its increase from 3.64 to 25.1 µmol/g wet weight. Maximal activities of several enzymes in brain were increased by hypoxia: hexokinase by 23%, phosphoglucoisomerase by 47% and phosphofructokinase (PFK by 56%. However, activities of other enzymes in brain as well as enzymes in liver and white muscle were largely unchanged or decreased during experimental hypoxia. Glycolytic enzymes in all three tissues were partitioned between soluble and particulate-bound forms. In several cases, the percentage of bound enzymes was reduced during hypoxia; bound aldolase in brain was reduced from 36.4 to 30.3% whereas glucose-6-phosphate dehydrogenase fell from 55.7 to 28.7% bound. In muscle PFK was reduced from 57.4 to 41.7% bound. Oppositely, the proportion of bound aldolase and triosephosphate isomerase increased in hypoxic muscle. Phosphoglucomutase did not appear to occur in a bound form in liver and bound phosphoglucomutase disappeared in muscle during hypoxia exposure. Anoxia exposure also led to the disappearance of bound fructose-1,6-bisphosphatase in liver, whereas a bound fraction of this enzyme appeared in white muscle of anoxic animals. The possible function of reversible binding of glycolytic enzymes to subcellular structures as a regulatory mechanism of carbohydrate metabolism is discussed.

  7. Acute and Chronic Sustained Hypoxia Do Not Substantially Regulate Amyloid-β Peptide Generation In Vivo

    Science.gov (United States)

    Heras-Garvín, Antonio; March-Díaz, Rosana; Navarro, Victoria; Vizuete, Marisa; López-Barneo, José; Vitorica, Javier; Pascual, Alberto

    2017-01-01

    Background Recent epidemiological evidence has linked hypoxia with the development of Alzheimer disease (AD). A number of in vitro and in vivo studies have reported that hypoxia can induce amyloid-β peptide accumulation through various molecular mechanisms including the up-regulation of the amyloid-β precursor protein, the β-secretase Bace1, or the γγ-secretase complex components, as well as the down-regulation of Aβ-degrading enzymes. Objectives To investigate the effects of acute and chronic sustained hypoxia in Aβ generation in vivo. Methods 2–3 month-old C57/Bl6J wild-type mice were exposed to either normoxia (21% O2) or hypoxia (9% O2) for either 4 to 72 h (acute) or 21–30 days (chronic sustained) in a hermetic chamber. Brain mRNA levels of Aβ-related genes were measured by quantitative real-time PCR, whereas levels of Bace1 protein, full length AβPP, and its C-terminal fragments (C99/C88 ratio) were measured by Western blot. In addition, 8 and 14-month-old APP/PS1 transgenic mice were subjected to 9% O2 for 21 days and levels of Aβ40, Aβ42, full length AβPP, and soluble AβPPα (sAβPPα) were measured by ELISA or WB. Results Hypoxia (either acute or chronic sustained) did not impact the transcription of any of the Aβ-related genes in young wild-type mice. A significant reduction of Bace1 protein level was noted with acute hypoxia for 16 h but did not correlate with an increased level of full length AβPP or a decreased C99/C83 ratio. Chronic sustained hypoxia did not significantly alter the levels of Bace1, full length AβPP or the C99/C83 ratio. Last, chronic sustained hypoxia did not significantly change the levels of Aβ40, Aβ42, full length AβPP, or sAβPPα in either young or aged APP/PS1 mice. Discussion Our results argue against a hypoxia-induced shift of AβPP proteolysis from the non-amyloidogenic to the amyloidogenic pathways. We discuss the possible methodological caveats of previous in vivo studies. PMID:28099462

  8. Hypoxia in CNS Pathologies: Emerging Role of miRNA-Based Neurotherapeutics and Yoga Based Alternative Therapies.

    Science.gov (United States)

    Minhas, Gillipsie; Mathur, Deepali; Ragavendrasamy, Balakrishnan; Sharma, Neel K; Paanu, Viraaj; Anand, Akshay

    2017-01-01

    Cellular respiration is a vital process for the existence of life. Any condition that results in deprivation of oxygen (also termed as hypoxia) may eventually lead to deleterious effects on the functioning of tissues. Brain being the highest consumer of oxygen is prone to increased risk of hypoxia-induced neurological insults. This in turn has been associated with many diseases of central nervous system (CNS) such as stroke, Alzheimer's, encephalopathy etc. Although several studies have investigated the pathophysiological mechanisms underlying ischemic/hypoxic CNS diseases, the knowledge about protective therapeutic strategies to ameliorate the affected neuronal cells is meager. This has augmented the need to improve our understanding of the hypoxic and ischemic events occurring in the brain and identify novel and alternate treatment modalities for such insults. MicroRNA (miRNAs), small non-coding RNA molecules, have recently emerged as potential neuroprotective agents as well as targets, under hypoxic conditions. These 18-22 nucleotide long RNA molecules are profusely present in brain and other organs and function as gene regulators by cleaving and silencing the gene expression. In brain, these are known to be involved in neuronal differentiation and plasticity. Therefore, targeting miRNA expression represents a novel therapeutic approach to intercede against hypoxic and ischemic brain injury. In the first part of this review, we will discuss the neurophysiological changes caused as a result of hypoxia, followed by the contribution of hypoxia in the neurodegenerative diseases. Secondly, we will provide recent updates and insights into the roles of miRNA in the regulation of genes in oxygen and glucose deprived brain in association with circadian rhythms and how these can be targeted as neuroprotective agents for CNS injuries. Finally, we will emphasize on alternate breathing or yogic interventions to overcome the hypoxia associated anomalies that could ultimately

  9. Hypoxia in CNS Pathologies: Emerging Role of miRNA-Based Neurotherapeutics and Yoga Based Alternative Therapies

    Directory of Open Access Journals (Sweden)

    Gillipsie Minhas

    2017-07-01

    Full Text Available Cellular respiration is a vital process for the existence of life. Any condition that results in deprivation of oxygen (also termed as hypoxia may eventually lead to deleterious effects on the functioning of tissues. Brain being the highest consumer of oxygen is prone to increased risk of hypoxia-induced neurological insults. This in turn has been associated with many diseases of central nervous system (CNS such as stroke, Alzheimer's, encephalopathy etc. Although several studies have investigated the pathophysiological mechanisms underlying ischemic/hypoxic CNS diseases, the knowledge about protective therapeutic strategies to ameliorate the affected neuronal cells is meager. This has augmented the need to improve our understanding of the hypoxic and ischemic events occurring in the brain and identify novel and alternate treatment modalities for such insults. MicroRNA (miRNAs, small non-coding RNA molecules, have recently emerged as potential neuroprotective agents as well as targets, under hypoxic conditions. These 18–22 nucleotide long RNA molecules are profusely present in brain and other organs and function as gene regulators by cleaving and silencing the gene expression. In brain, these are known to be involved in neuronal differentiation and plasticity. Therefore, targeting miRNA expression represents a novel therapeutic approach to intercede against hypoxic and ischemic brain injury. In the first part of this review, we will discuss the neurophysiological changes caused as a result of hypoxia, followed by the contribution of hypoxia in the neurodegenerative diseases. Secondly, we will provide recent updates and insights into the roles of miRNA in the regulation of genes in oxygen and glucose deprived brain in association with circadian rhythms and how these can be targeted as neuroprotective agents for CNS injuries. Finally, we will emphasize on alternate breathing or yogic interventions to overcome the hypoxia associated anomalies

  10. Insulin- and Warts-Dependent Regulation of Tracheal Plasticity Modulates Systemic Larval Growth during Hypoxia in Drosophila melanogaster

    Science.gov (United States)

    Wong, Daniel M.; Shen, Zhouyang; Owyang, Kristin E.; Martinez-Agosto, Julian A.

    2014-01-01

    Adaptation to dynamic environmental cues during organismal development requires coordination of tissue growth with available resources. More specifically, the effects of oxygen availability on body size have been well-documented, but the mechanisms through which hypoxia restricts systemic growth have not been fully elucidated. Here, we characterize the larval growth and metabolic defects in Drosophila that result from hypoxia. Hypoxic conditions reduced fat body opacity and increased lipid droplet accumulation in this tissue, without eliciting lipid aggregation in hepatocyte-like cells called oenocytes. Additionally, hypoxia increased the retention of Dilp2 in the insulin-producing cells of the larval brain, associated with a reduction of insulin signaling in peripheral tissues. Overexpression of the wildtype form of the insulin receptor ubiquitously and in the larval trachea rendered larvae resistant to hypoxia-induced growth restriction. Furthermore, Warts downregulation in the trachea was similar to increased insulin receptor signaling during oxygen deprivation, which both rescued hypoxia-induced growth restriction, inhibition of tracheal molting, and developmental delay. Insulin signaling and loss of Warts function increased tracheal growth and augmented tracheal plasticity under hypoxic conditions, enhancing oxygen delivery during periods of oxygen deprivation. Our findings demonstrate a mechanism that coordinates oxygen availability with systemic growth in which hypoxia-induced reduction of insulin receptor signaling decreases plasticity of the larval trachea that is required for the maintenance of systemic growth during times of limiting oxygen availability. PMID:25541690

  11. Insulin- and warts-dependent regulation of tracheal plasticity modulates systemic larval growth during hypoxia in Drosophila melanogaster.

    Directory of Open Access Journals (Sweden)

    Daniel M Wong

    Full Text Available Adaptation to dynamic environmental cues during organismal development requires coordination of tissue growth with available resources. More specifically, the effects of oxygen availability on body size have been well-documented, but the mechanisms through which hypoxia restricts systemic growth have not been fully elucidated. Here, we characterize the larval growth and metabolic defects in Drosophila that result from hypoxia. Hypoxic conditions reduced fat body opacity and increased lipid droplet accumulation in this tissue, without eliciting lipid aggregation in hepatocyte-like cells called oenocytes. Additionally, hypoxia increased the retention of Dilp2 in the insulin-producing cells of the larval brain, associated with a reduction of insulin signaling in peripheral tissues. Overexpression of the wildtype form of the insulin receptor ubiquitously and in the larval trachea rendered larvae resistant to hypoxia-induced growth restriction. Furthermore, Warts downregulation in the trachea was similar to increased insulin receptor signaling during oxygen deprivation, which both rescued hypoxia-induced growth restriction, inhibition of tracheal molting, and developmental delay. Insulin signaling and loss of Warts function increased tracheal growth and augmented tracheal plasticity under hypoxic conditions, enhancing oxygen delivery during periods of oxygen deprivation. Our findings demonstrate a mechanism that coordinates oxygen availability with systemic growth in which hypoxia-induced reduction of insulin receptor signaling decreases plasticity of the larval trachea that is required for the maintenance of systemic growth during times of limiting oxygen availability.

