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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

Rapid and complete tissue reoxygenation is a prime goal of present stroke therapy. However, reoxygenation may trigger detrimental cascades that partially antagonize beneficial effects. It was our goal to investigate selective grading of reoxygenation with targeting of single mitochondrial complexes in murine hippocampal slices. Population spike amplitude (PSAP) and NADH were measured during hypoxic hypoxia (15 min) and recovery (45 min). With onset of reoxygenation, slices were treated for different times with amobarbital (1 mM), malonate (2 mM), or cyanide (1 mM), inhibitors of mitochondrial complex I, II, or IV, respectively. Other slices were treated with nicotinamide (1 mM). Posthypoxic recovery of PSAP increased from 32% +/- 43% of onset in control slices to 52% +/- 59% (P <.05) upon treatment with amobarbital for 1 min and to 62% +/- 37% (P <.05) upon treatment with malonate. With nicotinamide, posthypoxic recovery improved to 73% +/- 25% (P <.05). Oxidation of NADH was prolonged upon treatment with amobarbital, whereas no change in NADH oxidation was observed with malonate and nicotinamide. Thus, grading of reoxygenation with selective targeting of mitochondrial complex I or II but not of complex IV improves outcome upon reoxygenation in murine hippocampal slices.
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PMID:Graded reoxygenation with chemical inhibition of oxidative phosphorylation improves posthypoxic recovery in murine hippocampal slices. 1474 58

Mutations in genes encoding the NADH ubiquinone oxidoreductase, complex I of the respiratory chain, cause a diverse group of diseases. They include Leber hereditary optic neuropathy, Leigh syndrome, and mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes. There is no effective treatment for these or any other mitochondrial disorder. Using a unique animal model of severe complex I deficiency induced by ribozymes targeted against a critical complex I subunit gene (NDUFA1), we attempted rescue of the optic nerve degeneration associated with Leber hereditary optic neuropathy. We used adenoassociated virus to deliver the human gene for SOD2 to the visual system of disease-induced mice. Relative to mock infection, SOD2 reduced apoptosis of retinal ganglion cells and degeneration of optic nerve fibers, the hallmarks of this disease. Rescue of this animal model supports a critical role for oxidative injury in disorders with complex I deficiency and shows that a respiratory deficit may be effectively treated in mammals, thus offering hope to patients.
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PMID:SOD2 gene transfer protects against optic neuropathy induced by deficiency of complex I. 1529 68

Besides aspirin several new drugs for inhibition of platelet aggregation and 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibition are used in secondary stroke prevention. Pharmacology and clinical effects, however, are not fully explained by current understanding of underlying mechanisms. Population spike amplitude (PSAP), an established marker of slice integrity, was measured during hypoxia and recovery thereof in hippocampal slices from control CD1 mice (25-35 g) and animals pretreated in vivo with a single i.p. injection of clopidogrel, ticlopidine, or atorvastatine at different time intervals and dosages. Posthypoxic recovery of PSAP was 20 +/- 35% in control CD1 mice. Upon pretreatment with clopidogrel (1-24 h, 0.5-2 mg/kg body weight) an increase up to 81 +/- 20% (p < 0.01 to control) was observed at 1h interval and 1mg/kg. Application of ticlopidine (1-24 h, 1-4 mg/kg body weight) resulted in an improvement of posthypoxic recovery to 61 +/- 41% (p < 0.05 to control) while administration of atorvastatine (1-24 h, 1-4 mg/kg body weight) caused an increase up to 87 +/- 31% (p < 0.01 to control) at 1h interval and 2 mg/kg. On application of these substances in vitro the NADH autofluorescence spectrum in hippocampal slices is blue-shifted suggesting an alteration of oxidative metabolism. The present data demonstrate a shared neuroprotective effect of agents known to inhibit platelets (acetylsalicylic acid, clopidogrel, and ticlopidine) and HMG-CoA reductase (atorvastatine). The time course of this neuroprotective action in the current experimental study (onset within an hour, duration of several hours in contrast to several days) resembles clinical practice in dosing these substances. We hypothesize that an increase of hypoxic tolerance resulting from mild mitochondrial inhibition by these substances is a principal constituent of the effectiveness of these drugs.
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PMID:Improved posthypoxic recovery in vitro on treatment with drugs used for secondary stroke prevention. 1575 83

