Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0917798 (cerebral ischemia)
 17,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Diphenyleneiodonium (DPI) is an inhibitor of the free radical producing NAD(P)H-oxidase. We tested whether DPI shows neuroprotective properties after focal cerebral ischemia and we used dimethylsulfoxide (DMSO), a nonspecific free radical scavenger, as a solvent. In male Wistar rats middle cerebral artery occlusion (1.5 h) and subsequent reperfusion (48 h) (MCAO/R) was induced with the filament model. Immediately after reperfusion the animals received either 0.25 ml normal saline, DMSO, or a combination of DMSO and DPI; each group consisted of 10 animals. MRI was performed at different times after reperfusion. Gelatine zymography of brain tissue for MMP-2 and MMP-9 was performed. The infarct sizes and BBB damage showed a significant difference between controls and the DPI/DMSO group for almost all points in time in all sequences. The activity of MMP-2 and MMP-9 was significantly reduced by DPI/DMSO but not by DMSO alone. DMSO treatment alone resulted in a protective effect with reduced lesion sizes measured by MRI at selected points of time, consistent with its known free radical scavenger effect. The combination of DMSO with DPI partly augmented this effect, presumably due to the additional inhibition of MMP-2 and MMP-9 by DPI. Moreover, the neurological outcome in both therapeutic groups was improved compared to controls with a significant difference between the therapeutic groups in favour of DPI and DMSO. The combination of DPI and DMSO reduced the activity of MMP-2 and MMP-9, attenuated the postischemic blood-brain barrier damage and improved neurological outcome. This was most likely due to reduced oxidative stress.
 ...
PMID:Diphenyleneiodonium and dimethylsulfoxide for treatment of reperfusion injury in cerebral ischemia of the rat. 1718 51

The catalytic properties of mitochondrial and cytoplasmic isoenzymes of NAD-dependent brain malate dehydrogenase (MDH) were studied under hypoxic or ischemic conditions. Hypoxia was modeled in animals in pressure chamber, while ischemia was achieved via bilateral ligation of common carotic arteries. The properties of MDH in mitochondria of rat brain were studied; they were significantly different from those of MDH purified from bovine brain. The study revealed the importance of mitochondrial membranes for the regulation of malate dehydrogenase catalytic properties in brain mitochondria. Cerebral ischemia changes mitochondrial malate dehydrogenase significantly, which demonstrates disorder in MDH-membrane interaction. Cytoplasmic enzyme displays high activity and stability of its catalytic properties. Under cerebral hypoxia or ischemia catalytic properties of cytoplasmic malate dehydrogenase change only slightly, maintaining enzyme activity at a constantly high level.
 ...
PMID:[Properties of NAD-dependent brain enzymes under the conditions of hypoxia and ischemia]. 1739 58

Poly(ADP-ribose) polymerases (PARPs) are members of a family of enzymes that utilize nicotinamide adenine dinucleotide (NAD(+)) as substrate to form large ADP-ribose polymers (PAR) in the nucleus. PAR has a very short half-life due to its rapid degradation by poly(ADP-ribose) glycohydrolase (PARG). PARP-1 mediates acute neuronal cell death induced by a variety of insults including cerebral ischemia, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinsonism, and CNS trauma. While PARP-1 is localized to the nucleus, PARG resides in both the nucleus and cytoplasm. Surprisingly, there appears to be only one gene encoding PARG activity, which has been characterized in vitro to generate different splice variants, in contrast to the growing family of PARPs. Little is known regarding the spatial and functional relationships of PARG and PARP-1. Here we evaluate PARG expression in the brain and its cellular and subcellular distribution in relation to PARP-1. Anti-PARG (alpha-PARG) antibodies raised in rabbits using a purified 30 kDa C-terminal fragment of murine PARG recognize a single band at 111 kDa in the brain. Western blot analysis also shows that PARG and PARP-1 are evenly distributed throughout the brain. Immunohistochemical studies using alpha-PARG antibodies reveal punctate cytosolic staining, whereas anti-PARP-1 (alpha-PARP-1) antibodies demonstrate nuclear staining. PARG is enriched in the mitochondrial fraction together with manganese superoxide dismutase (MnSOD) and cytochrome C (Cyt C) following whole brain subcellular fractionation and Western blot analysis. Confocal microscopy confirms the co-localization of PARG and Cyt C. Finally, PARG translocation to the nucleus is triggered by NMDA-induced PARP-1 activation. Therefore, the subcellular segregation of PARG in the mitochondria and PARP-1 in the nucleus suggests that PARG translocation is necessary for their functional interaction. This translocation is PARP-1 dependent, further demonstrating a functional interaction of PARP-1 and PARG in the brain.
 ...
PMID:Spatial and functional relationship between poly(ADP-ribose) polymerase-1 and poly(ADP-ribose) glycohydrolase in the brain. 1764 Aug 16

