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

Aspirin is widely used as an analgesic, in the secondary prevention of stroke, and has recently been suggested to be a putative neuroprotective agent, yet whether it acts directly on the central nervous system (CNS) is not yet clarified. We therefore examined the effect of lysine acetylsalicylate (L-ASA, 4-2000 microM) on neuronal function under normal conditions and following 1 h of ischemia using the in vitro rabbit retina preparation. L-ASA inhibited the light-evoked compound action potentials, but not the electroretinogram, in a concentration-dependent manner. In addition, L-ASA (2000 microM, but not 4, 40 or 200 microM) administered during ischemia, reduced the recovery of neuronal function compared to control (untreated) retinas. L-ASA therefore inhibits CNS neurotransmission, but not phototransduction, in a concentration-dependent manner. In addition, high concentration L-ASA impairs the recovery of neuronal function following an ischemic episode.
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PMID:Acetylsalicylate administered during simulated ischemia reduces the recovery of neuronal function in the in vitro rabbit retina. 968 41

We have shown that high-concentration albumin therapy is markedly neuroprotective in focal cerebral ischemia. The present study was conducted to ascertain the degree to which hemodynamic alterations are responsible for this therapeutic effect. Normothermic, physiologically regulated male Sprague-Dawley rats received a 2-h period of middle cerebral artery occlusion (MCAo) by insertion of an intraluminal suture coated with poly-L-lysine. Albumin (25% human serum albumin solution) or vehicle (0.9% sodium chloride) was administered intravenously at a dose of 1% of body weight immediately after suture withdrawal following 2-h MCAo. Local cerebral blood flow (LCBF) was measured autoradiographically with 14C-iodoantipyrine after 1 h of recirculation. Novel image-processing methods were used to compare average LCBF data sets against previously obtained infarction-frequency data on a pixel-by-pixel basis. Albumin therapy reduced mean hematocrit by 42% but produced no other systemic alterations. Pixel-based histopathological analysis revealed large, consistent cortical and subcortical infarcts in saline-treated rats with MCAo; albumin therapy reduced mean cortical infarct volume by 85%. Within regions showing albumin-associated neuroprotection, numbers of pixels having LCBF in the upper ischemic-core flow range (0.12-0.24 ml g-1 min-1) were reduced by 8.6-fold by albumin therapy when compared to saline-treated rats; and numbers of pixels with LCBF in the lower penumbral flow range (0.24-0.36 ml g-1 min-1) were reduced by 3. 1-fold in albumin-treated rats (p=0.04 by repeated-measures analysis of variance). Analysis of the [albumin-saline] 3-dimensional difference-image data set revealed a circumferential zone of statistically significant albumin-associated LCBF increase within the posterior portion of the ischemic hemisphere, surrounding the core-region of prior ischemia. Thus, high-concentration albumin therapy improves local perfusion to regions of critical LCBF reduction. The spatial extent of this LCBF effect, however, appears too small to account fully for the marked neuroprotective efficacy of this therapy. We suggest that other, non-hemodynamic mechanisms may also be contributory.
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PMID:The effect of high-dose albumin therapy on local cerebral perfusion after transient focal cerebral ischemia in rats. 972 10