  12. Design of optimized hypoxia-activated prodrugs using pharmacokinetic/pharmacodynamic modeling

    Directory of Open Access Journals (Sweden)

    Annika Bettina Foehrenbacher

    2013-12-01

    Full Text Available Hypoxia contributes to resistance of tumors to some cytotoxic drugs and to radiotherapy, but can in principle be exploited with hypoxia-activated prodrugs (HAP. HAP in clinical development fall into two broad groups. Class I HAP (like the benzotriazine N-oxides tirapazamine and SN30000, are activated under relatively mild hypoxia. In contrast, Class II HAP (such as the nitro compounds PR-104A or TH-302 are maximally activated only under extreme hypoxia, but their active metabolites (effectors diffuse to cells at intermediate O2 and thus also eliminate moderately hypoxic cells. Here, we use a spatially resolved pharmacokinetic/pharmacodynamic (SR-PK/PD model to compare these two strategies and to identify the features required in an optimal Class II HAP. The model uses a Green’s function approach to calculate spatial and longitudinal gradients of O2, prodrug and effector concentrations, and resulting killing in a digitized 3D tumor microregion to estimate activity as monotherapy and in combination with radiotherapy. An analogous model for a normal tissue with mild hypoxia and short intervesssel distances (based on a cremaster muscle microvessel network was used to estimate tumor selectivity of cell killing. This showed that Class II HAP offer advantages over Class I including higher tumor selectivity and greater freedom to vary prodrug diffusibility and rate of metabolic activation. The model suggests that the largest gains in class II HAP antitumor activity could be realized by optimizing effector stability and prodrug activation rates. We also use the model to show that diffusion of effector into blood vessels is unlikely to materially increase systemic exposure for realistic tumor burdens and effector clearances. However, we show that the tumor selectivity achievable by hypoxia-dependent prodrug activation alone is limited if dose-limiting normal tissues are even mildly hypoxic

  13. 2004 Hypoxia Watch Bottom CTD Station Locations

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The NOAA Hypoxia Watch project provides near-real-time, web-based maps of dissolved oxygen near the sea floor over the Texas-Louisiana continental shelf during a...

  14. 2002 Hypoxia Watch Bottom CTD Station Locations

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The NOAA Hypoxia Watch project provides near-real-time, web-based maps of dissolved oxygen near the sea floor over the Texas-Louisiana continental shelf during a...

  15. 2003 Hypoxia Watch Bottom CTD Station Locations

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The NOAA Hypoxia Watch project provides near-real-time, web-based maps of dissolved oxygen near the sea floor over the Texas-Louisiana continental shelf during a...

  16. 2006 Hypoxia Watch Bottom CTD Station Locations

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The NOAA Hypoxia Watch project provides near-real-time, web-based maps of dissolved oxygen near the sea floor over the Texas-Louisiana continental shelf during a...

  17. 2007 Hypoxia Watch Bottom CTD Station Locations

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The NOAA Hypoxia Watch project provides near-real-time, web-based maps of dissolved oxygen near the sea floor over the Texas-Louisiana continental shelf during a...

  18. 2005 Hypoxia Watch Bottom CTD Station Locations

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The NOAA Hypoxia Watch project provides near-real-time, web-based maps of dissolved oxygen near the sea floor over the Texas-Louisiana continental shelf during a...

  19. 2001 Hypoxia Watch Bottom CTD Station Locations

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The NOAA Hypoxia Watch project provides near-real-time, web-based maps of dissolved oxygen near the sea floor over the Texas-Louisiana continental shelf during a...

  20. Measuring and monitoring eutrophication and hypoxia

    Digital Repository Service at National Institute of Oceanography (India)

    Naqvi, S.W.A.; Heidemeier, J.

    Coastal hypoxia is a complex problem and, although research has made great strides in understanding its causes and remedies, more knowledge is needed to fill critical gaps that impede action. To establish long-term trends and identify changes...

  1. Triptolide protects astrocytes from hypoxia/ reoxygenation injury

    Institute of Scientific and Technical Information of China (English)

    Minfang Guo; Hongcui Fan; Jiezhong Yu; Ning Ji; Yongsheng Sun; Liyun Liang; Baoguo Xiao; Cungen Ma

    2011-01-01

    Astrocytes in an in vitro murine astrocyte model of oxygen and glucose deprivation/hypoxia and reoxygenation were treated with different concentrations of triptolide (250, 500, 1 000 ng/mL) in a broader attempt to elucidate the protection and mechanism underlying triptolide treatment on astrocytes exposed to hypoxia/reoxygenation injury. The results showed that the matrix metalloproteinase-9, interleukin-1β, tumor necrosis factor α and interleukin-6 expressions were significantly decreased after triptolide treatment in the astrocytes exposed to hypoxia/ reoxygenation injury, while interleukin-10 expression was upregulated. In addition, the vitality of the injured astrocytes was enhanced, the triptolide's effect was apparent at 500 ng/mL. These experimental findings indicate that triptolide treatment could protect astrocytes against hypoxia/ reoxygenation injury through the inhibition of inflammatory response and the reduction of matrix metalloproteinase-9 expression.

  2. The up regulation of phosphofructokinase1 (PFK1) protein during chemically induced hypoxia is mediated by the hypoxia-responsive internal ribosome entry site (IRES) element, present in its 5'untranslated region.

    Science.gov (United States)

    Ismail, Rehana; Ul Hussain, Mahboob

    2017-08-01

    Astrocytes cope-up the hypoxia conditions by up regulating the activity of the enzymes catalyzing the irreversible steps of the glycolytic pathway. The phosphofructokinase1 (PFK1), which converts fructose-6-phosphate to fructose-1, 6-bisphosphate, is the major regulatory enzyme of the glycolytic pathway. For this purpose, we investigated the expression regulation of the PFK1 during chemically induced hypoxia. After 48 h of the chemically induced hypoxia induction of the C6 glioma cells, the PFK1 protein depicted strong up regulation, with no appreciable change in its mRNA levels. The di-cistronic assay indicated the presence of a weak internal ribosome entry site (IRES) element in the 5'UTR of the PFK1 mRNA. Interestingly, the weak IRES element of the PFK1 was strongly up regulated after 48 h of the chemically induced hypoxia, indicative of a possible mechanism responsible for the induction of the PFK1 protein. The authenticity of the hypoxia-regulated IRES element of the PFK1, relative to the presence of the cryptic promoter element and/or the cryptic splicing was established using promoterless di-cistronic assay and the RT-PCR analysis. Moreover, the ectopic expression of the polypyrimidine tract binding (PTB) protein resulted in the enhanced activity of the IRES element of the PFK1. Additionally, it was established that the chemically induced hypoxia resulted in the increased shuttling of the PTB from the cell nucleus to the cytosol. The presence of a hypoxia responsive IRES element, in the 5'UTR of the PFK1 was established to be the possible mechanism responsible for the up regulation of the PFK1 protein. Our data provides an interesting mechanism that may explain the increased glycolytic capacity of the astrocytes after brain hypoxia. Copyright © 2017 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

  3. Role of mixed lineage kinase inhibition in neonatal hypoxia-ischemia.

    Science.gov (United States)

    Carlsson, Ylva; Leverin, Anna-Lena; Hedtjärn, Maj; Wang, Xiaoyang; Mallard, Carina; Hagberg, Henrik

    2009-01-01

    Hypoxic-ischemic brain injury is often delayed and involves both apoptotic and immunoregulatory mechanisms. In this study, we used a neonatal model of hypoxia-ischemia to examine the effect of the mixed lineage kinase (MLK) inhibitor CEP-1347 on brain damage, apoptosis and inflammation. The tissue volume loss was reduced by 28% (p = 0.019) in CEP-1347-treated versus vehicle-treated rats and CEP-1347 significantly attenuated microgliosis at 7 days (p = 0.038). CEP-1347 decreased TUNEL-positive staining as well as cleaved caspase 3 immunoreactivity. CEP-1347 did not affect the expression of pro-inflammatory cytokines IL-1 beta, IL-6 and MCP-1, nor did it affect the expression of OX-42 (CR3) and OX-18 (MHC I) 24 h after the insult. In conclusion, the MLK inhibitor CEP-1347 has protective effects in a neonatal rat model of hypoxia-ischemia, which is mainly related to reduced apoptosis.

  4. Sildenafil does not Improve Exercise Capacity under Acute Hypoxia Exposure.

    Science.gov (United States)

    Toro-Salinas, A H; Fort, N; Torrella, J R; Pagès, T; Javierre, C; Viscor, G

    2016-09-01

    The increase in pulmonary arterial pressure (PAP) due to hypoxic pulmonary vasoconstriction (HPV) could be a limiting factor for physical performance during hypoxic exposure. Sildenafil has been shown to reduce PAP in situations of moderate or severe hypoxia, and consequently its role as an ergogenic aid and even a possible doping substance must be considered. We performed a double-blind crossover study to determine the effects of sildenafil on cardiovascular, respiratory and metabolic parameters in normoxia and during acute exposure to hypobaric hypoxia (4 000 m) at rest and during maximal and submaximal (60% VO2 max) exercise tests. One hour before testing started, sildenafil (100 mg) or a placebo was orally administered to 11 volunteers. In normoxic conditions, sildenafil did not affect performance. Similarly, no significant differences were found in cardiovascular and respiratory parameters in hypoxic conditions at rest or during exercise. The use of sildenafil to improve physical performance in non-acclimatized subjects is not supported by our data. © Georg Thieme Verlag KG Stuttgart · New York.

  5. Hypoxia independent drivers of melanoma angiogenesis

    Directory of Open Access Journals (Sweden)

    Svenja eMeierjohann

    2015-05-01

    Full Text Available Tumor angiogenesis is a process which is traditionally regarded as the tumor`s response to low nutrient supply occurring under hypoxic conditions. However, hypoxia is not a prerequisite for angiogenesis. The fact that even single tumor cells or small tumor cell aggregates are capable of attracting blood vessels reveals the early metastatic capability of tumor cells. This review sheds light on the hypoxia independent mechanisms of tumor angiogenesis in melanoma.

