Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Different times of incomplete cerebral ischemia (2, 4, 6, 8, 10 and 30 min) were induced by bilateral common carotid artery occlusion in anesthetized rats to evaluate the time course of changes in lipid peroxidation and energy metabolism. Analysis of malondialdehyde (used to assess the levels of lipid peroxidation), ascorbic acid, oxypurines, nucleosides, nicotinic coenzymes and high-energy phosphates, was carried out by high-performance liquid chromatography on neutralized perchloric acid extract of brain tissue. Under the present experimental conditions, malondialdehyde, nicotinic coenzymes and ATP catabolites (oxypurines and nucleosides) were affected by increasing times of ischemia, with respect to control sham-operated rats. In particular, the concentration of malondialdehyde, undetectable in control brains, increased from 1.26 nmol/g wet weight after 2 min of carotid clamping to 13.42 nmol/g wet weight at the end of 30 min of incomplete cerebral ischemia. The presence of oxidative stress was further supported by ascorbic acid depletion, which was particularly significant after 10 and 30 min of incomplete ischemia. Carotid clamping provoked an imbalance between energy production and consumption that was evidenced by a reduction in ATP and GTP concentrations and an increase in ATP degradation products such as AMP, oxypurines and nucleosides. A decrement in the sum of adenine nucleotides and the energy charge potential indicated a progressive malfunctioning of energy-producing metabolic cycles. A possible contribution to such a severe change in energy state might be related to depletion of NAD and NADP, particularly noticeable after the longest incomplete brain ischemia times, that should have provoked a consequent lessening of oxido-reductive reactions. Bilateral carotid clamping causes a significant reduction in brain oxygen and substrate supply that results in inhibition of energy metabolism and triggering of oxygen-radical-induced lipid peroxidation.
 ...
PMID:Effects of increasing times of incomplete cerebral ischemia upon the energy state and lipid peroxidation in the rat. 943 8

Prolonged storage of organs for transplant results in tissue damage which may be compounded on reperfusion of the graft tissue. The effect of storage times was examined on hepatic mitochondrial oxygen consumption and activities of complexes I, II-III, IV, and V in mitochondria isolated from rat liver isografts stored for 25 min and 24 h pre- and posttransplantation. While Complex I activity was significantly (P < 0.05) inhibited under all the conditions studied, Complex II-III activity was only significantly (P < 0.05) reduced following transplantation of 24-h stored tissue. Complex IV activity remained unchanged under all the conditions studied. Although Complex V activity was significantly damaged within the first 25 min of ischemia, activity values were partially recovered to control levels following 3 h of reperfusion after transplantation. Prolonged (24 h) storage induced decreases in Complex V activity which were irrecoverable. Mitochondria subjected to 25 min ischemia alone also showed a significant (P < 0.01) decrease in NAD(+)-linked respiratory control indices due to a stimulated state 4 rate. The 24-h storage and transplantation brought about a significantly (P < 0.001) greater inhibition of respiratory control and state 3 respiration. FAD-linked respiration parameters were significantly (P < 0.05) affected in livers subjected to prolonged (24 h) storage or transplantation. These data suggest that a loss of membrane integrity coupled with an inhibition of Complexes I and V and an involvement of Complex II-III in 24-h stored hepatic transplants accounts for mitochondrial respiratory dysfunction in hepatic transplantation injury. No indication of Complex IV damage was found in this study. This study shows that damage to specific mitochondrial complexes occurs as a consequence of hypothermic ischemic injury.
 ...
PMID:Impairment of hepatic mitochondrial respiratory function following storage and orthotopic transplantation of rat livers. 950 Sep 32

