Oxygen insufficiency during hypoxic hypoxia in rat brain cortex (original) (raw)
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Reduced mitochondrial respiration in mouse cerebral cortex during chronic hypoxia
Neuroscience Letters, 1995
Respiratory activity and NADH CoQ reductase (complex I) and cytochrome c oxidase (complex IV) activities were measured in free (non-synaptosomal) mitochondria isolated from cerebral cortex of male Balb/c mice exposed to intermittent hypobaric hypoxia (450 Torr; 4300 m) for 21 days and compared to normoxic (sea level) controls. In the hypoxic we found a 47% reduction of oxygen uptake during state 3 (ADP and substrate present), 12% reduction during state 4 (no ADP present) and 20% reduction in the uncoupled respiration rate with pymvate plus malate as substrates. Respiratory control ratio (RCR) decreased by 24%. No change in the ADP/O ratio was seen. NADH CoQ reductase activity decreased by 30% and cytochrome c oxidase by 17%, suggesting that under conditions of chronic hypoxia, the reductions of mitochondrial respiratory activities are caused, at least in part, by enzymatic alterations of the electron transport chain (complex I and complex IV). The decreased activity of these enzymes could contribute to alterations in neuronal activity by reducing brain energy metabolism during development under conditions of chronic hypoxia.
Journal of Cerebral Blood Flow & Metabolism, 2011
Cellular hypoxia triggers a homeostatic increase in mitochondrial free radical signaling. In this study, blood was obtained from the radial artery and jugular venous bulb in 10 men during normoxia and 9 hours hypoxia (12.9% O 2 ). Mitochondrial oxygen tension ( P mit O 2 ) was derived from cerebral blood flow and blood gases. The ascorbate radical (A KÀ ) was detected by electron paramagnetic resonance spectroscopy and neuron-specific enolase (NSE), a biomarker of neuronal injury, by enzyme-linked immunosorbent assay. Hypoxia increased the cerebral output of A KÀ in proportion to the reduction in P mit O 2 , but did not affect NSE exchange. These findings suggest that neuro-oxidative stress may constitute an adaptive response.
Local tissue oxygen tension - cytochrome a,a3 redox relationships in rat cerebral cortex in vivo
Brain Research, 1981
K~JJ woutls: tissue pOz-cytochrome c oxidase-cerebral metabolism-mitochondria-redox states SUMMARY Simultaneous measurements were made from rat cerebral cortex, in situ, of focal changes in both tissue oxygen tension (ptOz) and the reduction/oxidation ratio of cytochrome c oxidase (cytochrome a,as) in order to study relationships between oxygen supply and consumption in small regions of tissue. Local ptOz was measured with polarographic microelectrodes and the redox state of cytochrome a,a3 with a dual wavelength reflectance spectrophotometer. Increased ptO2, produced by respiration of gas mixtures with elevated 02 and/or CO2 content, was accompanied by increased oxidation of cytochrome a,a3. This confirms that cytochrome oxidase is not fully oxidized in focal brain tissue regions in vivo, as it is in mitochrondria isolated in vitro. Decreased ptO2 was accompanied by cytochrome a,a3 reduction. The oxidative changes of cytochrome a,a3 with increases in ptO2 were smaller than the reductive changes associated with decreases in ptOz. Curves relating cytochrome a,a3 redox state to ptO2 were qualitatively alike, regardless of the initial ptOz value from which they were generated. Thus, the reduction level of cytochrome a,a3 varied with pt02 on a continuum. This consistent relationship demonstrates that changes in mitochondrial redox state provide an index of relative changes in tissue oxygenation in intact neocortex. The results suggest also that local rates of cerebral oxidative metabolism may not always be constant with changes in local ptO2.