Gene expression studies with in situ hybridization after focal brain ischemia indicate a variety of distinct anatomical patterns. An important question is to what extent such reactive gene expression correlates with neuronal damage or survival. To study these questions, we focused on two stressed-induced genes, heat shock protein 70 (HSP70) and growth-arrest and DNA damage-inducible gene (GADD) 45 mRNA, and we compared reactive changes in mRNA to loss of the constitutive signal for microtubule-associated protein 2 (MAP2) mRNA. A pixel-based image analysis of mRNA signals was carried out using a highly reproducible model of focal brain ischemia. A poly-l-lysine coated filament was used to occlude the origin of the middle cerebral artery (MCA) for 2 h in ventilated, normothermic rats. Brains were collected after 0, 1, 3 and 6 h, and 1, 3 and 7 days. In situ hybridization analysis was carried out for HSP70 mRNA, GADD45 mRNA and MAP2 mRNA. Autoradiographic data sets were averaged and co-mapped into a common template of the rat brain. These data sets were then compared on a pixel-by-pixel basis with previously acquired image data sets derived from quantitative studies of local cerebral blood flow (LCBF) (obtained at the end of 2-h ischemia) of and infarctive histopathology (obtained at 3 days) in the same focal ischemia model. HSP70 mRNA and GADD45 mRNA were grossly elevated in the hemisphere subjected to ischemia during the first day. Pixel-based analysis showed a strong correlation between HSP70 mRNA signals, the degree of early blood-flow reduction and the probability of histological infarction. GADD45 mRNA was expressed in a more variable fashion. Decreases in MAP2 mRNA signals at 1, 3 and 7 days correlated strongly with histological infarction. These co-mapping procedures allow us to conclude that HSP70 mRNA is a robust indicator of ischemic stress and histological outcome after 2 h of focal brain ischemia. The topographic features of GADD45 expression suggest its possible role in conferring resistance to ischemic injury. Finally, our results indicate that local decreases in constitutive MAP2 expression at 1 day and beyond may be used as a robust marker of tissue regions having a high probability of focal infarction.
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PMID:Pixel-based image analysis of HSP70, GADD45 and MAP2 mRNA expression after focal cerebral ischemia: hemodynamic and histological correlates. 983 56

1. One type of transglutaminase is usually accumulated in various forms of naturally occurring cell death and apoptosis. The accumulated enzyme is activated during the death process, leading to the formation of cross-linked protein structures. Degradation of the cross-linked apoptotic bodies results in the elevation of the epsilon (gamma-glutamyl)lysine isodipeptide concentration in body fluids, which may provide a diagnostic tool to monitor the apoptosis rate in various tissues under normal and pathologic conditions. 2. Extensive protein cross-linking may be directly related to the act of killing in some cells. In others, the effect of protein cross-linking is palliative, preventing leakage of macromolecules and enhancing phagocytosis of the dead cells. 3. Tissue transglutaminase has been implicated in some physiologic functions of the nervous system. 4. The molecular machinery of apoptosis is present and easily evoked in neuronal cells. 5. Effector elements of the apoptosis process have been associated with the pathogenesis of neurologic disorders. Tissue transglutaminase, representing one of the effector elements of apoptosis, may be induced and activated in cells following ischemia. It may also participate in the formation of abnormal cell inclusions and A beta deposits in amyloid plaques.
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PMID:Transglutaminase-catalyzed protein cross-linking in the molecular program of apoptosis and its relationship to neuronal processes. 987 74

Selective troponin I (TnI) modification has been demonstrated to be in part responsible for the contractile dysfunction observed with myocardial ischemia/reperfusion injury. We have isolated and characterized modified TnI products in isolated rat hearts after 0, 15, or 60 minutes of ischemia followed by 45 minutes of reperfusion using affinity chromatography with cardiac troponin C (TnC) and an anti-TnI antibody, immunological mapping, reversed-phase high-performance liquid chromatography, and mass spectrometry. Rat cardiac TnI becomes progressively degraded from 210 amino acid residues to residues 1-193, 63-193, and 73-193 with increased severity of injury. Degradation is accompanied by formation of covalent complexes between TnI 1-193 and, respectively, TnC residues 1-94 and troponin T (TnT) residues 191-298. The covalent complexes are likely a result of isopeptide bond formation between lysine 193 of TnI and glutamine 191 of TnT by the cross-linking enzyme transglutaminase. With severe ischemia, cellular necrosis results in specific release of TnI 1-193 into the reperfusion effluent and TnT degradation in the myocardium (25-, 27-, and 33-kDa products). Two-dimensional electrophoresis demonstrated that phosphorylation of TnI prevents ischemia-induced degradation. This study characterized the modified TnI products in isolated rat hearts reperfused after a brief or severe period of ischemia, revealing the progressive nature of TnI degradation, changes in phosphorylation, and covalent complexes with ischemia/reperfusion injury. Finally, we propose a model for ischemia/reperfusion injury in which the extent of proteolytic and transglutaminase activities ultimately determines whether apoptosis or necrosis is achieved.
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PMID:Troponin I degradation and covalent complex formation accompanies myocardial ischemia/reperfusion injury. 991 81