Cardiovascular pathologies in the French are not prevalent despite high dietary saturated fat consumption. This is commonly referred to as the "French Paradox" attributing its anti-lipidemic effects to moderate consumption of red wine. Resveratrol, a phytoalexin found in red wine, is currently the focus of intense research both in the cardiovascular system and the brain. Current research suggests resveratrol may enhance prognosis of neurological disorders such as, Parkinson's, Huntington's, Alzheimer's diseases and stroke. The beneficial effects of resveratrol include: antioxidation, free radical scavenger, and modulation of neuronal energy homeostasis and glutamatergic receptors/ion channels. Resveratrol directly increases sirtuin 1 (SIRT1) activity, a NAD(+) (oxidized form of nicotinamide adenine dinucleotide)-dependent histone deacetylase related to increased lifespan in various species similar to calorie restriction. We recently demonstrated that brief resveratrol pretreatment conferred neuroprotection against cerebral ischemia via SIRT1 activation. This neuroprotective effect produced by resveratrol was similar to ischemic preconditioning-induced neuroprotection, which protects against lethal ischemic insults in the brain and other organ systems. Inhibition of SIRT1 abolished ischemic preconditioning-induced neuroprotection in CA1 region of the hippocampus. Since resveratrol and ischemic preconditioning-induced neuroprotection require activation of SIRT1, this common signaling pathway may provide targeted therapeutic treatment modalities as it relates to stroke and other brain pathologies. In this review, we will examine common signaling pathways, cellular targets of resveratrol, and ischemic preconditioning-induced neuroprotection as it relates to the brain.
 ...
PMID:Resveratrol and ischemic preconditioning in the brain. 1853 30

In cerebral ischemia survival of neurons, astrocytes, oligodendrocytes and endothelial cells is threatened during energy deprivation and/or following re-supply of oxygen and glucose. After a brief summary of characteristics of different cells types, emphasizing the dependence of all on oxidative metabolism, the bioenergetics of focal and global ischemia is discussed, distinguishing between events during energy deprivation and subsequent recovery attempt after re-circulation. Gray and white matter ischemia are described separately, and distinctions are made between mature and immature brains. Next comes a description of bioenergetics in individual cell types in culture during oxygen/glucose deprivation or exposure to metabolic inhibitors and following re-establishment of normal aerated conditions. Due to their expression of NMDA and non-NMDA receptors neurons and oligodendrocytes are exquisitely sensitive to excitotoxicity by glutamate, which reaches high extracellular concentrations in ischemic brain for several reasons, including failing astrocytic uptake. Excitotoxicity kills brain cells by energetic exhaustion (due to Na(+) extrusion after channel-mediated entry) combined with mitochondrial Ca(2+)-mediated injury and formation of reactive oxygen species. Many (but not all) astrocytes survive energy deprivation for extended periods, but after return to aerated conditions they are vulnerable to mitochondrial damage by cytoplasmic/mitochondrial Ca(2+) overload and to NAD(+) deficiency. Ca(2+) overload is established by reversal of Na(+)/Ca(2+) exchangers following Na(+) accumulation during Na(+)-K(+)-Cl(-) cotransporter stimulation or pH regulation, compensating for excessive acid production. NAD(+) deficiency inhibits glycolysis and eventually oxidative metabolism, secondary to poly(ADP-ribose)polymerase (PARP) activity following DNA damage. Hyperglycemia can be beneficial for neurons but increases astrocytic death due to enhanced acidosis.
 ...
PMID:Bioenergetics of cerebral ischemia: a cellular perspective. 1863 6

