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Query: UMLS:C0917798 (cerebral ischemia)
 17,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nicotinamide adenine dinucleotide fluorescence, cortical reflectance, cortical blood flow, and electroencephalograms were recorded from squirrel monkey brains before, during, and after focal transient cerebral ischemia produced by the temporary clipping of the middle cerebral artery. After release of the occluding clip, the monkeys were followed through an N2-breathing cycle and then to death from anoxia. The effects of controlled variations in arterial carbon dioxide tensions (PaCO2) and mean arterial blood pressures (MABP) were investigated in normal and in ischemic brain. In normal brain, with preserved autoregulation, NADH fluorescence was constant through a wide range in Paco2, MABP, and cortical blood flow. In ischemic brain, NADH levels increased, correlated closely with decreased cortical blood flow and EEG abnormalities, and became dependent on MABP. Artifacts in fluorescent measurements were reduced by: monochromators for excitation, emission, and reflected light; low intensity vertical excitation energy and high sensitivity recording instrumentation; and a small avascular (123 microns) field.
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PMID:Effect of hypocapnia, hypercapnia, and blood pressure on NADH fluorescence, electrical activity, and blood flow in normal and partially ischemic monkey cortex. 1217 May 99

The purpose of the current study was to investigate aspects of improved bioenergetic function using nicotinamide during stroke. Using a global ischemia-reperfusion mouse model, ATP was depleted by 50% in the brain. The use of nicotinamide to provide a large reserve of brain NAD+ restored ATP levels to 61% of control levels. Alternatively, using nicotinamide as a PARP inhibitor restored ATP levels up to 72%. However, using a large reserve of NAD+ in the brain together with PARP inhibition proved to be additive, restoring ATP to 85% of control levels during the first critical 5 min of reperfusion. NAD+ and ATP levels correlated almost exactly. Brain mitochondrial function was also examined after cerebral ischemia-reperfusion. State 3 respiration of complex I was found to be abolished. However, this was a non-permanent inhibition of activity in vitro, since (NADH ubiquinone oxideroductase) complex I activity in these mitochondria was restored upon the addition of NADH. In vivo, the use of increased brain NAD+ and PARP inhibition was able to partially restore mitochondrial respiration. Taken together, the results show that nicotinamide offers a substantial protective role in terms of preservation of cellular ATP and mitochondrial NAD-linked respiration.
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PMID:Nicotinamide offers multiple protective mechanisms in stroke as a precursor for NAD+, as a PARP inhibitor and by partial restoration of mitochondrial function. 1451 2

The mammalian pyruvate dehydrogenase complex (PDHC) is a mitochondrial matrix enzyme complex (greater than 7 million Daltons) that catalyzes the oxidative decarboxylation of pyruvate to form acetyl CoA, nicotinamide adenine dinucleotide (the reduced form, NADH), and CO(2). This reaction constitutes the bridge between anaerobic and aerobic cerebral energy metabolism. PDHC enzyme activity and immunoreactivity are lost in selectively vulnerable neurons after cerebral ischemia and reperfusion. Evidence from experiments carried out in vitro suggests that reperfusion-dependent loss of activity is caused by oxidative protein modifications. Impaired enzyme activity may explain the reduced cerebral glucose and oxygen consumption that occurs after cerebral ischemia. This hypothesis is supported by the hyperoxidation of mitochondrial electron transport chain components and NAD(H) that occurs during reperfusion, indicating that NADH production, rather than utilization, is rate limiting. Additional support comes from the findings that immediate postischemic administration of acetyl-L-carnitine both reduces brain lactate/pyruvate ratios and improves neurologic outcome after cardiac arrest in animals. As acetyl-L-carnitine is converted to acetyl CoA, the product of the PDHC reaction, it follows that impaired production of NADH is due to reduced activity of either PDHC or one or more steps in glycolysis. Impaired cerebral energy metabolism and PDHC activity are associated also with neurodegenerative disorders including Alzheimer's disease and Wernicke-Korsakoff syndrome, suggesting that this enzyme is an important link in the pathophysiology of both acute brain injury and chronic neurodegeneration.
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PMID:Pyruvate dehydrogenase complex: metabolic link to ischemic brain injury and target of oxidative stress. 1556 36

NAD+ and NADH have been emerging as the common mediators of energy metabolism, mitochondrial functions, calcium homeostasis, aging and cell death. NAD+ and NADH can affect cell death by various mechanisms, such as influencing energy metabolism, mitochondrial permeability transition pores, and apoptosis-inducing factor. Because energy failure, calcium disregulation and cell death are the key components in the tissue damaging cascade initiated by cerebral ischemia, it is likely that NAD+ and NADH play significant roles in ischemic brain damage. Many studies, including the findings that poly(ADP-ribose) polymerase-1 mediates ischemic brain injury and that NAD+ administration can decrease ischemic brain damage, have suggested significant roles of NAD+ and NADH in the debilitating illness. However, there is still distinct insufficiency of the information regarding the roles of NAD+ and NADH in ischemic brain injury. Because increasing evidence has indicated critical functions of NAD+ and NADH in various biological processes, future studies on the roles of NAD+ and NADH in cerebral ischemia may expose essential mechanisms underlying ischemic brain injury and suggest novel therapeutic strategies for the illness.
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PMID:NAD+ and NADH in ischemic brain injury. 1798 19