Journal of Cerebral Blood Flow & Metabolism, 1984
The adaptation to repeated, alternate normo baric hypoxic and normoxic exposures (12 h/day, for 5 days) and to pharmacological treatment was evaluated by studying the specific activities of some enzymes related to cerebral energy metabolism, Measurements were car ried out on (a) the homogenate in toto, (b) the purified mitochondrial fraction, and (c) the crude synaptosomal fraction in different areas of rat brain-cerebral cortex, hippocampus, corpus striatum, hypothalamus, cere bellum, and medulla oblongata. The adaptation to inter mittent normobaric hypoxic-normoxic exposures was characterized by significant modifications of some en-A moderate decrease of the appropriate supply of oxygen causes a series of biochemical events leading to a rapid loss of neuronal function (Mas sopust et aI. , 1969; Mac Millan et aI. , 1976). Hypoxia is responsible for pronounced mod ifications of the contents of cerebral neurotrans mitters Bowen et aI. , 1976;; e. g. , at a Pao 2 of 35 mm Hg, the synthesis of catecholamines and indolamines is inhibited . Even under mild hypoxia, changes in the intermediate metabolism or in the metabolism of neurotransmitters may occur, as in the cases of acetylcholine, the synthesis of which decreases by 40-50% at a P a02 of 42-57 mm Hg (Gibson and Duffy, 1981), and glycolysis, which is stimulated even by a P a02 of 50 mm Hg . On the contrary, some aspects of cerebral metabolism are less sensitive to a decrease in Pao2.
Decreased rat brain cytochrome oxidase activity after prolonged hypoxia
Brain Research, 1996
Three weeks of hypoxic exposure results in a spectrum of systemic physiological and local brain tissue adaptations. Cytochrome oxidase histochemistry was used as an indicator of changes in energy demand in response to hypoxia. We found overall cytochrome oxidase activity decreased in hypoxic adapted rats as compared to normoxic control rats. Some regions, notably layer 3 of the frontal cerebral cortex, layer 4 of the parietal sensory barrel fields, lacunosum moleculare hippocampi, and specific nuclei of the rostra1 ventral medulla, though exhibiting cytochrome oxidase activity decreases of 16-27s. still retain their relatively higher levels of activity. We conclude that there is a hypometabolic component of the rat brain adaptation to continued hypoxia.
Energetic metabolism in mouse cerebral cortex during chronic hypoxia
Neuroscience Letters, 2001
We measured the activities of Na 1 K 1 ATPase and of enzymes of the glycolytic pathway, Krebs cycle, and the respiratory chain in cerebral cortex of mice exposed to chronic hypoxia for three weeks and compared their values with those of sea level controls. There were no differences in Na 1 K 1 ATPase activity or in the activity of glycolytic enzymes. In the Krebs cycle, a 66% increase of succinate dehydrogenase activity was found due to a lower Km. In contrast, respiratory chain cytochrome oxidase activity was reduced by 12% in mice exposed to hypoxia. This suggested that the metabolic demand would be satis®ed despite the respiratory chain depression (cytochrome oxidase), probably due to anaerobic energy production within the mitochondria (succinate dehydrogenase). q
Brain Research Reviews, 2007
To determine the HbO 2 oxygenation level at the microcirculation, we used the hyperbaric chamber. The effects of hyperbaric oxygenation (HBO) were tested on vitality parameters in the brain at various pressures. Microcirculatory hemoglobin oxygen saturation (HbO 2 ), cerebral blood flow (CBF) and mitochondrial NADH redox state were assessed in the brain of awake restrained rats using a fiber optic probe. The hypothesis was that HBO may lead to maximal level in microcirculatory HbO 2 due to the amount of the dissolved O 2 to provide the O 2 consumed by the brain, and therefore no O 2 will be dissociated from the HbO 2 . Awake rats were exposed progressively to 15 min normobaric hyperoxia, 100% O 2 (NH) and to 90 min hyperbaric hyperoxia (HH) from 1.75 to 6.0 absolute atmospheres (ATA). NH and HH gradually decreased the blood volume measured by tissue reflectance and NADH but increased HbO 2 in relation to pO 2 in the chamber up to a nearly maximum effect at 2.5 ATA.