  6. Thirty Minutes of Hypobaric Hypoxia Provokes Alterations of Immune Response, Haemostasis, and Metabolism Proteins in Human Serum

    Directory of Open Access Journals (Sweden)

    Jochen Hinkelbein

    2017-08-01

    Full Text Available Hypobaric hypoxia (HH during airline travel induces several (patho- physiological reactions in the human body. Whereas severe hypoxia is investigated thoroughly, very little is known about effects of moderate or short-term hypoxia, e.g. during airline flights. The aim of the present study was to analyse changes in serum protein expression and activation of signalling cascades in human volunteers staying for 30 min in a simulated altitude equivalent to airline travel. After approval of the local ethics committee, 10 participants were exposed to moderate hypoxia (simulation of 2400 m or 8000 ft for 30 min in a hypobaric pressure chamber. Before and after hypobaric hypoxia, serum was drawn, centrifuged, and analysed by two-dimensional gel electrophoresis (2-DIGE and matrix-assisted laser desorption/ionization followed by time-of-flight mass spectrometry (MALDI-TOF. Biological functions of regulated proteins were identified using functional network analysis (GeneMania®, STRING®, and Perseus® software. In participants, oxygen saturation decreased from 98.1 ± 1.3% to 89.2 ± 1.8% during HH. Expression of 14 spots (i.e., 10 proteins: ALB, PGK1, APOE, GAPDH, C1QA, C1QB, CAT, CA1, F2, and CLU was significantly altered. Bioinformatic analysis revealed an association of the altered proteins with the signalling cascades “regulation of haemostasis” (four proteins, “metabolism” (five proteins, and “leukocyte mediated immune response” (five proteins. Even though hypobaric hypoxia was short and moderate (comparable to an airliner flight, analysis of protein expression in human subjects revealed an association to immune response, protein metabolism, and haemostasis

  7. Sensing and surviving hypoxia in vertebrates.

    Science.gov (United States)

    Jonz, Michael G; Buck, Leslie T; Perry, Steve F; Schwerte, Thorsten; Zaccone, Giacomo

    2016-02-01

    Surviving hypoxia is one of the most critical challenges faced by vertebrates. Most species have adapted to changing levels of oxygen in their environment with specialized organs that sense hypoxia, while only few have been uniquely adapted to survive prolonged periods of anoxia. The goal of this review is to present the most recent research on oxygen sensing, adaptation to hypoxia, and mechanisms of anoxia tolerance in nonmammalian vertebrates. We discuss the respiratory structures in fish, including the skin, gills, and air-breathing organs, and recent evidence for chemosensory neuroepithelial cells (NECs) in these tissues that initiate reflex responses to hypoxia. The use of the zebrafish as a genetic and developmental model has allowed observation of the ontogenesis of respiratory and chemosensory systems, demonstration of a putative intracellular O2 sensor in chemoreceptors that may initiate transduction of the hypoxia signal, and investigation into the effects of extreme hypoxia on cardiorespiratory development. Other organisms, such as goldfish and freshwater turtles, display a high degree of anoxia tolerance, and these models are revealing important adaptations at the cellular level, such as the regulation of glutamatergic and GABAergic neurotransmission in defense of homeostasis in central neurons.

  8. Cardiovascular function in term fetal sheep conceived, gestated and studied in the hypobaric hypoxia of the Andean altiplano.

    Science.gov (United States)

    Herrera, Emilio A; Rojas, Rodrigo T; Krause, Bernardo J; Ebensperger, Germán; Reyes, Roberto V; Giussani, Dino A; Parer, Julian T; Llanos, Aníbal J

    2016-03-01

    High-altitude hypoxia causes intrauterine growth restriction and cardiovascular programming. However, adult humans and animals that have evolved at altitude show certain protection against the effects of chronic hypoxia. Whether the highland fetus shows similar protection against high altitude gestation is unclear. We tested the hypothesis that high-altitude fetal sheep have evolved cardiovascular compensatory mechanisms to withstand chronic hypoxia that are different from lowland sheep. We studied seven high-altitude (HA; 3600 m) and eight low-altitude (LA; 520 m) pregnant sheep at ∼90% gestation. Pregnant ewes and fetuses were instrumented for cardiovascular investigation. A three-period experimental protocol was performed in vivo: 30 min of basal, 1 h of acute superimposed hypoxia (∼10% O2) and 30 min of recovery. Further, we determined ex vivo fetal cerebral and femoral arterial function. HA pregnancy led to chronic fetal hypoxia, growth restriction and altered cardiovascular function. During acute superimposed hypoxia, LA fetuses redistributed blood flow favouring the brain, heart and adrenals, whereas HA fetuses showed a blunted cardiovascular response. Importantly, HA fetuses have a marked reduction in umbilical blood flow versus LA. Isolated cerebral arteries from HA fetuses showed a higher contractile capacity but a diminished response to catecholamines. In contrast, femoral arteries from HA fetuses showed decreased contractile capacity and increased adrenergic contractility. The blunting of the cardiovascular responses to hypoxia in fetuses raised in the Alto Andino may indicate a change in control strategy triggered by chronic hypoxia, switching towards compensatory mechanisms that are more cost-effective in terms of oxygen uptake.

  9. The effect of aprotinin on hypoxia-reoxygenation-induced changes in neutrophil and endothelial function.

    LENUS (Irish Health Repository)

    Harmon, D

    2012-02-03

    BACKGROUND AND OBJECTIVE: An acute inflammatory response associated with cerebral ischaemia-reperfusion contributes to the development of brain injury. Aprotinin has potential, though unexplained, neuroprotective effects in patients undergoing cardiac surgery. METHODS: Human neutrophil CD11 b\\/CD18, endothelial cell intercellular adhesion molecule-1 (ICAM-1) expression and endothelial interleukin (IL)-1beta supernatant concentrations in response to in vitro hypoxia-reoxygenation was studied in the presence or absence of aprotinin (1600 KIU mL(-1)). Adhesion molecule expression was quantified using flow cytometry and IL-1beta concentrations by enzyme-linked immunosorbent assay. Data were analysed using ANOVA and post hoc Student-Newman-Keuls test as appropriate. RESULTS: Exposure to 60-min hypoxia increased neutrophil CD11b expression compared to normoxia (170+\\/-46% vs. 91+\\/-27%, P = 0.001) (percent intensity of fluorescence compared to time 0) (n = 8). Hypoxia (60 min) produced greater upregulation of CD11b expression in controls compared to aprotinin-treated neutrophils [(170+\\/-46% vs. 129+\\/-40%) (P = 0.04)] (n = 8). Hypoxia-reoxygenation increased endothelial cell ICAM-1 expression (155+\\/-3.7 vs. 43+\\/-21 mean channel fluorescence, P = 0.0003) and IL-1beta supernatant concentrations compared to normoxia (3.4+\\/-0.4 vs. 2.6+\\/-0.2, P = 0.02) (n = 3). Hypoxia-reoxygenation produced greater upregulation of ICAM- 1 expression [(155+\\/-3.3 vs. 116+\\/-0.7) (P = 0.001)] and IL-1beta supernatant concentrations [(3.4+\\/-0.3 vs. 2.6+\\/-0.1) (P = 0.01)] in controls compared to aprotinin-treated endothelial cell preparation (n = 3). CONCLUSIONS: Hypoxia-reoxygenation-induced upregulation of neutrophil CD11b, endothelial cell ICAM-1 expression and IL-1beta concentrations is decreased by aprotinin at clinically relevant concentrations.

  10. Molecular evolution of globin genes in Gymnotiform electric fishes: relation to hypoxia tolerance.

    Science.gov (United States)

    Tian, Ran; Losilla, Mauricio; Lu, Ying; Yang, Guang; Zakon, Harold

    2017-02-13

    Nocturnally active gymnotiform weakly electric fish generate electric signals for communication and navigation, which can be energetically taxing. These fish mainly inhabit the Amazon basin, where some species prefer well-oxygenated waters and others live in oxygen-poor, stagnant habitats. The latter species show morphological, physiological, and behavioral adaptations for hypoxia-tolerance. However, there have been no studies of hypoxia tolerance on the molecular level. Globins are classic respiratory proteins. They function principally in oxygen-binding and -delivery in various tissues and organs. Here, we investigate the molecular evolution of alpha and beta hemoglobins, myoglobin, and neuroglobin in 12 gymnotiforms compared with other teleost fish. The present study identified positively selected sites (PSS) on hemoglobin (Hb) and myoglobin (Mb) genes using different maximum likelihood (ML) methods; some PSS fall in structurally important protein regions. This evidence for the positive selection of globin genes suggests that the adaptive evolution of these genes has helped to enhance the capacity for oxygen storage and transport. Interestingly, a substitution of a Cys at a key site in the obligate air-breathing electric eel (Electrophorus electricus) is predicted to enhance oxygen storage of Mb and contribute to NO delivery during hypoxia. A parallel Cys substitution was also noted in an air-breathing African electric fish (Gymnarchus niloticus). Moreover, the expected pattern under normoxic conditions of high expression of myoglobin in heart and neuroglobin in the brain in two hypoxia-tolerant species suggests that the main effect of selection on these globin genes is on their sequence rather than their basal expression patterns. Results indicate a clear signature of positive selection in the globin genes of most hypoxia-tolerant gymnotiform fishes, which are obligate or facultative air breathers. These findings highlight the critical role of globin genes in

  11. Inhalation of hydrogen gas attenuates left ventricular remodeling induced by intermittent hypoxia in mice.

    Science.gov (United States)

    Hayashi, Tetsuya; Yoshioka, Toshitaka; Hasegawa, Kenichi; Miyamura, Masatoshi; Mori, Tatsuhiko; Ukimura, Akira; Matsumura, Yasuo; Ishizaka, Nobukazu

    2011-09-01

    Sleep apnea syndrome increases the risk of cardiovascular morbidity and mortality. We previously reported that intermittent hypoxia increases superoxide production in a manner dependent on nicotinamide adenine dinucleotide phosphate and accelerates adverse left ventricular (LV) remodeling. Recent studies have suggested that hydrogen (H(2)) may have an antioxidant effect by reducing hydroxyl radicals. In this study, we investigated the effects of H(2) gas inhalation on lipid metabolism and LV remodeling induced by intermittent hypoxia in mice. Male C57BL/6J mice (n = 62) were exposed to intermittent hypoxia (repetitive cycle of 1-min periods of 5 and 21% oxygen for 8 h during daytime) for 7 days. H(2) gas (1.3 vol/100 vol) was given either at the time of reoxygenation, during hypoxic conditions, or throughout the experimental period. Mice kept under normoxic conditions served as controls (n = 13). Intermittent hypoxia significantly increased plasma levels of low- and very low-density cholesterol and the amount of 4-hydroxy-2-nonenal-modified protein adducts in the LV myocardium. It also upregulated mRNA expression of tissue necrosis factor-α, interleukin-6, and brain natriuretic peptide, increased production of superoxide, and induced cardiomyocyte hypertrophy, nuclear deformity, mitochondrial degeneration, and interstitial fibrosis. H(2) gas inhalation significantly suppressed these changes induced by intermittent hypoxia. In particular, H(2) gas inhaled at the timing of reoxygenation or throughout the experiment was effective in preventing dyslipidemia and suppressing superoxide production in the LV myocardium. These results suggest that inhalation of H(2) gas was effective for reducing oxidative stress and preventing LV remodeling induced by intermittent hypoxia relevant to sleep apnea.

