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

Nontraumatic arterial dissection of the anterior cerebral artery (NAD-ACA) is a relatively rare disease entity, although case reports have recently been increased. We treated 6 patients suffering from NAD-ACA from January 1996 to December 2003, and the neuroradiological findings together with the clinical courses were reviewed. There were 3 males and 3 females with a mean age of 57.7-year-old, ranging from 41 to 65. Five patients had a past history of hypertension and one diabetes mellitus. At the onset, all patients presented with clinical manifestations of cerebral ischemia. Among them, all exhibited contralateral hemiparesis with greater weakness of the lower extremity, and two patients exhibited headache. Initial angiography revealed the pearl and string sign in four patients and string sign, tapered occlusion in each one. Follow-up angiographies revealed sequential changes in all patients; four improved and two progressed. Main anatomic site of the lesion was as follows; five in the A2 and one in the A1 portion, in addition, one patient was complicated by saccular aneurysm, one by PCA dissection, and two had with saccular aneurysm contralateral ACA & MCA and VA dissection each other. Four patients were treated conservatively by intravenous administration of argatroban, one by intravenous administration of Dextrane and one by anti-platelet agent in the acute stage. All patients were treated by anti-platelet agents in the chronic stage. Good recovery was achieved in five patients, but one who suffered from severe subarachnoid hemorrhage in the chronic stage died. Our experience suggests that hypertension and/or the succeeding abnormal structural changes in the arterial wall may contribute to the occurrence of this disease. NAD-ACA showing clinical manifestations of cerebral ischemia could result in a relatively good prognosis; however, attention should be paid to patients treated conservatively with a very closed follow-up angiography to prevent a possibility of severe hemorrhage.
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PMID:[Nontraumatic arterial dissection of the anterior cerebral artery: six cases report]. 1602 47

Neuronal cells injured by ischemia and reperfusion to a certain extent are committed to death in necrotic or apoptotic form. Necrosis is induced by gross ATP depletion or 'energy crisis' of the cell, whereas apoptosis is induced by a mechanism still to be defined in detail. Here, we investigated this mechanism by focusing on a DNA damage-sensor, poly(ADP-ribose) polymerase-1 (PARP-1). A 2-h oxygen and glucose deprivation (OGD) followed by reoxygenation (Reox) induced apoptosis, rather than necrosis, in rat cortical neurons. During the Reox, PARP-1 was much activated and autopoly(ADP-ribosyl)ated, consuming the substrate, NAD+. Induction of apoptosis by OGD/Reox was suppressed by overexpression of Bcl-2, indicating mitochondrial impairment in this induction process. Mitochondrial permeability transition (MPT), or membrane depolarization, and a release of proapoptotic proteins, i.e. cytochrome c, apoptosis-inducing factor and endonuclease G, from mitochondria were observed during the Reox. These apoptotic changes of mitochondria and the nucleus were attenuated by PARP-1 inhibitors, 1,5-dihydroxyisoquinoline and benzamide, and also by small interfering RNA specific for PARP-1. These results indicated that PARP-1 plays a principal role in inducing mitochondrial impairment that ultimately leads to apoptosis of neurons after cerebral ischemia.
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PMID:Mitochondrial impairment induced by poly(ADP-ribose) polymerase-1 activation in cortical neurons after oxygen and glucose deprivation. 1618 22

Nicotinamide, the amide form of niacin (vitamin B(3)), is the precursor for the coenzyme beta-nicotinamide adenine dinucleotide (NAD(+)) and plays a significant role during the enhancement of cell survival as well as cell longevity. Yet, these abilities of nicotinamide appear to be diametrically opposed. Here we describe the development of nicotinamide as a novel agent that is critical for modulating cellular metabolism, plasticity, longevity, and inflammatory microglial function as well as for influencing cellular life span. The capacity of nicotinamide to govern not only intrinsic cellular integrity, but also extrinsic cellular inflammation rests with the modulation of a host of cellular targets that involve mitochondrial membrane potential, poly(ADP-ribose) polymerase, protein kinase B (Akt), Forkhead transcription factors, Bad, caspases, and microglial activation. Further knowledge acquired in regards to the ability of nicotinamide to foster cellular survival and regulate cellular lifespan should significantly promote the development of therapies against a host of disorders, such as aging, Alzheimer's disease, diabetes, cerebral ischemia, Parkinson's disease, and cancer.
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PMID:Cell Life versus cell longevity: the mysteries surrounding the NAD+ precursor nicotinamide. 1661 Oct 73

Oxidative stress induced cell injury is reported to contribute to the pathogenesis of cerebral ischemia. Reactive oxygen species such as hydrogen peroxide (H2O2) and superoxide radical along with nitric oxide and peroxynitrite generated during ischemia-reperfusion injury, causes the overactivation of poly (ADP-ribose) polymerase (PARP) leading to neuronal cell death. In the present study we have evaluated the effects of PARP inhibitor, 8-hydroxy-2 methyl-quinazolin-4-[3H]one (NU1025) in H2O2 and 3-morphilinosyndonimine (SIN-1) induced cytotoxicity in PC12 cells as well as in middle cerebral artery occlusion (MCAO) induced focal cerebral ischemia in rats. Exposure of PC12 cells to H2O2 (0.4 mM) and SIN-1 (0.8 mM) resulted in a significant decrease in cell viability after 6 h. Pretreatment with NU1025 (0.2 mM) restored cell viability to approximately 73 and 82% in H2O2 and SIN-1 injured cells, respectively. In MCAO studies, NU1025 was administered at different time points (1 h before reperfusion, immediately before reperfusion, 3 h after reperfusion and 6 h after reperfusion). NU1025 at 1 and 3 mg/kg reduced total infarct volume to 25% and 45%, respectively, when administered 1 h before reperfusion. NU1025 also produced significant improvement in neurological deficits. Neuroprotection with NU1025 was associated with reduction in PAR accumulation, reversal of brain NAD depletion and reduction in DNA fragmentation. Results of this study demonstrate the neuroprotective activity of NU1025 and suggest its potential in cerebral ischemia.
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PMID:Neuroprotective effects of NU1025, a PARP inhibitor in cerebral ischemia are mediated through reduction in NAD depletion and DNA fragmentation. 1693 10