Suppression of peri-infarct depolarizations (PIDs) is one of the major mechanisms of hypothermic protection against transient focal cerebral ischemia. Previous studies have shown the lack of hypothermic protection against permanent focal ischemia. We hypothesized the lack of hypothermic protection was due to the poor efficacy in suppression of PIDs. To examine the hypothesis, we elucidated the effects of hypothermia on the manner of propagation of PIDs with temporal and spatial resolutions using NADH (reduced nicotinamide adenine dinucleotide) fluorescence images by illuminating the parietal-temporal cortex with ultraviolet light. Spontaneously hypertensive rats (n=14) were subjected to permanent focal ischemia by occlusion of the middle cerebral and left common carotid arteries. 2-h hypothermia (30 degrees C) was initiated before ischemia. Although hypothermia delayed the appearance of PIDs, it did not suppress their appearance. Furthermore, 54% of the PIDs enlarged the high-intensity area of NADH fluorescence in the hypothermia group, similar to the normothermia group (53%). The high-intensity area of NADH fluorescence widened by each PID was larger in the hypothermia group than in the normothermia group. These findings suggest that PIDs even in hypothermia are one of the major factors causing growth of infarction, emphasizing the importance of therapy that targets suppression of PIDs even during hypothermia.
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PMID:Dynamic changes in cortical NADH fluorescence in rat focal ischemia: evaluation of the effects of hypothermia on propagation of peri-infarct depolarization by temporal and spatial analysis. 1897 97

Thiopental, a well-known barbiturate, is often used in patients who are at high risk of developing cerebral ischemia, especially during brain surgery. Although barbiturates are known to affect a variety of processes in the cerebral cortex, including oxygen consumption by the mitochondria, the interrelation between mitochondrial function and anesthetics has not been investigated in detail under in vivo conditions. The aim of this study was to examine the effects of thiopental on brain functions in normoxia and under partial or complete ischemia. The use of the multiparametric monitoring system permitted simultaneous measurements of microcirculatory blood flow, NADH fluorescence, tissue reflectance, and ionic and electrical activities of the cerebral cortex. Thiopental caused a significant, dose-dependent decrease in blood flow and a significant decrease in extracellular levels of potassium, with no significant changes in NADH levels in normoxic and ischemic rats. Following complete ischemia (death), the increase in the reflectance was significantly smaller in the anesthetized normoxic group versus the awake normoxic group. The time until the secondary increase in reflectance, seen in death, was significantly shorter in the anesthetized ischemic group. In conclusion, it seems that the protective effect of thiopental occurs only under partial ischemia and not under complete ischemia.
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PMID:Effects of anesthesia on brain mitochondrial function, blood flow, ionic and electrical activity monitored in vivo. 1922 49

This study demonstrates a new electroanalytical method with a high physiological relevance for simultaneous online monitoring of glucose and lactate in the striatum of the rat brain following global cerebral ischemia/reperfusion. The online analytical method is based on the efficient integration of in vivo microdialysis sampling with an online selective electrochemical detection with the electrochemical biosensors with dehydrogenases, i.e., glucose and lactate dehydrogenases, as recognition elements. The dehydrogenase-based electrochemical biosensors are developed onto the dual split-disk plastic carbon film (SPCF) electrodes with methylene green (MG) adsorbed onto single-walled carbon nanotubes (SWNTs) as the electrocatalyst for the oxidation of dihydronicotiamide adenine dinucleotide (NADH) at a low potential of 0.0 V (vs Ag/AgCl). Artificial cerebrospinal fluid (aCSF) containing NAD(+) is externally perfused from a second pump and online mixed with the brain microdialysates to minimize the variation of pH that occurred following the cerebral ischemia/reperfusion and to supply NAD(+) cofactor and O(2) for the enzymatic reactions of dehydrogenases and ascorbate oxidase, respectively. As a result, the developed online electroanalytical method exhibits a high selectivity against the electrochemically active species endogenously existing in the cerebral systems and a high tolerance against the variation of pH and O(2) following cerebral ischemia/reperfusion. This property, along with the good linearity and a high stability toward glucose and lactate as well as little cross-talk between two biosensors, substantially makes this method possible for the continuous, simultaneous, and online monitoring of glucose and lactate in the rat brain following global cerebral ischemia/reperfusion. This study establishes a new and effective platform for the investigation of the energy metabolism in physiological and pathological processes.
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PMID:Physiologically relevant online electrochemical method for continuous and simultaneous monitoring of striatum glucose and lactate following global cerebral ischemia/reperfusion. 1928 Dec 58