  12. Heart rate and blood pressure responses during hypoxic cycles of a 3-week intermittent hypoxia breathing program in patients at risk for or with mild COPD.

    Science.gov (United States)

    Faulhaber, Martin; Gatterer, Hannes; Haider, Thomas; Linser, Tobias; Netzer, Nikolaus; Burtscher, Martin

    2015-01-01

    The aim of this study was to provide information on heart rate and blood pressure responses during a 3-week intermittent hypoxia breathing program in COPD patients. Sixteen participants with COPD symptoms were randomly assigned to a hypoxia or control group and completed a 3-week intermittent hypoxia breathing program (five sessions per week, each consisting of three to five breathing cycles, each cycle lasting 3-5 minutes with 3-minute breaks between cycles). During the breathing cycles, the hypoxia group received hypoxic air (inspired fraction of oxygen 15%-12%), whereas the control group received normal air (sham hypoxia). During the breaks, all participants breathed normoxic room air. Arterial oxygen saturation, systolic and diastolic blood pressure, and heart rate were measured during the normoxic and hypoxic/sham hypoxic periods. For each breathing cycle, changes from normoxia to hypoxia/sham hypoxia were calculated, and changes were averaged for each of the 15 sessions and for each week. Changes in arterial oxygen saturation were significantly different between groups in the course of the 3 weeks (two-way analysis of variance for repeated measures), with post hoc differences in weeks 1, 2, and 3. During the course of the intermittent hypoxia application, no between-group differences were detected for blood pressure or rate pressure product values. Changes in heart rate were significantly different between groups in the course of the 3 weeks (two-way analysis of variance for repeated measures), with post hoc differences only in week 3. Averages over all 15 sessions were significantly higher in the hypoxia group for heart rate and rate pressure product, and tended to be increased for systolic blood pressure. The applied intermittent hypoxia breathing program resulted in specific and moderate heart rate and blood pressure responses, and did not provoke a progressive increase in blood pressure during the hypoxic cycles in the course of the application.

  13. Effect of Angelica sinensis on neural stem cell proliferation in neonatal rats following intrauterine hypoxia

    Institute of Scientific and Technical Information of China (English)

    Hesheng Yue; Xudong Chen; Xiaoming Zhong; Hong Yu

    2008-01-01

    BACKGROUND:Angelica sinensis is a widely used herb in Chinese traditional medicine.It has been shown to improve hypoxia in embryonic rats and reduce nestin expression in neural stem cells,resulting in proliferation of neural stem cells.OBJECTIVE:To study the protective effect of Angelica on neural stem cell proliferation in neonatal rats after intrauterine hypoxia.DESIGN,TIME AND SETTING:The randomized,controlled,experiment was performed at the Department of Histology and Embryology,Luzhou Medical College,China from July 2007 to January 2008.MATERIALS:Because gestational days 14-15 are a key stage in rat nervous system development,21 healthy,pregnant Sprague Dawley rats(14 days after conception)were used for this study.Nestin monoclonal primary antibody was obtained from Chemicon,USA.Angelica parenteral solution(250 g/L)was obtained from Pharmaceutical Preparation Section,Second Affiliated Hospital of Wuhan University,China.METHODS:Rats were randomly divided into a control group(n=5),a hypoxia group(n=8),and an Angelica group(n=8).Saline(8 mL/kg)was injected into the caudal vein of rats in the hypoxia group once a day for seven consecutive days.Intrauterine hypotonic hypoxia was induced using 13% O2 for two hours per day on three consecutive days.Rats in the Angelica group received injections of Angelica parenteral solution(250 g/L);all other protocols were the same as the hypoxia group.The control group procedures were identical to the hypoxia group,but under normal,non-hypoxic conditions.After birth,brain tissues were immediately obtained from neonatal rats and prepared for nestin immunohistochemistry.MAIN OUTCOME MEASURES:Nestin-positive cells in hippocampal CA3 area of neonatal rats in each group were quantified using image analysis to detect signal absorbance.RESULTS:The number of nestin-positive cells increased in the hippocampal CA3 area of neonatal rats in the hypoxia group.The number of nestin-positive cells was less in the Angelica group than in the

  14. Dendritic development of hippocampal CA1 pyramidal cells in a neonatal hypoxia-ischemia injury model.

    Science.gov (United States)

    Zhao, Yan Dong; Ou, Shan; Cheng, Sai Yu; Xiao, Zhi; He, Wen Juan; Zhang, Jin Hai; Ruan, Huai Zhen

    2013-09-01

    It is believed that neonatal hypoxia-ischemia (HI) brain injury causes neuron loss and brain functional defects. However, the effect of HI brain injury on dendritic development of the remaining pyramidal cells of the hippocampus and the reaction of contralateral hippocampal neurons require further studies. The Morris water maze and Golgi-Cox staining were used to evaluate the learning and memory and dendritic morphology of pyramidal cells. The results of Golgi-Cox staining showed CA1 pyramidal neurons of HI injury models with fewer bifurcations and shorter dendrite length than the naive control group. The density of dendritic spines of hippocampal CA1 pyramidal neurons was significantly lower in the HI brain injury group than in controls. With respect to hippocampal function, the HI brain injury group presented cognitive deficits in the reference memory task and probe trail. In the HI group, the pyramidal cells of left hippocampus that did not experienced ischemia but did experience hypoxia had more complex dendrites and higher density of spine than the HI injury side and control. The functional implementation of injured hippocampus might depend mainly on the hypertrophy of contralateral hippocampus after HI brain injury. Corticosterone can partially prevent the hippocampal pyramidal cells from HI injury and reduce the difference of the bilateral hippocampus pyramidal cells, but there was no improvement in learning and memory.

  15. Protective effect of astrocyte-conditioned medium on neurons following hypoxia and mechanical injury

    Directory of Open Access Journals (Sweden)

    YAN Ji-wen

    2013-02-01

    Full Text Available 【Abstract】Objective: To investigate the protec-tive effect of mouse astrocyte-conditioned medium (ACM on hypoxic and mechanically injured neurons by a cell model in vitro, and to explore the possible mechanism. Methods: The model of hypoxic neuronal injury was caused by 3% O 2 in three-gas incubator. Neurons were cul-tured with ordinary medium or 20% ACM respectively and randomly divided into hypoxic group (hypoxia for 4, 8, 24 h and marked as H4R0, H8R0, H24R0 and hypoxia reoxygenation group (H4R24, H8R24, H24R24. Mechanical injury model was developed by scratching neurons cultured in 20% ACM or ordinary medium to different degrees. Neu-rons in both medium were divided into normal control group, mild, moderate and severe injury groups. The 20% ACM was added 24 h before hypoxia/reoxygenation or mechanical injury. The morphology and survival of neurons were observed and counted by trypan blue staining. The concentration of NO, lactic dehydrogenase (LDH and membrane ATPase activity were detected by corresponding kits. Results: It was showed that 20% ACM can obviously promote the survival rate of hypoxia/reoxygenated neurons and scratched neurons as well. The morphology and num-ber of neurons exposed to hypoxia or scratch injury showed great difference between groups with or without ACM treatment. Compared with control group, the concentration of NO and LDH was much lower in hypoxic/reoxygenated neurons treated with 20% ACM, and the ATPase activity was higher. For the mechanical injury model, neurons with moderate injury also revealed a lower NO and LDH concen-tration than the control group. All the differences were sta-tistically significant (P<0.05. Conclusion: ACM can promote the survival and func-tional recovery of neurons following hypoxia or scratching to a certain degree. The mechanism may be associated with reducing the synthesis and release of NO and LDH as well as increasing the activity of membrane ATPase. Key words: Glial cell line

  16. Hypoxic stress up-regulates Kir2.1 expression and facilitates cell proliferation in brain capillary endothelial cells

    Energy Technology Data Exchange (ETDEWEB)

    Yamamura, Hideto; Suzuki, Yoshiaki; Yamamura, Hisao [Department of Molecular & Cellular Pharmacology, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya (Japan); Asai, Kiyofumi [Department of Molecular Neurobiology, Graduate School of Medical Sciences, Nagoya City University, Nagoya (Japan); Imaizumi, Yuji, E-mail: yimaizum@phar.nagoya-cu.ac.jp [Department of Molecular & Cellular Pharmacology, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya (Japan)

    2016-08-05

    The blood-brain barrier (BBB) is mainly composed of brain capillary endothelial cells (BCECs), astrocytes and pericytes. Brain ischemia causes hypoxic encephalopathy and damages BBB. However, it remains still unclear how hypoxia affects BCECs. In the present study, t-BBEC117 cells, an immortalized bovine brain endothelial cell line, were cultured under hypoxic conditions at 4–5% oxygen for 72 h. This hypoxic stress caused hyperpolarization of resting membrane potential. Patch-clamp recordings revealed a marked increase in Ba{sup 2+}-sensitive inward rectifier K{sup +} current in t-BBEC117 cells after hypoxic culture. Western blot and real-time PCR analyses showed that Kir2.1 expression was significantly up-regulated at protein level but not at mRNA level after the hypoxic culture. Ca{sup 2+} imaging study revealed that the hypoxic stress enhanced store-operated Ca{sup 2+} (SOC) entry, which was significantly reduced in the presence of 100 μM Ba{sup 2+}. On the other hand, the expression of SOC channels such as Orai1, Orai2, and transient receptor potential channels was not affected by hypoxic stress. MTT assay showed that the hypoxic stress significantly enhanced t-BBEC117 cell proliferation, which was inhibited by approximately 60% in the presence of 100 μM Ba{sup 2+}. We first show here that moderate cellular stress by cultivation under hypoxic conditions hyperpolarizes membrane potential via the up-regulation of functional Kir2.1 expression and presumably enhances Ca{sup 2+} entry, resulting in the facilitation of BCEC proliferation. These findings suggest potential roles of Kir2.1 expression in functional changes of BCECs in BBB following ischemia. -- Highlights: •Hypoxic culture of brain endothelial cells (BEC) caused membrane hyperpolarization. •This hyperpolarization was due to the increased expression of Kir2.1 channels. •Hypoxia enhanced store-operated Ca{sup 2+} (SOC) entry via Kir2.1 up-regulation. •Expression levels of putative SOC

  17. Hypoxia inducible factor 1α promotes survival of mesenchymal stem cells under hypoxia

    Science.gov (United States)

    Lv, Bingke; Li, Feng; Fang, Jie; Xu, Limin; Sun, Chengmei; Han, Jianbang; Hua, Tian; Zhang, Zhongfei; Feng, Zhiming; Jiang, Xiaodan

    2017-01-01

    Mesenchymal stem cells (MSCs) are ideal materials for cell therapy. Research has indicated that hypoxia benefits MSC survival, but little is known about the underlying mechanism. This study aims to uncover potential mechanisms involving hypoxia inducible factor 1α (HIF1A) to explain the promoted MSC survival under hypoxia. MSCs were obtained from Sprague-Dawley rats and cultured under normoxia or hypoxia condition. The overexpression vector or small interfering RNA of Hif1a gene was transfected to MSCs, after which cell viability, apoptosis and expression of HIF1A were analyzed by MTT assay, flow cytometry, qRT-PCR and Western blot. Factors in p53 pathway were detected to reveal the related mechanisms. Results showed that hypoxia elevated MSCs viability and up-regulated HIF1A (P cell CLL/lymphoma 2 (BCL2) expression had the opposite pattern (P cell therapy.