The in vivo state of phosphorylation and the modification of two Cys residues of neuromodulin/ GAP-43 (Nm) were analyzed by electrospray ionization-mass spectrometry (ES-MS). The protein was purified from rat brain with homogenization buffer containing 1% Nonidet P-40, protease inhibitors, protein phosphatase inhibitors, and sulfhydryl reagent, 4-vinylpyridine. Nm was purified by HPLC and ion-exchange chromatography, and the various fractions were identified by ES-MS as unphosphorylated and mono-, di-, tri-, and tetraphosphorylated species. All of these Nm species contained 2 mol of added 4-vinylpyridine per mol of Nm, suggesting that the two Cys residues are in the reduced form in the brain. In vivo, the majority of Nm is in the phosphorylated form (approximately 80%), of which the levels of the mono- and diphospho forms are higher than those of the tri- and tetraphospho species. Four in vivo phosphorylation sites, Ser41, Thr95, Ser142, and Thr172, were identified by amino acid sequencing and tandem ES-MS of the peptides derived from Lys-C endoproteinase digestion. Among these sites, only Ser41 is a known target of PKC, whereas the kinases responsible for the phosphorylation of the other three novel sites are unknown. Hypoxia/ischemia caused a preferential dephosphorylation of Ser41 and Thr172, whereas Thr95 is the least susceptible to dephosphorylation.
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PMID:Hypoxia/ischemia induces dephosphorylation of rat brain neuromodulin/GAP-43 in vivo. 1003 3

4-Hydroxy-2-nonenal (HNE) is a major lipid peroxidation product formed during oxidative stress. Because of its reactivity with nucleophilic compounds, particularly metabolites and proteins containing thiol groups, HNE is cytotoxic. The aim of this study was to assess the extent and time course for the formation of HNE-modified proteins during ischemia and ischemia plus reperfusion in isolated rat hearts. With an antibody to HNE-Cys/His/Lys and densitometry of Western blots, we quantified the amount of HNE-protein adduct in the heart. By taking biopsies from single hearts (n = 5) at various times (0, 5, 10, 15, 20, 35, and 40 min) after onset of zero-flow global ischemia, we showed a progressive, time-dependent increase (which peaked after 30 min) in HNE-mediated modification of a discrete number of proteins. In studies with individual hearts (n = 4/group), control aerobic perfusion (70 min) resulted in a very low level (296 arbitrary units) of HNE-protein adduct formation; by contrast, after 30-min ischemia HNE-adduct content increased by >50-fold (15,356 units, P < 0.05). In other studies (n = 4/group), administration of N-(2-mercaptopropionyl)glycine (MPG, 1 mM) to the heart for 5 min immediately before 30-min ischemia reduced HNE-protein adduct formation during ischemia by approximately 75%. In studies (n = 4/group) that included reperfusion of hearts after 5, 10, 15, or 30 min of ischemia, there was no further increase in the extent of HNE-protein adduct formation over that seen with ischemia alone. Similarly, in experiments with MPG, reperfusion did not significantly influence the tissue content of HNE-protein adduct. Western immunoblot results were confirmed in studies using in situ immunofluorescent localization of HNE-protein in cryosections. In conclusion, ischemia causes a major increase in HNE-protein adduct that would be expected to reflect a toxic sequence of events that might act to compromise tissue survival during ischemia and recovery on reperfusion.
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PMID:Formation of 4-hydroxy-2-nonenal-modified proteins in ischemic rat heart. 1007 77