We investigated the effects of cinnarizine and flunarizine on mitochondrial permeability transition, ATP synthesis, membrane potential and NAD(P)H oxidation. Both drugs were effective in inhibiting the mitochondrial permeability transition induced either by Ca2+ alone or in the presence of tert-butylhydroperoxide. This protective effect occurred at low concentrations (< 50 microM) of these drugs and was accompanied by the inhibition of NAD(P)H oxidation and the restoration of the mitochondrial membrane potential decreased by a high concentration of Ca2+ (25 microM). However, at higher concentrations (> 50 microM) of cinnarizine and flunarizine and in the absence of both tert-butylhydroperoxide and Ca2+, their effects on the mitochondria were reversed as follows: mitochondrial permeability transition was generated, mitochondrial NAD(P)H was oxidized and membrane potential collapsed. These deleterious effects were not antagonized by cyclosporine A, the most potent inhibitor of the mitochondrial permeability transition, but by 2,6-di-tert-butyl-4-methylphenol, a known antioxidant agent. This mitochondrial effect was neither accompanied by an increase in malondialdehyde production nor by an increase in H2O2 generation, which attested that the effect of both drugs was not due to an increase in reactive oxygen species production. The dual effects of both cinnarizine and flunarizine on mitochondrial functions is discussed with regard to both the protective effect afforded by these drugs against ischemia-reperfusion injury and their side effect observed in some therapeutic situations where an overdosage seems likely.
 ...
PMID:Dose-related inversion of cinnarizine and flunarizine effects on mitochondrial permeability transition. 965 Aug 38

Recent studies suggest a crucial role played by mitochondria in the pathogenesis of ischemia-reperfusion injury. This study was conducted to clarify the role of trimetazidine, a cellular anti-ischemic agent, on mitochondria isolated from rat liver subjected to 120-min normothermic ischemia followed by 30-min reperfusion. Rats were divided into groups, pretreated with different doses of trimetazidine (5, 10 and 20 mg/kg/day) or saline and subjected to the ischemia-reperfusion process; another group served as the sham-operated controls. Alanine aminotransferase and aspartate aminotransferase activities and hepatocyte ATP content, bile flow and mitochondrial functions were assessed. Ischemia-reperfusion caused membrane leakage from hepatocytes and a decrease in ATP content and in bile flow. These effects were well correlated with alterations in mitochondrial function, namely, decrease in ATP synthesis, NAD(P)H level and mitochondrial membrane potential and generation of mitochondrial permeability transition. The pretreatment of rats with trimetazidine prevented these ischemia-reperfusion deleterious effects at both the cellular and mitochondrial level in a dose-dependent manner. It is concluded that trimetazidine at an optimal dosage of 10 mg/kg/day protects mitochondria against the deleterious effects of ischemia-reperfusion. This protective effect appears to be the key factor through which this drug exerts its cytoprotective activity.
 ...
PMID:Trimetazidine counteracts the hepatic injury associated with ischemia-reperfusion by preserving mitochondrial function. 965 37

The relationships between mitochondrial derangements and cell necrosis are exemplified by the changes in the function and metabolism of mitochondria that occur in the ischemic heart. From a mitochondrial point of view, the evolution of ischemic damage can be divided into three phases. The first is associated with the onset of ischemia, and changes mitochondria from ATP producers into powerful ATP utilizers. During this phase, the inverse operation of F0F1 ATPase maintains the mitochondrial membrane potential by using the ATP made available by glycolysis. The second phase can be identified from the functional and structural alterations of mitochondria caused by prolongation of ischemia, such as decreased utilization of NAD-linked substrates, release of cytochrome c and involvement of mitochondrial channels. These events indicate that the relationship between ischemic damage and mitochondria is not limited to the failure in ATP production. Finally, the third phase links mitochondria to the destiny of the myocytes upon post-ischemic reperfusion. Indeed, depending on the duration and the severity of ischemia, not only is mitochondrial function necessary for cell recovery, but it can also exacerbate cell injury.
 ...
PMID:The role of mitochondria in the salvage and the injury of the ischemic myocardium. 971 44