  18. Hypoxia-on-a-chip

    Directory of Open Access Journals (Sweden)

    Busek Mathias

    2016-09-01

    Full Text Available In this work a microfluidic cell cultivation device for perfused hypoxia assays as well as a suitable controlling unit are presented. The device features active components like pumps for fluid actuation and valves for fluid direction as well as an oxygenator element to ensure a sufficient oxygen transfer. It consists of several individually structured layers which can be tailored specifically to the intended purpose. Because of its clearness, its mechanical strength and chemical resistance as well as its well-known biocompatibility polycarbonate was chosen to form the fluidic layers by thermal diffusion bonding. Several oxygen sensing spots are integrated into the device and monitored with fluorescence lifetime detection. Furthermore an oxygen regulator module is implemented into the controlling unit which is able to mix different process gases to achieve a controlled oxygenation. First experiments show that oxygenation/deoxygenation of the system is completed within several minutes when pure nitrogen or air is applied to the oxygenator. Lastly the oxygen input by the pneumatically driven micro pump was quantified by measuring the oxygen content before and after the oxygenator.

  19. 自愿适量运动对脑的有益作用及其生物学机制%Beneficial effects of moderate voluntary physical exercise and its biological mechanisms on brain health

    Institute of Scientific and Technical Information of China (English)

    马强

    2008-01-01

    本文综述了在人和动物方面有关自愿适量运动有益于脑作用的研究,包括改善心理状态和认知功能、增强心理幸福感、降低老年痴呆症发生危险度和发挥抗抑郁及抗焦虑药的作用等.运动对脑的作用机制包含上游和下游两方面:上游途径主要涉及投射到海马的几种神经递质系统的功能增强,其中包括去甲肾上腺素、5.羟色胺、乙酰胆碱和γ-氨基丁酸;下游途径主要涉及脑源性神经营养因子的表达提高和神经元发生的增强;其中,激活β-受体介导的去甲肾上腺素能神经的传递被认为是运动导致脑源性神经营养因子表达增强的前提,上述过程在细胞内的可能信号转导机制主要涉及G-蛋白偶联受体-促分裂原活化蛋白激酶-磷脂酰肌醇(-3)激酶等细胞信号转导通路的交互及正反馈调控.%This article reviewed the beneficial effects of moderate voluntary physical exercise on brain health according to the studies on humans and animals, which includes improving psychological status and cognitive function, enhancing psycho- logical well-being, decreasing the risks of Alzheimer's disease (AD) and dementia, and promoting the effects of antidepressant and anxiolytic. The possible underlying neurobiological mechanisms are involved up-active and down-active pathways. The up-active pathway is associated with enhancements of several neurotransmitters systems afferent to hippocampus, including norepinephrine (NE), serotonin (5-Hydroxytryptamine, 5-HT), acetylcholine (ACh) and γ-aminobutyric acid (GABA). The down-active pathway is mainly concerned with up-regulation of the brain-derived neurotrophic factor (BDNF) and neurogenesis. It is suggested that NE activation via β-adrenergic receptors may be essential for exercise-induced BDNF up-regulation. The possible intraceUular signaling pathways of NE-mediated BDNF up-expression may be involved in GPCR-MAPK-PI-3K crosstalk and positive feedback.

  20. Enhanced hypoxia-inducible factor (HIF)-1α stability induced by 5-hydroxymethyl-2-furfural (5-HMF) contributes to protection against hypoxia.

    Science.gov (United States)

    He, Yun-Ling; Li, Ming-Ming; Wu, Li-Ying; Zhao, Tong; Di, Yao; Huang, Xin; Ding, Xue-Feng; Wu, Kui-Wu; Fan, Ming; Zhu, Ling-Ling

    2014-01-01

    We first reported the role of 5-hydroxymethyl-2-furfural (5-HMF) against hypoxia. Here, we studied the mechanism by using oxygen-dependent degradation domain (ODD)-Luc mice, which are a useful model to probe the stabilization of hypoxia-inducible factor 1α (HIF-1α). Compared with three other compounds that have been reported to have a role in stabilizing HIF-1α, 5-HMF caused stronger bioluminescence, which is indicative of HIF-1α stability in the brain and kidney of ODD-Luc mice. We further demonstrated that the HIF-1α protein accumulated in response to 5-HMF in the brains and kidneys of these mice, as well as in PC12 cells. Additionally, 5-HMF promoted the nuclear translocation of HIF-1α and the transcriptional activity of HIF-1, which was evaluated by detecting vascular endothelial growth factor (VEGF ) mRNA expression. These results suggest that 5-HMF stabilized HIF-1α and increased its activity. Considering the role of proline hydroxylases (PHDs) in negatively regulating HIF-1α stability, we explored whether 5-HMF interacts with the substrates and cofactors of PHDs, such as 2-oxoglutarate (2-OG), Fe(2+) and vitamin C (VC), which affects the activity of PHDs. The result revealed that 5-HMF did not interact with Fe(2+) or 2-OG but interacted with VC. This interaction was confirmed by subsequent experiments, in which 5-HMF entered into cells and reduced the VC content. The enhanced stability of HIF-1α by 5-HMF was reversed by VC supplementation, and the improved survival of mice caused by 5-HMF under hypoxia was abrogated by VC supplementation. Thus, we demonstrated for the first time that 5-HMF increases HIF-1α stability by reducing the VC content, which mediates the protection against hypoxia.

  1. Bacopa monniera leaf extract ameliorates hypobaric hypoxia induced spatial memory impairment.

    Science.gov (United States)

    Hota, Sunil Kumar; Barhwal, Kalpana; Baitharu, Iswar; Prasad, Dipti; Singh, Shashi Bala; Ilavazhagan, Govindasamy

    2009-04-01

    Hypobaric hypoxia induced memory impairment has been attributed to several factors including increased oxidative stress, depleted mitochondrial bioenergetics, altered neurotransmission and apoptosis. This multifactorial response of the brain to hypobaric hypoxia limits the use of therapeutic agents that target individual pathways for ameliorating hypobaric hypoxia induced memory impairment. The present study aimed at exploring the therapeutic potential of a bacoside rich leaf extract of Bacopa monniera in improving the memory functions in hypobaric conditions. The learning ability was evaluated in male Sprague Dawley rats along with memory retrieval following exposure to hypobaric conditions simulating an altitude of 25,000 ft for different durations. The effect of bacoside administration on apoptosis, cytochrome c oxidase activity, ATP levels, and oxidative stress markers and on plasma corticosterone levels was investigated. Expression of NR1 subunit of N-methyl-d-aspartate receptors, neuronal cell adhesion molecules and was also studied along with CREB phosphorylation to elucidate the molecular mechanisms of bacoside action. Bacoside administration was seen to enhance learning ability in rats along with augmentation in memory retrieval and prevention of dendritic atrophy following hypoxic exposure. In addition, it decreased oxidative stress, plasma corticosterone levels and neuronal degeneration. Bacoside administration also increased cytochrome c oxidase activity along with a concomitant increase in ATP levels. Hence, administration of bacosides could be a useful therapeutic strategy in ameliorating hypobaric hypoxia induced cognitive dysfunctions and other related neurological disorders.

  2. [Effects of palmitic acid on activity of uncoupling proteins and proton leak in in vitro cerebral mitochondria from the rats exposed to simulated high altitude hypoxia].

    Science.gov (United States)

    Xu, Yu; Liu, Jun-Ze; Xia, Chen

    2008-02-25

    To reveal the roles of uncoupling proteins (UCPs) in disorder of mitochondrial oxidative phosphorylation induced by free fatty acid during hypoxic exposure, the effects of palmitic acid on activity of UCPs, proton leak and mitochondrial membrane potential in hypoxia-exposed rat brain mitochondria were observed in vitro. Adult Sprague-Dawley (SD) rats were set randomly into control, acute hypoxia and chronic hypoxia groups (n=8 in each group). The acute and chronic hypoxic rats were exposed to simulated 5000 m high altitude in a hypobaric chamber 23 h/d for 3 d and 30 d, respectively. The brain mitochondria were isolated by centrifugation. UCP content and activity were detected by [(3)H]-GTP binding method. The proton leak was measured by TPMP(+) electrode and oxygen electrode. The membrane potential of mitochondria was calculated by detecting the fluorescence from Rodamine 123. Hypoxic exposure resulted in an increase in UCP activity and content as well as proton leak, but a decrease in the membrane potential of rat brain mitochondria. Palmitic acid resulted in further increases in UCP activity and content as well as proton leak, and further decrease in membrane potential of brain mitochondria in vitro from hypoxia-exposed rats, but hypoxic exposure decreased the reactivity of cerebral mitochondria to palmitic acid, especially in the acute hypoxia group. There was a negative correlation between mitochondrial proton leak and K(d) value (representing derivative of UCP activity, PB(max) (representing the maximal content of UCPs in mitochondrial inner membrane, P<0.01, r = 0.856). Cerebral mitochondrial membrane potential was negatively correlated with proton leak (P<0.01, r = -0.880). It is suggested that hypoxia-induced proton leak enhancement and membrane potential decrease are correlated with the increased activity of UCPs. Hypoxia can also decrease the sensitivity of cerebral mitochondria to palmitic acid, which may be a self-protective mechanism in high altitude

  3. Hypoxia-induced angiogenesis: good and evil.

    Science.gov (United States)

    Krock, Bryan L; Skuli, Nicolas; Simon, M Celeste

    2011-12-01

    The vascular network delivers oxygen (O(2)) and nutrients to all cells within the body. It is therefore not surprising that O(2) availability serves as a primary regulator of this complex organ. Most transcriptional responses to low O(2) are mediated by hypoxia-inducible factors (HIFs), highly conserved transcription factors that control the expression of numerous angiogenic, metabolic, and cell cycle genes. Accordingly, the HIF pathway is currently viewed as a master regulator of angiogenesis. HIF modulation could provide therapeutic benefit for a wide array of pathologies, including cancer, ischemic heart disease, peripheral artery disease, wound healing, and neovascular eye diseases. Hypoxia promotes vessel growth by upregulating multiple pro-angiogenic pathways that mediate key aspects of endothelial, stromal, and vascular support cell biology. Interestingly, recent studies show that hypoxia influences additional aspects of angiogenesis, including vessel patterning, maturation, and function. Through extensive research, the integral role of hypoxia and HIF signaling in human disease is becoming increasingly clear. Consequently, a thorough understanding of how hypoxia regulates angiogenesis through an ever-expanding number of pathways in multiple cell types will be essential for the identification of new therapeutic targets and modalities.