Although interleukin-1beta (IL-1beta) has recently been implicated in neuronal cell death in vitro and in vivo after global forebrain ischemia, the role of IL-1beta in the functional injuries, i.e. impairment of synaptic transmission, after cerebral ischemia that does not cause neuronal death in the nervous system remains unknown. To address this question, we investigated the effect of short-term incomplete ischemia without apparent neural death on hippocampal long-term potentiation (LTP) in anesthetized rats, and examined the possible role of IL-1beta as an intermediary in this effect. Short-term incomplete cerebral ischemia (10 min) was induced in halothane-anesthetized rats by bilaterally clamping the common carotid arteries. Four days after ischemia, functional injuries in neuronal transmission in the hippocampal formation were observed without significant changes in pathological studies such as neuronal cell death. The LTP elicited in both Shaffer-CA1 synapses and perforant path-dentate gyrus synapses was significantly inhibited by the short-term incomplete ischemia. This inhibition of LTP was blocked by IL-1beta tripeptide antagonist (Lys-D-Pro-Thr), suggesting that the inhibitory effect of mild ischemia on synaptic potentials and LTP may be mediated by the generation of IL-1beta. These findings have important implications for the role of IL-1beta in not only neuronal cell death but also functional injuries without cell loss, perhaps elicited by transient cerebral ischemia.
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PMID:Effects of an interleukin-1beta analogue [Lys-D-Pro-Thr], on incomplete cerebral ischemia-induced inhibition of long-term potentiation in rat hippocampal neurons in vivo. 1008 76

The present study was conducted to validate a modified method of temporary focal cerebral ischemia in the mouse; neurobehavioral function and histopathological infarction were quantitated following various periods of middle cerebral artery occlusion (MCAo). Male C57BL/6 mice were anesthetized with 3% halothane in a mixture of 30%O2/70%N2O delivered by face mask and were subjected to 30- to 180-min of temporary middle cerebral artery occlusion (MCAo) by an intraluminal suture coated with poly-l-lysine. Twenty-eight of 40 mice showed an initial high-grade neurological deficit (30-min MCAo, n=7; 60-min, n=8; 120-min, n=8; 180-min, n=5) when examined during MCAo; these were used for subsequent study. One day after MCAo, behavioral function was re-evaluated, and brains were perfusion-fixed and infarct volumes were measured. The initial neurological deficit improved at 24 h in mice with 30- or 60-min of prior MCAo but tended to persist in mice with 120- or 180-min insults. Following each duration of ischemia, mice exhibited ipsilateral infarcts. Small, inconsistent predominantly subcortical infarcts were present after 30-min MCAo, while longer occlusion periods gave rise to consistent foci of subcortical infarction involving striatum, septum, thalamus, and hippocampus, as well as areas of frontoparietal cortical infarction. The major advantages of the improved intraluminal MCAo model reported here, incorporating sutures coated with poly-l-lysine, include: a 100% incidence of infarction of predictable location and size in mice having an initial neurological deficit. Periods of 60- to 180-min MCA occlusion in this model yield sufficiently reproducible sequelae to permit the effects of various therapeutic agents on neurological outcome and size of infarction to be readily studied.
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PMID:Middle cerebral artery occlusion in the mouse by intraluminal suture coated with poly-L-lysine: neurological and histological validation. 1037 93

Recent advances in computerized image-averaging, used in conjunction with refined techniques for engendering highly reproducible rodent models of focal ischemia, now make it possible to derive topographically precise, quantitative descriptors of the ischemic penumbra--its localization, lifespan, metabolic and hemodynamic features, and responses to therapy. Physiologically monitored normothermic rats received 2-h middle cerebral artery occlusion (MCAo) by means of a poly-L-lysine-coated intraluminal suture. In matched groups, local cerebral blood flow (LCBF) or glucose utilization (LCMRglc) were measured autoradiographically at either 2-h MCAo or at 1-h recirculation and were correlated on a pixel-by-pixel basis with histopathological infarction after 3-day survival. A large, consistent ischemic penumbra (defined as LCBF 20-40% of control) surrounded the core (0-20% of control). Penumbral LCMRglc at 2-h MCAo was near-normal, and its metabolism/flow ratio was elevated 4-fold above normal. By 1-h recirculation, however, LCMRglc throughout the prior zone of ischemia was depressed. Infarctive histopathology was precisely determined by the antecedent LCBF decrement during ischemia: 70% and 89% of infarcted pixels had antecedent LCBF values below the upper-core and upper-penumbral ranges, respectively, at 2-h MCAo. High-dose albumin therapy at the onset of recirculation dramatically attenuated cortical infarction and brain edema and appeared, by LCBF analysis at 1-h recirculation, to increase postischemic LCBF primarily in the former penumbra.
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PMID:The acute ischemic penumbra: topography, life span, and therapeutic response. 1049 40


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