Poly(ADP-ribose) polymerase (PARP) is a highly abundant nuclear enzyme which metabolizes NAD, in response to DNA strand breakage, to produce chains of poly(ADP-ribose) attached to nuclear proteins. PARP activation has been implicated in ischemia/reperfusion injury, but its biological significance is not fully understood. We have modified an existing in situ method for detection of PARP activity by using an NAD analogue in which adenine is modified by an "etheno" (vinyl) bridge. Etheno-NAD serves as a PARP substrate in an initial enzymatic reaction; a specific antibody to ethenoadenosine is then used in an immunohistochemical reaction to detect the production of modified poly(ADP-ribose). The method produces strong and specific labeling of nuclei in which PARP has been activated, i.e., those in which DNA strand breaks have been produced, and the results can be analyzed by microscopy, flow cytometry, or colorimetry. The method is applicable to cultured cells in several formats and to frozen tissue sections. The particular characteristics of the new method may assist in future in situ studies of PARP activation.
 ...
PMID:In situ staining for poly(ADP-ribose) polymerase activity using an NAD analogue. 977 27

A comparative study of the effects of excitotoxic levels of glutamate with ischemia on the cerebral energy metabolism and [NAD]/[NADH] ratio was carried out in adult rat brain slices. Glutamate moderately decreased the high energy phosphates and intracellular pH whereas ischemia showed a pronounced decrease in the high energy phosphates and intracellular pH. The [NAD]/[NADH] ratio increased continuously during glutamate exposure whereas an initial reduction and subsequent oxidation occurred during ischemia. Uptake of glutamate prevailed throughout the glutamate exposure to brain slices signifying favorable glial energy levels while efflux occurred during ischemia indicating complete neuronal and glial depolarization. A net synthesis of glutamate was also observed during ischemia. A small but significant increase in lactate may be a result of increased glycolysis during glutamate exposure, on the other hand a large increase in lactate during ischemia suggests a total failure of oxidative metabolism. Our results show that glutamate exposure to brain slices causes a mild energetic stress and an increase in [NAD]/[NADH] ratio whereas predominant inhibition of phosphate metabolites and dual effect on NAD/NADH redox state was observed during ischemia. It is suggested that the NAD/NADH redox state together with phosphate metabolites and intracellular pH of the periinfarct region could provide vital evidence about the possible involvement of glutamate.
 ...
PMID:Energy metabolism and NAD-NADH redox state in brain slices in response to glutamate exposure and ischemia. 1034 12

Mitochondrial membrane potential (delta psi(m)) was determined in intact isolated nerve terminals using the membrane potential-sensitive probe JC-1. Oxidative stress induced by H2O2 (0.1-1 mM) caused only a minor decrease in delta psi(m). When complex I of the respiratory chain was inhibited by rotenone (2 microM), delta psi(m) was unaltered, but on subsequent addition of H2O2, delta psi(m) started to decrease and collapsed during incubation with 0.5 mM H2O2 for 12 min. The ATP level and [ATP]/[ADP] ratio were greatly reduced in the simultaneous presence of rotenone and H2O2. H2O2 also induced a marked reduction in delta psi(m) when added after oligomycin (10 microM), an inhibitor of F0F1-ATPase. H2O2 (0.1 or 0.5 mM) inhibited alpha-ketoglutarate dehydrogenase and decreased the steady-state NAD(P)H level in nerve terminals. It is concluded that there are at least two factors that determine delta psi(m) in the presence of H2O2: (a) The NADH level reduced owing to inhibition of alpha-ketoglutarate dehydrogenase is insufficient to ensure an optimal rate of respiration, which is reflected in a fall of delta psi(m) when the F0F1-ATPase is not functional. (b) The greatly reduced ATP level in the presence of rotenone and H2O2 prevents maintenance of delta psi(m) by F0F1-ATPase. The results indicate that to maintain delta psi(m) in the nerve terminal during H2O2-induced oxidative stress, both complex I and F0F1-ATPase must be functional. Collapse of delta psi(m) could be a critical event in neuronal injury in ischemia or Parkinson's disease when H2O2 is generated in excess and complex I of the respiratory chain is simultaneously impaired.
 ...
PMID:Depolarization of in situ mitochondria due to hydrogen peroxide-induced oxidative stress in nerve terminals: inhibition of alpha-ketoglutarate dehydrogenase. 1038 74