  4. Preparation and Preservation of Hypoxia UW Solution

    Institute of Scientific and Technical Information of China (English)

    WAN Chidang; WANG Chunyou; LIU Tan; CHENG Rui; YANG Zhiyong

    2007-01-01

    In order to explore the method to prepare hypoxia UW solution and the stability and preservation of hypoxia UW solution, UW solution was purged by argon or air for 15 min or 60 at a flow rate of 0.8 or 2 L/min, and the oxygen partial pressure of UW solution was detected. The hy-poxia UW solution was exposed to the air or sealed up to preserve by using different methods, and the changes of oxygen partial pressure was tested. The results showed that oxygen partial pressure of 50 mL UW solution, purged by argon for 15 min at a flow rate of 2 L/min, was declined from 242±6 mmHg to 83±10 mmHg. After exposure to the air, oxygen partial pressure of hypoxia UW solution was gradually increased to 160±7 mmHg at 48 h. After sealed up by the centrifuge tube and plastic bad filled with argon, oxygen partial pressure of hypoxia UW solution was stable, about 88±13 mmHg at 72 h. It was concluded that oxygen of UW solution could be purged by argon efficiently. Sealed up by the centrifuge tube and plastic bag filled with argon, oxygen partial pressure of UW so- lution could be stabilized.

  5. Hypoxia Inhibits Hypertrophic Differentiation and Endochondral Ossification in Explanted Tibiae

    NARCIS (Netherlands)

    Leijten, Jeroen Christianus Hermanus; Moreira Teixeira, Liliana; Landman, Ellie; van Blitterswijk, Clemens; Karperien, Hermanus Bernardus Johannes

    2012-01-01

    Purpose: Hypertrophic differentiation of growth plate chondrocytes induces angiogenesis which alleviates hypoxia normally present in cartilage. In the current study, we aim to determine whether alleviation of hypoxia is merely a downstream effect of hypertrophic differentiation as previously

  6. Hypoxia-regulated target genes implicated in tumor metastasis

    Directory of Open Access Journals (Sweden)

    Tsai Ya-Ping

    2012-12-01

    Full Text Available Abstract Hypoxia is an important microenvironmental factor that induces cancer metastasis. Hypoxia/hypoxia-inducible factor-1α (HIF-1α regulates many important steps of the metastatic processes, especially epithelial-mesenchymal transition (EMT that is one of the crucial mechanisms to cause early stage of tumor metastasis. To have a better understanding of the mechanism of hypoxia-regulated metastasis, various hypoxia/HIF-1α-regulated target genes are categorized into different classes including transcription factors, histone modifiers, enzymes, receptors, kinases, small GTPases, transporters, adhesion molecules, surface molecules, membrane proteins, and microRNAs. Different roles of these target genes are described with regards to their relationship to hypoxia-induced metastasis. We hope that this review will provide a framework for further exploration of hypoxia/HIF-1α-regulated target genes and a comprehensive view of the metastatic picture induced by hypoxia.

  7. Neuroprotection via RNA-binding protein RBM3 expression is regulated by hypothermia but not by hypoxia in human SK-N-SH neurons

    Directory of Open Access Journals (Sweden)

    Rosenthal LM

    2017-05-01

    Full Text Available Lisa-Maria Rosenthal,1 Giang Tong,1 Christoph Walker,1 Sylvia J Wowro,1 Jana Krech,1 Constanze Pfitzer,1,2 Georgia Justus,1 Felix Berger,1,3 Katharina Rose Luise Schmitt1 1Department of Congenital Heart Disease/Pediatric Cardiology, German Heart Institute Berlin, 2Berlin Institute of Health (BIH, 3Department of Pediatric Cardiology, Charité – University Medical Center, Berlin, Germany Objective: Therapeutic hypothermia is an established treatment for perinatal asphyxia. Yet, many term infants continue to die or suffer from neurodevelopmental disability. Several experimental studies have demonstrated a beneficial effect of mild-to-moderate hypothermia after hypoxic injury, but the understanding of hypothermia-induced neuroprotection remains incomplete. In general, global protein synthesis is attenuated by hypothermia, but a small group of RNA-binding proteins including the RNA-binding motif 3 (RBM3 is upregulated in response to cooling. The aim of this study was to establish an in vitro model to investigate the effects of hypoxia and hypothermia on neuronal cell survival, as well as to examine the kinetics of concurrent cold-shock protein RBM3 gene expression. Methods: Experiments were performed by using human SK-N-SH neurons exposed to different oxygen concentrations (21%, 8%, or 0.2% O2 for 24 hours followed by moderate hypothermia (33.5°C or normothermia for 24, 48, or 72 hours. Cell death was determined by quantification of lactate dehydrogenase and neuron-specific enolase releases into the cell cultured medium, and cell morphology was assessed by using immunofluorescence staining. The regulation of RBM3 gene expression was assessed by reverse transcriptase-quantitative polymerase chain reaction and Western blot analysis.Results: Exposure to hypoxia (0.2% O2 for 24 hours resulted in significantly increased cell death in SK-N-SH neurons, whereas exposure to 8% O2 had no significant impact on cell viability. Post-hypoxia treatment with

  8. Rat reaction to hypokinesia after prior adaptation to hypoxia

    Science.gov (United States)

    Barashova, Z. I.; Tarakanova, O. I.

    1980-01-01

    The effect of prior hypoxia adaptation on body tolerance to hypokinesia was investigated. Rats trained to a 50 day period of hypokinesia and hypoxia with a preliminary month of adaptation to hypoxia showed less weight loss, higher indices for red blood content, heightened reactivity of the overall organism and the central nervous system to acute hypoxia, and decreased modification of the skeletal muscles compared to rats subjected to hypokinesia alone.

  9. Analysis of hypoxia and hypoxia-like states through metabolite profiling.

    Directory of Open Access Journals (Sweden)

    Julie E Gleason

    Full Text Available BACKGROUND: In diverse organisms, adaptation to low oxygen (hypoxia is mediated through complex gene expression changes that can, in part, be mimicked by exposure to metals such as cobalt. Although much is known about the transcriptional response to hypoxia and cobalt, little is known about the all-important cell metabolism effects that trigger these responses. METHODS AND FINDINGS: Herein we use a low molecular weight metabolome profiling approach to identify classes of metabolites in yeast cells that are altered as a consequence of hypoxia or cobalt exposures. Key findings on metabolites were followed-up by measuring expression of relevant proteins and enzyme activities. We find that both hypoxia and cobalt result in a loss of essential sterols and unsaturated fatty acids, but the basis for these changes are disparate. While hypoxia can affect a variety of enzymatic steps requiring oxygen and heme, cobalt specifically interferes with diiron-oxo enzymatic steps for sterol synthesis and fatty acid desaturation. In addition to diiron-oxo enzymes, cobalt but not hypoxia results in loss of labile 4Fe-4S dehydratases in the mitochondria, but has no effect on homologous 4Fe-4S dehydratases in the cytosol. Most striking, hypoxia but not cobalt affected cellular pools of amino acids. Amino acids such as aromatics were elevated whereas leucine and methionine, essential to the strain used here, dramatically decreased due to hypoxia induced down-regulation of amino acid permeases. CONCLUSIONS: These studies underscore the notion that cobalt targets a specific class of iron proteins and provide the first evidence for hypoxia effects on amino acid regulation. This research illustrates the power of metabolite profiling for uncovering new adaptations to environmental stress.

  10. Overexpression of Hypoxia-Inducible Factor-1α Exacerbates Endothelial Barrier Dysfunction Induced by Hypoxia

    Directory of Open Access Journals (Sweden)

    Pei Wang

    2013-09-01

    Full Text Available Background/Aims: The mechanisms involved in endothelial barrier dysfunction induced by hypoxia are incompletely understood. There is debate about the role of hypoxia-inducible factor-1α (HIF-1α in endothelial barrier disruption. The aim of this study was to investigate the effect of genetic overexpression of HIF-1α on barrier function and the underlying mechanisms in hypoxic endothelial cells. Methods: The plasmid pcDNA3.1/V5-His-HIF-1α was stably transfected into human endothelial cells. The cells were exposed to normoxia or hypoxia. The mRNA and protein expressions of HIF-1α were detected by RT-PCR and Western blot respectively. The barrier function was assessed by measuring the transendothelial electrical resistance (TER. The Western blot analysis was used to determine the protein expression of glucose transporter-1 (GLUT-1, zonular occludens-1 (ZO-1, occludin, and myosin light chain kinase (MLCK in endothelial cells. The mRNA expression of proinflammatory cytokines was detected by qRT-PCR. Results: Genetic overexpression of HIF-1α significantly increased the mRNA and protein expression of HIF-1α in endothelial cells. The overexpression of HIF-1α enhanced the hypoxia-induced increase of HIF-1α and GLUT-1 protein expression. HIF-1α overexpression not only exacerbated hypoxia-induced endothelial barrier dysfunction but also augmented hypoxia-induced up-regulation of MLCK protein expression. HIF-1α overexpression also enhanced IL-1β, IL-6 and TNF-α mRNA expression. Conclusion: We provide evidence that genetic overexpression of HIF-1α aggravates the hypoxia-induced endothelial barrier dysfunction via enhancing the up-regulation of MLCK protein expression caused by hypoxia, suggesting a potential role for HIF-1α in the pathogenesis of endothelial barrier dysfunction in hypoxia.