The oxidation of xanthine by xanthine oxidase (XO) or xanthine dehydrogenase represents an important source of reactive oxygen species (ROS), which contribute to the damaging consequences of cerebral ischemia, inflammation, and neurodegenerative disorders. However, both enzymes are also able to act on reduced nicotinamide adenine dinucleotide (NADH). The FAD binding site to which NADH binds is distinct from that of the xanthine binding site. We report that the combination of xanthine oxidase and NADH is toxic to cultures of cerebellar granule neurons. Protection by superoxide dismutase (Cu,Zn-SOD or Mn-SOD) or catalase indicates mediation of the toxicity by superoxide and hydrogen peroxide. In addition, pre-incubating XO with EDTA at concentrations as low as 2 microM, prevented the toxicity, indicating that a metal contaminating XO is involved in producing the toxic effects of XO/NADH. It is possible that such a metal might play a role in the toxicity of XO in vivo.
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PMID:Xanthine oxidase-induced neuronal death via the oxidation of NADH: prevention by micromolar EDTA. 1945 May 65

The effect of ageing and the relationships between the catalytic properties of enzymes linked to Krebs' cycle, electron transfer chain, glutamate and aminoacid metabolism of cerebral cortex, a functional area very sensitive to both age and ischemia, were studied on mitochondria of adult and aged rats, after complete ischemia of 15 minutes duration. The maximum rate (Vmax) of the following enzyme activities: citrate synthase, malate dehydrogenase, succinate dehydrogenase for Krebs' cycle; NADH-cytochrome c reductase as total (integrated activity of Complex I-III), rotenone sensitive (Complex I) and cytochrome oxidase (Complex IV) for electron transfer chain; glutamate dehydrogenase, glutamate-oxaloacetate-and glutamate-pyruvate transaminases for glutamate metabolism were assayed in non-synaptic, perikaryal mitochondria and in two populations of intra-synaptic mitochondria, i.e., the light and heavy mitochondrial fraction. The results indicate that in normal, steady-state cerebral cortex, the value of the same enzyme activity markedly differs according (a) to the different populations of mitochondria, i.e., non-synaptic or intra-synaptic light and heavy, (b) and respect to ageing. After 15 min of complete ischemia, the enzyme activities of mitochondria located near the nucleus (perikaryal mitochondria) and in synaptic structures (intra-synaptic mitochondria) of the cerebral tissue were substantially modified by ischemia. Non-synaptic mitochondria seem to be more affected by ischemia in adult and particularly in aged animals than the intra-synaptic light and heavy mitochondria. The observed modifications in enzyme activities reflect the metabolic state of the tissue at each specific experimental condition, as shown by comparative evaluation with respect to the content of energy-linked metabolites and substrates. The derangements in enzyme activities due to ischemia is greater in aged than in adult animals and especially the non-synaptic and the intra-synaptic light mitochondria seems to be more affected in aged animals. These data allow the hypothesis that the observed modifications of catalytic activities in non-synaptic and intra-synaptic mitochondrial enzyme systems linked to energy metabolism, amino acids and glutamate metabolism are primary responsible for the physiopathological responses of cerebral tissue to complete cerebral ischemia for 15 min duration during ageing.
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PMID:Effect of ageing and ischemia on enzymatic activities linked to Krebs' cycle, electron transfer chain, glutamate and aminoacids metabolism of free and intrasynaptic mitochondria of cerebral cortex. 1949 70

Middle cerebral artery occlusion (MCAO), which leads to focal cerebral ischemia, serves as an experimental model for brain stroke. There is a large variation in protocols and techniques using the MCAO model, which may affect the outcomes seen in different studies. The current work presents and compares the diverse responses in mitochondrial NADH and cerebral blood flow (CBF) following focal ischemia induced by the MCAO technique. Ninety-six Wistar rats underwent focal cerebral ischemia by MCAO, and monitored in the core and the penumbra using a unique Multi-Site-Multi-Parametric (MSMP) system, which measures mitochondrial NADH using the fluorometric technique, and CBF using laser Doppler flowmetry (LDF). Following MCAO, 58% of the experiments yielded expected responses, namely a decrease in CBF and an increase in NADH. However, 42% of the experiments showed six other profiles of responses, in which CBF, NADH and tissue reflectance (Ref) responded differently. These profiles included: ischemia without reperfusion, death following reperfusion, minor responses in parameters during ischemia, CBF elevation in the penumbra following MCAO, spontaneous early reperfusion and late reperfusion. These results demonstrate that MCAO is a complex model, which may lead to different responses other than the common expected outcomes, i.e. mitochondrial damage and reduced blood flow in both core and penumbra. The MSMP monitoring system may serve as an important tool in early diagnosis of successful focal cerebral ischemia, reducing the percentage of unsuccessful experiments.
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PMID:Mitochondrial function and cerebral blood flow variable responses to middle cerebral artery occlusion. 2010 93


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