From in vivo models of stroke it is known that ischemia/reperfusion induces oxidative stress that is accompanied by deterioration of brain mitochondria. Previously, we reported that the increase in Ca2+ induces functional breakdown and morphological disintegration in brain mitochondria subjected to hypoxia/reoxygenation (H/R). Protection by ADP indicated the involvement of the mitochondrial permeability transition pore in the mechanism of membrane permeabilization. Until now it has been unclear how reactive oxygen species (ROS) contribute to this process. We now report that brain mitochondria which had been subjected to H/R in the presence of low micromolar Ca2+ display low state 3 respiration (20% of control), loss of cytochrome c, and reduced glutathione levels (75% of control). During reoxygenation, significant mitochondrial generation of hydrogen peroxide (H2O2) was detected. The addition of the membrane permeant superoxide anion scavenger TEMPOL (4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl) suppressed the production of H2O2 by brain mitochondria metabolizing glutamate plus malate by 80% under normoxic conditions. TEMPOL partially protected brain mitochondria exposed to H/R and low micromolar Ca2+ from decrease in state 3 respiration (from 25% of control to 60% of control with TEMPOL) and permeabilization of the inner membrane. Membrane permeabilization was obvious, because state 3 respiration could be stimulated by extramitochondrial NADH. Our data suggest that ROS and Ca2+ synergistically induce permeabilization of the inner membrane of brain mitochondria exposed to H/R. However, permeabilization can only partially be prevented by suppressing mitochondrial generation of ROS. We conclude that transient deprivation of oxygen and glucose during temporary ischemia coupled with elevation in cytosolic Ca2+ concentration triggers ROS generation and mitochondrial permeabilization, resulting in neural cell death.
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PMID:Oxidative stress is involved in the permeabilization of the inner membrane of brain mitochondria exposed to hypoxia/reoxygenation and low micromolar Ca2+. 1600 59

Degenerative brain disorders (neurodegeneration) can be frustrating for both conventional and alternative practitioners. A more comprehensive, integrative approach is urgently needed. One emerging focus for intervention is brain energetics. Specifically, mitochondrial insufficiency contributes to the etiopathology of many such disorders. Electron leakages inherent to mitochondrial energetics generate reactive oxygen free radical species that may place the ultimate limit on lifespan. Exogenous toxins, such as mercury and other environmental contaminants, exacerbate mitochondrial electron leakage, hastening their demise and that of their host cells. Studies of the brain in Alzheimer's and other dementias, Down syndrome, stroke, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, Huntington's disease, Friedreich's ataxia, aging, and constitutive disorders demonstrate impairments of the mitochondrial citric acid cycle and oxidative phosphorylation (OXPHOS) enzymes. Imaging or metabolic assays frequently reveal energetic insufficiency and depleted energy reserve in brain tissue in situ. Orthomolecular nutrients involved in mitochondrial metabolism provide clinical benefit. Among these are the essential minerals and the B vitamin group; vitamins E and K; and the antioxidant and energetic cofactors alpha-lipoic acid (ALA), ubiquinone (coenzyme Q10; CoQ10), and nicotinamide adenine dinucleotide, reduced (NADH). Recent advances in the area of stem cells and growth factors encourage optimism regarding brain regeneration. The trophic nutrients acetyl L-carnitine (ALCAR), glycerophosphocholine (GPC), and phosphatidylserine (PS) provide mitochondrial support and conserve growth factor receptors; all three improved cognition in double-blind trials. The omega-3 fatty acid docosahexaenoic acid (DHA) is enzymatically combined with GPC and PS to form membrane phospholipids for nerve cell expansion. Practical recommendations are presented for integrating these safe and well-tolerated orthomolecular nutrients into a comprehensive dietary supplementation program for brain vitality and productive lifespan.
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PMID:Neurodegeneration from mitochondrial insufficiency: nutrients, stem cells, growth factors, and prospects for brain rebuilding using integrative management. 1636 37

It is proposed that the redox state of mitochondrial NADH will complement blood gas analysis for measuring the health and welfare of human tissues. Use of arterial oxygen saturation levels (SaO2), especially as assayed by the Nellcor instrument, has spread almost everywhere in medicine despite the fact that hypoxia of internal organs, liver, kidney, brain, pancreas, etc. is not well indicated by peripheral digital oxygenation. Indeed, there is an implied liability in the failure to infer central oxygenation from peripheral values. Near infrared (NIR) sensing of deep tissue saturation of hemoglobin (StO2) requires multi-wavelength, multi-site measurement of both absorption and scattering properties by time or frequency domain NIR methods. Corrections for underlying water and lipid absorptions can be made so that the correct value for, and saturation oh hemoglobin are obtained. Nevertheless, the significance of blood oxygen saturation, even localized to particular organs, can be questioned from the standpoint of what is the critical value of the desaturation from which the tissue can recover; for example, in the case of cortical neurons where stroke, compression ischemia, etc. cause O2 lack, this value becomes of significant clinical importance in both the brain and the spinal chord. These approaches are actively pursued and the possibility of subsurface redox state measurement in human tissues may eventually emerge as the quantitative metric of tissue metabolic state and of hypoxic stress. The great flexibility and versatility of the fast, economical and "tetherless" nature of opto-electronic technology is appropriate to the manifold challenges of neuronal function as currently measured by intrinsic signals and soon to be studiable by extrinsic signals of metabolism and electrophysiological functions.
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PMID:Mitochondrial NADH as the bellwether of tissue O2 delivery. 1659 57