  11. Protective effect of salidroside on cardiac apoptosis in mice with chronic intermittent hypoxia.

    Science.gov (United States)

    Lai, Mei-Chih; Lin, Jaung-Geng; Pai, Pei-Ying; Lai, Mei-Hsin; Lin, Yueh-Min; Yeh, Yu-Lan; Cheng, Shiu-Min; Liu, Yi-fan; Huang, Chih-Yang; Lee, Shin-Da

    2014-07-01

    The goal of this study is to determine if salidroside has protective effects on hypoxia-induced cardiac widely dispersed apoptosis in mice with severe sleep apnea model. Sixty-four C57BL/6J mice 5-6 months of age were divided into four groups, i.e. Control group (21% O2, 24h per day, 8 weeks, n=16); Hypoxia group (Hypoxia: 7% O2 60s, 20% O2 alternating 60s, 8h per day, 8 weeks, n=16); and Hypoxia+S10 and Hypoxia+S 30 groups (Hypoxia for 1st 4 weeks, hypoxia pretreated 10mg/kg and 30 mg/kg salidroside by oral gavage per day for 2nd 4 weeks, n=16 and 16). The excised hearts from four groups were measured by the heart weight index, H&E staining, TUNEL-positive assays and Western blotting. TUNEL-positive apoptotic cells in mice heart were less in Hypoxia+S10 and Hypoxia+S30 than those in the Hypoxia group. Compared with Hypoxia, the protein levels of Fas ligand, Fas death receptors, Fas-Associated Death Domain (FADD), activated caspase 8, and activated caspase 3 (Fas pathways) were decreased in Hypoxia+S10 and Hypoxia+S30. In the mitochondria pathway, the protein levels of BcLx, Bcl2, and Bid (anti-apoptotic Bcl2 family) in Hypoxia+S10 and Hypoxia+S30 were more than those in Hypoxia. The protein levels of Bax, t-Bid, activated caspase 9, and activated caspase 3 were less in Hypoxia+S10 and Hypoxia+S30 than those in hypoxia. Our findings suggest that salidroside has protective effects on chronic intermittent hypoxia-induced Fas-dependent and mitochondria-dependent apoptotic pathways in mice hearts. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  12. Pheochromocytomas: the (pseudo)-hypoxia hypothesis.

    Science.gov (United States)

    Favier, Judith; Gimenez-Roqueplo, Anne-Paule

    2010-12-01

    Hypoxia and pheochromocytoma/paraganglioma have a long common history. Since the description, almost 40 years ago, of an increased incidence of head and neck paragangliomas in chronic hypoxia, discoveries on oxygen-sensing and on hereditary paraganglioma in the beginning of years 2000 provided the proof of concept of a strong link between these neuroendocrine tumors and the hypoxic pathway. It was demonstrated that both SDH and VHL genes mutations lead to the abnormal stabilization and activation of hypoxia-inducible factors, and to the subsequent regulation of multiple target genes, the products of which are implicated in proliferation, apoptosis, angiogenesis, energy metabolism or invasiveness and metastases. Altogether, physiological, genetic, cellular and molecular data collected over years all point to a central role of the hypoxic or pseudohypoxic pathway in pheochromocytoma and paraganglioma tumorigenesis. 2010 Elsevier Ltd. All rights reserved.

  13. Hypoxia tolerance, nitric oxide, and nitrite

    DEFF Research Database (Denmark)

    Fago, Angela; Jensen, Frank Bo

    2015-01-01

    Among vertebrates able to tolerate periods of oxygen deprivation, the painted and red-eared slider turtles (Chrysemys picta and Trachemys scripta) and the crucian carp (Carassius carassius) are the most extreme and can survive even months of total lack of oxygen during winter. The key to hypoxia ...... of NO and nitrite signaling in the adaptive response to hypoxia in vertebrate animals....... survival resides in concerted physiological responses, including strong metabolic depression, protection against oxidative damage and – in air breathing animals - redistribution of blood flow. Each of these responses is known to be tightly regulated by nitric oxide (NO) and during hypoxia by its metabolite...... nitrite. The aim of this review is to highlight recent work illustrating the widespread roles of NO and nitrite in the tolerance to extreme oxygen deprivation, in particular in the red-eared slider turtle and crucian carp, but also in diving marine mammals. The emerging picture underscores the importance...

  14. Hypoxia-induced 15-HETE enhances the constriction of internal carotid arteries by down-regulating potassium channels.

    Science.gov (United States)

    Zhu, Yanmei; Chen, Li; Liu, Wenjuan; Wang, Weizhi; Zhu, Daling; Zhu, Yulan

    2010-08-15

    Severe hypoxia induces the constriction of internal carotid arteries (ICA), which worsens ischemic stroke in the brain. A few metabolites are presumably involved in hypoxic vasoconstriction, however, less is known about how such molecules provoke this vasoconstriction. We have investigated the influence of 15-hydroxyeicosatetrienoic acid (15-HETE) produced by 15-lipoxygenase (15-LOX) on vasoconstriction during hypoxia. As showed in our results, 15-LOX level increases in ICA endothelia and smooth muscles. 15-HETE enhances the tension of ICA ring in a dose-dependent manner, as well as attenuates the activities and expression of voltage-gated potassium channels (Kv 1.5 and Kv 2.1). Therefore, the down-regulation of Kv channels by 15-HETE during hypoxia may weaken the repolarization of action potentials and causes a dominant influx of calcium ions to enhance smooth muscle tension and ICA constriction.

  15. REACTOR MODERATOR STRUCTURE

    Science.gov (United States)

    Greenstreet, B.L.

    1963-12-31

    A system for maintaining the alignment of moderator block structures in reactors is presented. Integral restraining grids are placed between each layer of blocks in the moderator structure, at the top of the uppermost layer, and at the bottom of the lowermost layer. Slots are provided in the top and bottom surfaces of the moderator blocks so as to provide a keying action with the grids. The grids are maintained in alignment by vertical guiding members disposed about their peripheries. (AEC)

  16. [Reactive microglial changes in rat neocortex and hippocampus after exposure to acute perinatal hypoxia].

    Science.gov (United States)

    Khozhaĭ, L I; Otellin, V A

    2013-01-01

    The dynamics of reactive changes of a population density of microglial cells and the reversibility of their phenotypic forms were studied in the brain of neonatal rats at different time intervals after 1 hr-long exposure to acute normobaric hypoxia in the pressure chamber at the second postnatal day. Different areas of the neocortex (frontal, motor, somatosensory and visual) and of the hippocampus (CAI, CA3, CA4 and fascia dentata) were examined 1 hr, 3 hrs, 1 and 5 days after exposure to hypoxia. Microglial cells were demonstrated using an immunocytochemical staining with the monoclonal antibodies against Iba- 1 antigen. The results have shown that the reaction of microglia to acute hypoxia in both the neocortex and the hippocampus of the new-borns developed simultaneously and synchronously with the augmentation of cell death. The increase of a population density of amoeboid form of microglial cells in the brain areas studied was recorded already after 1 hour as a result of their migration from the subventricular region and the areas adjacent to large vessels from where they practically disappeared. The number of amoeboid microglial cells in this area has recovered rather quickly (in 3 hrs). The population densify of microglial cells, especially of amoeboid forms, sharply increased with the augmentation of cell death and remained unchanged for about 5 days.

  17. The induction of tuftelin expression in PC12 cell line during hypoxia and NGF-induced differentiation.

    Science.gov (United States)

    Leiser, Yoav; Silverstein, Nechama; Blumenfeld, Anat; Shilo, Dekel; Haze, Amir; Rosenfeld, Eli; Shay, Boaz; Tabakman, Rinat; Lecht, Shimon; Lazarovici, Philip; Deutsch, Dan

    2011-01-01

    The tuftelin protein isoforms undergo post-translation modifications, and are ubiquitously expressed in various tissues in embryos, adults, and tumors. Developmental and pathological studies suggested an apparent correlation between oxygen deprivation and tuftelin expression. The aim of the study was therefore to investigate the effect of a pathological insult (hypoxia) and a physiological growth factor (NGF), which antagonistically regulate HIF1 expression, on tuftelin expression using the neuronal PC12 cell model. In the present study, we first demonstrated the expression of tuftelin in PC12 cells, providing an experimental system to investigate the pathophysiological role of tuftelin. Furthermore, we demonstrated the induction of tuftelin during hypoxia by oxygen deprivation and during chemical hypoxia by cobalt chloride. Down-regulation of HIF1α mRNA blocked hypoxia-induced HIF1α expression, and reduced by 89% hypoxia-induced tuftelin expression. In mice, intraperitoneal injection of cobalt chloride significantly induced tuftelin mRNA and protein expression in the brain. During NGF-mediated PC12 differentiation, tuftelin expression was significantly induced in correlation with neurite outgrowth. This induction was partially blocked by K252a, a selective antagonist of the NGF receptor TrkA, indicating the involvement of the TrkA-signaling pathways in tuftelin induction by NGF. Revealing the physiological role of tuftelin will clarify mechanisms related to the "hypoxic genome," and NGF-induced neurotrophic and angiogenic effects.

  18. Hypoxia/Aglycemia-induced endothelial barrier dysfunction and tight junction protein downregulation can be ameliorated by citicoline.

    Directory of Open Access Journals (Sweden)

    Xiaotang Ma

    Full Text Available This study explores the effect of citicoline on the permeability and expression of tight junction proteins (TJPs in endothelial cells under hypoxia/aglycemia conditions. Hypoxia or oxygen and glucose deprivation (OGD was utilized to induce endothelial barrier breakdown model on human umbilical vein endothelial cells (HUVECs and mouse brain microvascular endothelial cells (bEnd.3s. The effect of citicoline on endothelial barrier breakdown models was determined at either low or high concentrations. FITC-Dextran flux was used to examine the endothelial permeability. The expression of TJPs was measured by immunofluorescence, Real-time PCR and Western Blot methods. Results showed that hypoxia or OGD increased the permeability of HUVECs accompanied with down-regulation of occludens-1 (ZO-1 and occludin at both mRNA and protein levels. Similarly in bEnd.3s, hypoxia increased the permeability and decreased the expression of ZO-1 and claudin-5. Citicoline treatment dose-dependently decreased the permeability in these two models, which paralleled with elevated expression of TJPs. The data demonstrate that citicoline restores the barrier function of endothelial cells compromised by hypoxia/aglycemia probably via up-regulating the expression of TJPs.

  19. Hypoxia/Aglycemia-induced endothelial barrier dysfunction and tight junction protein downregulation can be ameliorated by citicoline.

    Science.gov (United States)

    Ma, Xiaotang; Zhang, Huiting; Pan, Qunwen; Zhao, Yuhui; Chen, Ji; Zhao, Bin; Chen, Yanfang

    2013-01-01

    This study explores the effect of citicoline on the permeability and expression of tight junction proteins (TJPs) in endothelial cells under hypoxia/aglycemia conditions. Hypoxia or oxygen and glucose deprivation (OGD) was utilized to induce endothelial barrier breakdown model on human umbilical vein endothelial cells (HUVECs) and mouse brain microvascular endothelial cells (bEnd.3s). The effect of citicoline on endothelial barrier breakdown models was determined at either low or high concentrations. FITC-Dextran flux was used to examine the endothelial permeability. The expression of TJPs was measured by immunofluorescence, Real-time PCR and Western Blot methods. Results showed that hypoxia or OGD increased the permeability of HUVECs accompanied with down-regulation of occludens-1 (ZO-1) and occludin at both mRNA and protein levels. Similarly in bEnd.3s, hypoxia increased the permeability and decreased the expression of ZO-1 and claudin-5. Citicoline treatment dose-dependently decreased the permeability in these two models, which paralleled with elevated expression of TJPs. The data demonstrate that citicoline restores the barrier function of endothelial cells compromised by hypoxia/aglycemia probably via up-regulating the expression of TJPs.