The level of tissue oxygenation provides information related to the balance between oxygen delivery, oxygen utilization, tissue reactivity and morphology during physiological conditions. Tissue partial pressure of oxygen (PtO 2 ) is influenced by the use of anesthesia or restraint. These factors may impact the absolute level of PtO 2 . In this study we present a novel fiber optic method to measure brain PtO 2 . This method can be used in unanesthetized, unrestrained animals, provides absolute values for PO 2 , has a stable calibration, does not consume oxygen and is MRI compatible. Brain PtO 2 was studied during acute hypoxia, as well as before and after 28 days of high altitude acclimatization. A sensor was chronically implanted in the frontal cortex of eight Wistar rats. It is comprised of a fiber optic probe with a tip containing material that fluoresces with an oxygen dependent lifetime. Brain PtO 2 declines by 80% and 76% pre-and post-acclimatization, respectively, when the fraction of inspired oxygen declines from 0.21 to 0.08. In addition, a linear relationship between brain PtO 2 and inspired O 2 levels was demonstrated r 2 = 0.98 and r 2 = 0.99 (pre-and post-acclimatization). Hypoxia acclimatization resulted in an increase in the overall brain PtO 2 by approximately 35%. This paper demonstrates the use of a novel chronically implanted fiber optic based sensor for measuring absolute PtO 2 . It shows a very strong linear relationship in awake animals between inspired O 2 and tissue O 2 , and shows that there is a proportional increase in PtO 2 over a range of inspired values after exposure to chronic hypoxia.
Journal of Cerebral Blood Flow and Metabolism, 2012
The dynamic properties of the cerebral metabolic rate of oxygen consumption (CMR O2 ) during changes in brain activity remain unclear. Therefore, the spatial and temporal evolution of functional increases in CMR O2 was investigated in the rat somato-sensory cortex during forelimb stimulation under a suppressed blood flow response condition. Temporally, stimulation elicited a fast increase in tissue mitochondria CMR O2 described by a time constant of B1 second measured using flavoprotein autofluorescence imaging. CMR O2 -driven changes in the tissue oxygen tension measured using an oxygen electrode and blood oxygenation measured using optical imaging of intrinsic signal followed; however, these changes were slow with time constants of B5 and B10 seconds, respectively. This slow change in CMR O2 -driven blood oxygenation partly explains the commonly observed post-stimulus blood oxygen level-dependent (BOLD) undershoot. Spatially, the changes in mitochondria CMR O2 were similar to the changes in blood oxygenation. Finally, the increases in CMR O2 were well correlated with the evoked multi-unit spiking activity. These findings show that dynamic CMR O2 calculations made using only blood oxygenation data (e.g., BOLD functional magnetic resonance imaging (fMRI)) do not directly reflect the temporal changes in the tissue's mitochondria metabolic rate; however, the findings presented can bridge the gap between the changes in cellular oxidative rate and blood oxygenation.
Hypoxemia, oxygen content, and the regulation of cerebral blood flow
American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 2016
This review highlights the influence of oxygen (O2) availability on cerebral blood flow (CBF). Evidence for reductions in O2content (CaO2) rather than arterial O2tension (PaO2) as the chief regulator of cerebral vasodilation, with deoxyhemoglobin as the primary O2sensor and upstream response effector, is discussed. We review in vitro and in vivo data to summarize the molecular mechanisms underpinning CBF responses during changes in CaO2. We surmise that 1) during hypoxemic hypoxia in healthy humans (e.g., conditions of acute and chronic exposure to normobaric and hypobaric hypoxia), elevations in CBF compensate for reductions in CaO2and thus maintain cerebral O2delivery; 2) evidence from studies implementing iso- and hypervolumic hemodilution, anemia, and polycythemia indicate that CaO2has an independent influence on CBF; however, the increase in CBF does not fully compensate for the lower CaO2during hemodilution, and delivery is reduced; and 3) the mechanisms underpinning CBF regul...