Mitochondria are frequently the target of injury after stresses leading to necrotic and apoptotic cell death. Inhibition of oxidative phosphorylation progresses to uncoupling when opening of a high conductance permeability transition (PT) pore in the mitochondrial inner membrane abruptly increases the permeability of the mitochondrial inner membrane to solutes of molecular mass up to 1500 Da. Cyclosporin A (CsA) blocks this mitochondrial permeability transition (MPT) and prevents necrotic cell death from oxidative stress, Ca2+ ionophore toxicity, Reye-related drug toxicity, pH-dependent ischemia/reperfusion injury, and other models of cell injury. Confocal fluorescence microscopy directly visualizes onset of the MPT from the movement of green-fluorescing calcein into mitochondria and the simultaneous release from mitochondria of red-fluorescing tetramethylrhodamine methylester, a membrane potential-indicating fluorophore. In oxidative stress to hepatocytes induced by tert-butylhydroperoxide, NAD(P)H oxidation, increased mitochondrial Ca2+, and mitochondrial generation of reactive oxygen species precede and contribute to onset of the MPT. Confocal microscopy also shows directly that the MPT is a critical event in apoptosis of hepatocytes induced by tumor necrosis factor-alpha. Progression to necrotic and apoptotic cell killing depends, at least in part, on the effect the MPT has on cellular ATP levels. If ATP levels fall profoundly, necrotic killing ensues. If ATP levels are at least partially maintained, apoptosis follows the MPT. Cellular features of both apoptosis and necrosis frequently occur together after death signals and toxic stresses. A new term, necrapoptosis, describes such death processes that begin with a common stress or death signal, progress by shared pathways, but culminate in either cell lysis (necrosis) or programmed cellular resorption (apoptosis) depending on modifying factors such as ATP.
 ...
PMID:Mitochondrial dysfunction in the pathogenesis of necrotic and apoptotic cell death. 1066 21

The protective effect of O-(3-piperidino-2-hydroxy-1-propyl)nicotinic amidoxime (BGP-15) against ischemia-reperfusion-induced injury was studied in the Langendorff heart perfusion system. To understand the molecular mechanism of the cardioprotection, the effect of BGP-15 on ischemic-reperfusion-induced reactive oxygen species (ROS) formation, lipid peroxidation single-strand DNA break formation, NAD(+) catabolism, and endogenous ADP-ribosylation reactions were investigated. These studies showed that BGP-15 significantly decreased leakage of lactate dehydrogenase, creatine kinase, and aspartate aminotransferase in reperfused hearts, and reduced the rate of NAD(+) catabolism. In addition, BGP-15 dramatically decreased the ischemia-reperfusion-induced self-ADP-ribosylation of nuclear poly(ADP-ribose) polymerase(PARP) and the mono-ADP-ribosylation of an endoplasmic reticulum chaperone GRP78. These data raise the possibility that BGP-15 may have a direct inhibitory effect on PARP. This hypothesis was tested on isolated enzyme, and kinetic analysis showed a mixed-type (noncompetitive) inhibition with a K(i) = 57 +/- 6 microM. Furthermore, BGP-15 decreased levels of ROS, lipid peroxidation, and single-strand DNA breaks in reperfused hearts. These data suggest that PARP may be an important molecular target of BGP-15 and that BGP-15 decreases ROS levels and cell injury during ischemia-reperfusion in the heart by inhibiting PARP activity.
 ...
PMID:BGP-15, a nicotinic amidoxime derivate protecting heart from ischemia reperfusion injury through modulation of poly(ADP-ribose) polymerase. 1069 58


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>