  20. Pharmacological Neuroprotection after Perinatal Hypoxic-Ischemic Brain Injury

    NARCIS (Netherlands)

    Fan, Xiyong; Kavelaars, Annemieke; Heijnen, Cobi J.; Groenendaal, Floris; van Bel, Frank

    2010-01-01

    Perinatal hypoxia-ischemia (HI) is an important cause of neonatal brain injury. Recent progress in the search for neuroprotective compounds has provided us with several promising drugs to reduce perinatal HI-induced brain injury. In the early stage (first 6 hours after birth) therapies are concentra

  1. Protective effect of astrocyte-conditioned medium on neurons following hypoxia and mechanical injury

    Institute of Scientific and Technical Information of China (English)

    YAN Ji-wen; TAN Tong-yan; HUANG Qi-lin

    2013-01-01

    Objective:To investigate the protective effect of mouse astrocyte-conditioned medium (ACM)on hypoxic and mechanically injured neurons by a cell model in vitro,and to explore the possible mechanism.Methods:The model of hypoxic neuronal injury was caused by 3% O2 in three-gas incubator.Neurons were cultured with ordinary medium or 20% ACM respectively and randomly divided into hypoxic group (hypoxia for 4,8,24 h and marked as H4R0,H8R0,H24R0) and hypoxia reoxygenation group (H4R24,HSR24,H24R24).Mechanical injury model was developed by scratching neurons cultured in 20% ACM or ordinary medium to different degrees.Neurons in both medium were divided into normal control group,mild,moderate and severe injury groups.The 20% ACM was added 24 h before hypoxia/reoxygenation or mechanical injury.The morphology and survival of neurons were observed and counted by trypan blue staining.The concentration of NO,lactic dehydrogenase (LDH) and membrane ATPase activity were detected by corresponding kits.Results:It was showed that 20% ACM can obviously promote the survival rate of hypoxia/reoxygenated neurons and scratched neurons as well The morphology and number of neurons exposed to hypoxia or scratch injury showed great difference between groups with or without ACM treatment.Compared with control group,the concentration of NO and LDH was much lower in hypoxic/reoxygenated neurons treated with 20% ACM,and the ATPase activity was higher.For the mechanical injury model,neurons with moderate injury also revealed a lower NO and LDH concentration than the control group.All the differences were statistically significant (P<0.05).Conclusion:ACM can promote the survival and functional recovery of neurons following hypoxia or scratching to a certain degree.The mechanism may be associated with reducing the synthesis and release of NO and LDH as well as increasing the activity of membrane ATPase.

  2. Human erythropoietin response to hypocapnic hypoxia, normocapnic hypoxia, and hypocapnic normoxia

    DEFF Research Database (Denmark)

    Klausen, T; Christensen, H; Hansen, J M

    1996-01-01

    This study investigated the human erythropoietin (EPO) response to short-term hypocapnic hypoxia, its relationship to a normoxic or hypoxic increase of the haemoglobin oxygen affinity, and its suppression by the addition of CO2 to the hypoxic gas. On separate days, eight healthy male subjects were...... (10% Co2 with 10% O2) to the hypoxic gas mixture. This elicited an increased ventilation, unaltered arterial pH and haemoglobin oxygen affinity, a lower degree of hypoxia than during hypocapnic hypoxia, and no significant changes in serum-EPO (ANOVA P > 0.05). Hypocapnic normoxia, produced...... by hyperventilation of room air, elicited a normoxic increase in the haemoglobin oxygen affinity without changing serum-EPO. Among the measured blood gas and acid-base parameters, only the partial pressures of oxygen in arterial blood during hypocapnic hypoxia were related to the peak values of serum-EPO (r = -0...

  3. Glucose and Intermediary Metabolism and Astrocyte-Neuron Interactions Following Neonatal Hypoxia-Ischemia in Rat.

    Science.gov (United States)

    Brekke, Eva; Berger, Hester Rijkje; Widerøe, Marius; Sonnewald, Ursula; Morken, Tora Sund

    2017-01-01

    Neonatal hypoxia-ischemia (HI) and the delayed injury cascade that follows involve excitotoxicity, oxidative stress and mitochondrial failure. The susceptibility to excitotoxicity of the neonatal brain may be related to the capacity of astrocytes for glutamate uptake. Furthermore, the neonatal brain is vulnerable to oxidative stress, and the pentose phosphate pathway (PPP) may be of particular importance for limiting this kind of injury. Also, in the neonatal brain, neurons depend upon de novo synthesis of neurotransmitters via pyruvate carboxylase in astrocytes to increase neurotransmitter pools during normal brain development. Several recent publications describing intermediary brain metabolism following neonatal HI have yielded interesting results: (1) Following HI there is a prolonged depression of mitochondrial metabolism in agreement with emerging evidence of mitochondria as vulnerable targets in the delayed injury cascade. (2) Astrocytes, like neurons, are metabolically impaired following HI, and the degree of astrocytic malfunction may be an indicator of the outcome following hypoxic and hypoxic-ischemic brain injury. (3) Glutamate transfer from neurons to astrocytes is not increased following neonatal HI, which may imply that astrocytes fail to upregulate glutamate uptake in response to the massive glutamate release during HI, thus contributing to excitotoxicity. (4) In the neonatal brain, the activity of the PPP is reduced following HI, which may add to the susceptibility of the neonatal brain to oxidative stress. The present review aims to discuss the metabolic temporal alterations observed in the neonatal brain following HI.

  4. Protective effect of Angelica sinensis on cerebral neurons from rat embryos under hypoxia

    Institute of Scientific and Technical Information of China (English)

    Yuling Wu; Hongxian Zhao; Hong Yu

    2007-01-01

    L/kg),then put into 2 L wide-mouthed bottle containing 100 g sodalime, and then the lid of the bottle was closed tightly to induce hypotonic hypoxia for 1 hour followed by 1-hour re-oxygenation. The pregnant rats were killed under anesthesia, and then fetuses were taken out by rapid cesarean. Part of the brain tissues were exposed and then fixed in formaldehyde (40 g/L). The pregnant rats in the Angelica group were treated the same as those in the hypoxia group except that saline was replaced by 250 g/L Angelica sinensis injection which was injected via caudal vein (8 mL/kg). The rats in the control group were injected with saline (8 mL/kg) slowly via caudal vein, but not put into the wide-mouthed bottle for hypoxia, and then the brain tissues were removed and fixed as those in the hypoxia group after 1 hour. ② Twenty embryos from rats were chosen randomly in each group and then routinely embedded in paraffin. Paraffin sections of 4 μm thick were prepared through the anterior fontanelle of head of the fetal rats. The sections were immunohistologically stained with c-Fos/NSE. ③ The one-way analysis of variance (ANOVA) was used to compare the differences of measurement data among the groups, and the q test was applied in the two-two comparison.MAIN OUTCOME MEASURES: The numbers of c-Fos and c-Fos/NSE positive neurons in cerebrum from rat embryos were observed.RESULTS: ① Numbers of NSE positive neurons in cerebrum of rat embryos in the control group, hypoxia group and Angelica group were (84.3 ± 9.0), (90.2 ± 12.5) and (86.7 ± 9.7) cells/high power field (P > 0.05).② The number of c-Fos/NSE positive neurons was more in the hypoxia group than in the control group and Angelica group [(38.4±5.28), (11.35±2.67), (20.65±4.07) cells/high power field, q =29.17, 19.14, P <0.05].CONCLUSION: Hypoxia can stimulate the expression of c-Fos in cerebral neurons from rat embryos.Angelica sinensis injection could reducing the damage of hypoxia to neurons and play a

  5. Frequently asked questions in hypoxia research

    Directory of Open Access Journals (Sweden)

    Wenger RH

    2015-09-01

    Full Text Available Roland H Wenger,1,2 Vartan Kurtcuoglu,1,2 Carsten C Scholz,1,2 Hugo H Marti,3 David Hoogewijs1,2,4 1Institute of Physiology and Zurich Center for Human Physiology (ZIHP, University of Zurich, 2National Center of Competence in Research “Kidney.CH”, Zurich, Switzerland; 3Institute of Physiology and Pathophysiology, University of Heidelberg, Heidelberg, 4Institute of Physiology, University of Duisburg-Essen, Essen, Germany Abstract: “What is the O2 concentration in a normoxic cell culture incubator?” This and other frequently asked questions in hypoxia research will be answered in this review. Our intention is to give a simple introduction to the physics of gases that would be helpful for newcomers to the field of hypoxia research. We will provide background knowledge about questions often asked, but without straightforward answers. What is O2 concentration, and what is O2 partial pressure? What is normoxia, and what is hypoxia? How much O2 is experienced by a cell residing in a culture dish in vitro vs in a tissue in vivo? By the way, the O2 concentration in a normoxic incubator is 18.6%, rather than 20.9% or 20%, as commonly stated in research publications. And this is strictly only valid for incubators at sea level. Keywords: gas laws, hypoxia-inducible factor, Krogh tissue cylinder, oxygen diffusion, partial pressure, tissue oxygen levels

  6. Hypoxia, HIF-1 Regulation and Cancer Therapy

    NARCIS (Netherlands)

    Groot, A.J.

    2008-01-01

    Oxygen insufficiency (hypoxia) is a common feature of human cancer and associated with tumor aggressiveness and poor clinical outcome. Furthermore, hypoxic tumors are more resistant to ionizing radiation and chemotherapy contributing to their unfavorable prognosis. The oxygen sensing pathway is cont

  7. Hypoxia and Angiogenesis in Endometrioid Endometrial Carcinogenesis

    Directory of Open Access Journals (Sweden)

    Nicole Horrée

    2007-01-01

    Full Text Available Background: Hypoxia-inducible factor 1α (HIF-1α plays an essential role in the adaptive response of cells to hypoxia, triggering biologic events associated with aggressive tumor behavior. Methods: Expression of HIF-1α and proteins in the HIF-1α pathway (Glut-1, CAIX, VEGF in paraffin-embedded specimens of normal (n = 17, premalignant (n = 17 and endometrioid endometrial carcinoma (n = 39 was explored by immunohistochemistry, in relation to microvessel density (MVD. Results: HIF-1α overexpression was absent in inactive endometrium but present in hyperplasia (61% and carcinoma (87%, with increasing expression in a perinecrotic fashion pointing to underlying hypoxia. No membranous expression of Glut-1 and CAIX was noticed in inactive endometrium