Scutellarin (Scu) is the major active principle (flavonoid) extracted from Erigeron breviscapus (Vant.) Hand-Mazz, a Chinese herbal medicine. In this paper, we investigated the effects of Scu on brain injury through the inhibition of AIF-mediated apoptosis induced by transient focal brain ischemia in rats. Rats were treated with Scu for 7 d and then subjected to cerebral ischemia/reperfusion (I/R) injury induced by a middle cerebral artery occlusion (MCAO). After 2 h of ischemia and 22 h of reperfusion, the infarct volume and the neurological deficit were determined by TTC staining and Longa's score. IN SITU end-labeling of nuclear DNA fragments (TUNEL) was employed to determine the degree of DNA fragmentation. NAD content and PARP activity in brain homogenate were determined. The expression of AIF in the nucleus was analyzed by Western blot. The present study showed that Scu significantly reduced the infarct volume and ameliorated the neurological deficit. An increase in the number of TUNEL-positive cells and a decrease in the NAD level were also observed after 2 h of ischemia and 22 h of reperfusion. At the same time, Scu (50 and 75 mg kg (-1), i. g.) treatment reversed brain NAD depletion and reduced DNA fragmentation. Scu also inhibited PARP overactivation and AIF translocation from the mitochondria to the nucleus following cerebral I/R. These findings suggested that the neuroprotective effects of Scu on brain ischemic injury-induced apoptosis might be associated with inhibition of PARP-dependent mitochondrial dysfunction and subsequent translocation of AIF.
 ...
PMID:Protective effects of scutellarin against cerebral ischemia in rats: evidence for inhibition of the apoptosis-inducing factor pathway. 1903 63

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.
 ...
PMID:Physiologically relevant online electrochemical method for continuous and simultaneous monitoring of striatum glucose and lactate following global cerebral ischemia/reperfusion. 1928 Dec 58

Resveratrol is a natural polyphenol found in grapes and wine and has been associated with protective effects against cardiovascular diseases. In vitro, both resveratrol preconditioning (RPC) and ischemic preconditioning (IPC) require activation of sirtuin 1 (SIRT1), a nicotinamide adenine dinucleotide (NAD(+))-dependent deacetylase, to induce neuroprotection against cerebral ischemia. In the present study, we tested two hypotheses: (a) that neuroprotection against cerebral ischemia can be induced by RPC in vivo; and (b) that RPC neuroprotection involves alterations in mitochondrial function via the SIRT1 target mitochondrial uncoupling protein 2 (UCP2). IPC was induced by 2 min of global ischemia (temporary bilateral carotid artery occlusion with hypotension), and RPC, by i.p. injection of resveratrol at 10, 50 and 100 mg/kg dosages. Forty-eight hours later, we compared the neuroprotective efficacy of RPC and IPC in vulnerable cornu ammonis 1 hippocampal pyramidal neurons using a rat model of asphyxial cardiac arrest (ACA). SIRT1 activity was measured using a SIRT1-specific fluorescent enzyme activity assay. In hippocampal mitochondria isolated 48 h after IPC or RPC, we measured UCP2 levels, membrane potential, respiration, and the mitochondrial ATP synthesis efficiency (ADP/O ratio). Both IPC and RPC induced tolerance against brain injury induced by cardiac arrest in this in vivo model. IPC increased SIRT1 activity at 48 h, while RPC increased SIRT1 activity at 1 h but not 48 h after treatment in hippocampus. Resveratrol significantly decreased UCP2 levels by 35% compared to sham-treated rats. The SIRT1-specific inhibitor sirtinol abolished the neuroprotection afforded by RPC and the decrease in UCP2 levels. Finally, RPC significantly increased the ADP/O ratio in hippocampal mitochondria reflecting enhanced ATP synthesis efficiency. In conclusion, in vivo resveratrol pretreatment confers neuroprotection similar to IPC via the SIRT1-UCP2 pathway.
 ...
PMID:Resveratrol pretreatment protects rat brain from cerebral ischemic damage via a sirtuin 1-uncoupling protein 2 pathway. 1935 83