Excessive poly(ADP-ribose) polymerase-1 (PARP-1) activation plays a significant role in ischemic brain damage. Increasing evidence has supported the hypothesis that PARP-1 induces cell death by depleting intracellular NAD+. Based on our in vitro finding that NAD+ treatment can abolish PARP-1-mediated cell death, we hypothesized that NAD+ administration may decrease ischemic brain injury. In this study, we used a rat model of transient focal ischemia to test this hypothesis. We observed that intranasal NAD+ delivery significantly increased NAD+ contents in the brains. Intranasal delivery with 10 mg/kg NAD+ at 2 hours after ischemic onset profoundly decreased infarct formation when assessed either at 24 or 72 hours after ischemia. The NAD+ administration also significantly attenuated ischemia-induced neurological deficits. In contrast, intranasal administration with 10 mg/kg nicotinamide did not decrease ischemic brain damage. These results provide the first in vivo evidence that NAD+ metabolism is a new target for treating brain ischemia, and that NAD+ administration may be a novel strategy for decreasing brain damage in cerebral ischemia and possibly other PARP-1-associated neurological diseases.
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PMID:Intranasal administration with NAD+ profoundly decreases brain injury in a rat model of transient focal ischemia. 1712 75

Mild hypothermia, applied either during or soon after cerebral ischemia, has been shown to confer robust neuroprotection against brain injury in experimental stroke and in patients recovering from cardiac arrest. However, the mechanism underlying hypothermic neuroprotection is not completely understood. In this study, the effect of mild hypothermia on the induction of oxidative DNA damage, an early harmful event during post-ischemic reperfusion that triggers both necrotic and apoptotic cell death in the brain, was studied using the rat model of middle cerebral artery occlusion (MCAO) and reperfusion. Rats were subjected to 2-hr MCAO and reperfusion of various durations up to 3 days. Selective brain hypothermia (33 degrees C) was induced at the onset of ischemia and terminated at the beginning of reperfusion, and this significantly decreased infarct volume 72 hr later. Correlated with this protective effect, intraischemic mild hypothermia markedly attenuated the nuclear accumulations of several oxidative DNA lesions, including 8-oxodG, AP sites, and DNA single-strand breaks, after 2-hr MCAO. Consequently, harmful DNA damage-dependent signaling events, including NAD depletion, p53 activation, and mitochondrial translocation of PUMA and NOXA, were reduced during post-ischemic reperfusion in hypothermia-treated brains. These results suggest that the attenuation of oxidative DNA damage and DNA damage-triggered pro-death signaling events may be an important mechanism underlying the neuroprotective effect of mild hypothermia against ischemic brain injury.
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PMID:Mild hypothermia diminishes oxidative DNA damage and pro-death signaling events after cerebral ischemia: a mechanism for neuroprotection. 1712 18

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.
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PMID:Diphenyleneiodonium and dimethylsulfoxide for treatment of reperfusion injury in cerebral ischemia of the rat. 1718 51

Increasing evidence indicates that neurosteroid 17beta-Estradiol (E2), a type of female sex hormone, has a neuroprotective effect against cerebral injury. However, it remains unknown whether E2 can also protect the hippocampal CA1 neurons from functional deficits in synaptic transmission and plasticity caused by ischemia. To address this issue, adult male Wistar rats were subjected to mild global cerebral ischemia created by four-vessel occlusion (4VO) for 10min, and the effects of E2 administration against the ischemic injury were investigated. The electrophysiological properties of Schaffer collateral-CA1 synapses were examined 7days after ischemia by applying a real-time optical recording technique to the hippocampal slices stained with a voltage-sensitive dye (RH482). The ischemic brain showed a decreased basal synaptic transmission and an impairment of LTP induction, but no alteration in paired-pulse facilitation. The administration of E2 (1mg/kg) 3h before ischemia was able to protect CA1 neurons from these ischemia-induced synaptic dysfunctions. The estrogen receptor-alpha (ERalpha) selective agonist, propyl pyrazole triol (PPT, 2mg/kg), exerted a similar protective effect, but the estrogen receptor-beta (ERbeta) agonist, diarylpropiolnitrile (DPN, 8mg/kg), failed to do so. A histological examination revealed that the transient global cerebral ischemia markedly reduced the density of pyramidal neurons in the CA1 region. The cell loss was significantly attenuated by E2 and PPT but not by DPN, as observed in synaptic functions. These findings suggest that E2 can protect neurons not only from cell death but also from functional damages due to a relatively mild degree of transient cerebral ischemia, and this effect is mediated by ERalpha, but not by ERbeta.
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PMID:Neurosteroid estradiol rescues ischemia-induced deficit in the long-term potentiation of rat hippocampal CA1 neurons. 1725 38

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.
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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.
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PMID:Spatial and functional relationship between poly(ADP-ribose) polymerase-1 and poly(ADP-ribose) glycohydrolase in the brain. 1764 Aug 16


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