Cortical spreading depression (CSD) is a self-propagating wave of cellular depolarization that has been implicated in migraine and in progressive neuronal injury after stroke and head trauma. Using two-photon microscopic NADH imaging and oxygen sensor microelectrodes in live mouse cortex, we find that CSD is linked to severe hypoxia and marked neuronal swelling that can last up to several minutes. Changes in dendritic structures and loss of spines during CSD are comparable to those during anoxic depolarization. Increasing O2 availability shortens the duration of CSD and improves local redox state. Our results indicate that tissue hypoxia associated with CSD is caused by a transient increase in O2 demand exceeding vascular O2 supply.
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PMID:Cortical spreading depression causes and coincides with tissue hypoxia. 1752 59

Mitochondrial dysfunction is part of many pathological states in patients, such as sepsis or stroke. Presently, the monitoring of mitochondrial function in patients is extremely rare, even though NADH redox state is routinely measured in experimental animals. In this article, we describe the scientific backgrounds and practical use of mitochondrial NADH fluorescence measurement that was applied to patients in the past few years. In addition to NADH, we optically measured the microcirculatory blood flow and volume, as well as HbO(2) oxygenation, from the same tissue area. The four detected parameters provide real time data on tissue viability, which is critical for patients monitoring.
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PMID:Oxidation-reduction states of NADH in vivo: from animals to clinical use. 1757 1

Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are closely linked to degenerative diseases such as Alzheimer's disease, Parkinson's, neuronal death including ischemic and hemorrhagic stroke, acute and chronic degenerative cardiac myocyte death, and cancer. As a byproduct of oxidative phosphorylation, a steady stream of reactive species emerge from our cellular energy plants, the mitochondria. ROS and RNS potentially cause damage to all cellular components. Structure alteration, biomolecule fragmentation, and oxidation of side chains are trade-offs of cellular energy production. ROS and RNS escape results in the activation of cytosolic stress pathways, DNA damage, and the upregulation of JNK, p38, and p53. Incomplete scavenging of ROS and RNS particularly affects the mitochondrial lipid cardiolipin (CL), triggers the release of mitochondrial cytochrome c, and activates the intrinsic death pathway. Due to the active redox environment and the excess of NADH and ATP at the inner mitochondrial membrane, a broad range of agents including electron acceptors, electron donors, and hydride acceptors can be used to influence the biochemical pathways. The key to therapeutic value is to enrich selective redox modulators at the target sites. Our approach is based on conjugating nitroxides to segments of natural products with relatively high affinity for mitochondrial membranes. For example, a modified gramicidin S segment was successfully used for this purpose and proven to be effective in preventing superoxide production in cells and CL oxidation in mitochondria and in protecting cells against a range of pro-apoptotic triggers such as actinomycin D, radiation, and staurosporine. More importantly, these mitochondria-targeted nitroxide/gramicidin conjugates were able to protect against apoptosis in vivo by preventing CL oxidation induced by intestinal hemorrhagic shock. Optimization of nitroxide carriers could lead to a new generation of effective antiapoptotic agents acting at an early mitochondrial stage. Alternative chemistry-based approaches to targeting mitochondria include the use of proteins and peptides, as well as the attachment of payloads to lipophilic cationic compounds, sulfonylureas, anthracyclines, and other agents with proven or hypothetical affinities for mitochondria. Manganese superoxide dismutase (MnSOD), SS tetrapeptides with 2',6'-dimethyltyrosine (Dmt) residues, rhodamine, triphenylphosphonium salts, nonopioid analgesics, adriamycin, and diverse electron-rich aromatics and stilbenes were used to influence mitochondrial biochemistry and the biology of aging. Some general structural principles for effective therapeutic agents are now emerging. Among these are the presence of basic or positively charged functional groups, hydrophobic substructures, and, most promising for future selective strategies, classes of compounds that are actively shuttled into mitochondria, bind to mitochondria-specific proteins, or show preferential affinity to mitochondria-specific lipids.
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PMID:Targeting mitochondria. 1819 22


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