Oxidative stress is a mediator of cell death following cerebral ischemia/reperfusion and heme toxicity, which can be an important pathogenic factor in acute brain injury. Induced expression of phase II detoxification enzymes through activation of the antioxidant response element (ARE)/Nrf2 pathway has emerged as a promising approach for neuroprotection. Little is known, however, about the neuroprotective potential of this strategy against injury in immature brain cells. In this study, we tested the hypothesis that sulforaphane (SFP), a naturally occurring isothiocyanate that is also a known activator of the ARE/Nrf2 antioxidant pathway, can protect immature neurons from oxidative stress-induced death. The hypothesis was tested with primary mouse hippocampal neurons exposed to either O(2) and glucose deprivation (OGD) or hemin. Treatment of immature neurons with SFP immediately after the OGD during reoxygenation was effective in protecting immature neurons from delayed cell death. Exposure of immature hippocampal neurons to hemin induced significant cell death, and both pre- and cotreatment with SFP were remarkably effective in blocking cytotoxicity. RT-PCR analysis indicated that several Nrf2-dependent cytoprotective genes, including NAD(P)H quinone oxidoreductase 1 (NQO1), heme oxygenase 1 (HO1), and glutamate-cysteine ligase modifier subunit (GCLM), which is involved in glutathione biosynthesis, were up-regulated following SFP treatment both in control neurons and following exposure to OGD and hemin. These results indicate that SFP activates the ARE/Nrf2 pathway of antioxidant defense and protects immature neurons from death caused by stress paradigms relevant to those associated with ischemic and traumatic injury to the immature brain.
 ...
PMID:Sulforaphane protects immature hippocampal neurons against death caused by exposure to hemin or to oxygen and glucose deprivation. 1999 83

Activation of poly (ADP-ribose) polymerases (PARP) contributes to ischemic damage by causing neuronal nicotinamide adenine dinucleotide (NAD(+)) depletion, release of apoptosis-inducing factor and consequent caspase-independent cell death. PARP-mediated cell death is sexually dimorphic, participating in ischemic damage in the male brain, but not the female brain. We tested the hypothesis that androgen signaling is required for this male-specific neuronal cell death pathway. We observed smaller damage following focal cerebral ischemia (MCAO) in male PARP-1 knockout mice compared to wild type (WT) as well as decreased damage in male mice treated with the PARP inhibitor PJ34. Protection from ischemic damage provided by PJ-34 in WT mice is lost after removal of testicular androgens (CAST) and rescued by androgen replacement. CAST PARP-1 KO mice exhibit increased damage compared to intact male KO mice, an effect reversed by androgen replacement in an androgen receptor-dependent manner. Lastly, we observed that ischemia causes an increase in PARP-1 expression that is diminished in the absence of testicular androgens. Our data indicate that PARP-mediated neuronal cell death in the male brain requires intact androgen-androgen receptor signaling.
 ...
PMID:Poly (ADP-ribose) polymerase-1 initiated neuronal cell death pathway--do androgens matter? 2003 40


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