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)

Consumption of alcohol during pregnancy can result in central nervous system deficits in infants ranging from fetal alcohol effects to fetal alcohol syndrome. Changes in cerebral metabolism causing ischemic in utero conditions can also result from ethanol (EtOH). Growth factors have been shown to ameliorate ischemic damage and EtOH-induced neurotoxicity. However, using an in vitro model system of fetal alcohol effects/fetal alcohol syndrome, this study examines the neuroprotective effects of nerve growth factor, brain-derived neurotrophic factor, or glial cell line derived neurotrophic factor against EtOH treatment (0, 200, 400, 800, or 1, 600 mg/dl) combined with acute ischemia (2-hour hypoxia in EtOH-containing glucose-free media) followed by chronic hypoglycemia (16-hour glucose deprivation in EtOH-containing media). 3-(4, 5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assays assessed relative neurotoxicity. Glial cell derived neurotrophic factor was not neuroprotective. Nerve growth factor protected against ischemia/hypoglycemia combined with 0-1,600 mg/dl EtOH. Brain-derived neurotrophic factor protected against ischemia/hypoglycemia combined with 0-800 mg/dl EtOH. These studies demonstrate marked growth factor neuroprotection against a myriad of conditions encountered by developing EtOH-exposed fetuses.
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PMID:BDNF and NGF afford in vitro neuroprotection against ethanol combined with acute ischemia and chronic hypoglycemia. 1007 4

Neurodevelopmental damage can occur as a result of in utero exposure to alcohol. Oxidative stress processes are one of many proposed mechanisms thought to contribute to nervous system dysfunction characterized in fetal alcohol syndrome (FAS). Therefore, this study examined neuroprotective effects of antioxidant supplementation during ethanol (EtOH) treatment (0, 200, 400, 800 or 1600 mg/dl) combined with concomitants of EtOH exposure: acute (2-h) ischemia (aISCH) and chronic (16-h) hypoglycemia (cHG). The antioxidants vitamin E and beta-carotene protected embryonic hippocampal cultures against 0-1600 mg/dl EtOH/aISCH/cHG treatments. In addition, neuronal viability, as measured by MTT ((3,4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide; 5 mg/ml)), was equal to untreated cultures when supplemented with vitamin E or beta-carotene at 0-800 mg/dl or 0-200 mg/dl EtOH/aISCH/cHG, respectively. These in vitro studies mirror potential in utero ethanol-exposed CNS conditions and may lead to therapeutic strategies targeted at attenuating neurodevelopmental FAS-related deficits.
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PMID:Vitamin E and beta-carotene protect against ethanol combined with ischemia in an embryonic rat hippocampal culture model of fetal alcohol syndrome. 1021 67

Cerebral hypoxia/ischemia was shown to induce delayed, apoptotic neuronal death occurring through biochemical pathways potentially sharing common events with cell proliferation. This study was designed to test the hypothesis that a sublethal hypoxia may promote mitotic activity in developing central neurons. After six days in vitro, cultured neurons from the forebrain of 14-day-old rat embryos were exposed to hypoxia (95% N2/5% CO2) for 3 h and re-oxygenated for up to 96 h. Controls were kept in normoxia. As a function of time, cell viability was measured by diphenyltetrazolium bromide, and rates of DNA and protein synthesis were monitored using [3H]thymidine and [3H]leucine, respectively. Morphological features of apoptosis, necrosis and mitosis were scored under fluorescence microscopy after nuclear staining with 4,6-diamidino-2-phenylindole, and the expression profile of proliferating cell nuclear antigen, a cofactor for DNA polymerase, was analysed by immunohistochemistry. Data were compared to those obtained after transient hypoxia for 6 h followed by re-oxygenation for 96 h and which was shown to induce apoptosis. Whereas a 6-h insult reduced cell viability, with 23% of the neurons exhibiting apoptosis by the end of re-oxygenation, a 3-h hypoxia led to a cycloheximide-sensitive increase in the final number of living neurons compared to controls (13%, P < 0.01), with no signs of apoptosis, significantly increased thymidine incorporation into acid-precipitable fraction, and persistent over-expression of proliferating cell nuclear antigen. Accordingly, final score of mitotic nuclei was significantly enhanced. In addition, the cell cycle inhibitor olomoucine (50 microM) prevented apoptosis consecutive to a 6-h hypoxia, but impaired the stimulatory effects of a 3-h insult. These findings support the conclusion that some neurons exposed to sublethal hypoxia may dodge apoptotic death by fully achieving the cell cycle.
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PMID:Transient hypoxia may lead to neuronal proliferation in the developing mammalian brain: from apoptosis to cell cycle completion. 1033 73

In an evaluation of the contribution of swelling-induced amino acid release, through the regulatory volume decrease (RVD) process, to cerebral ischemic injury, studies of the role of phospholipases and protein kinases in the response to hyposmotic stress were undertaken using an in vivo rat cortical cup model. Hyposmotic stress induced significant releases of aspartate, glutamate, glycine, phosphoethanolamine, taurine and GABA from the rat cerebral cortex. Taurine release was most affected, exhibiting a greater than 9-fold increase during the hyposmotic stimulus. The phospholipase A2 (PLA2) inhibitors 4-bromophenacyl bromide (1 microM) and 7,7-dimethyleicosadienoic acid (5 microM) had no significant effects on hyposmotically induced amino acid release. AACOCF3 (50 microM), an inhibitor of cytosolic PLA2 decreased taurine release to 84% of DMSO controls. The release of the other amino acids was not affected. The phospholipase C inhibitor U73122 (5 microM) had no significant effects on amino acid release. The protein kinase C (PKC) inhibitor chelerythrine (5 microM) significantly reduced hyposmotically induced taurine release to 72% of saline controls but had no significant effects on the other amino acids. Stimulation of PKC with phorbol 12-myristate, 13-acetate (10 microM) did not significantly change taurine, glutamate, glycine or phosphethanolamine release. The releases of aspartate and GABA were enhanced 2 to 3 fold. Phorbol 12,13-didecanoate (10 microM), another potent stimulator of PKC, significantly increased taurine release to 122% of DMSO controls. The releases of aspartate, glutamate and glycine were enhanced 2.5 to 3.5 fold. Similarly, stimulation of protein kinase A with forskolin (100 microM) significantly increased taurine, aspartate, and glycine release 1.5- to 2-fold compared to DMSO controls. In summary, phospholipases may play a minor role in volume regulation. These studies also support the hypothesis that protein kinases play a modulatory role in the RVD response. The results show that although RVD may play a role, additional mechanisms, including phospholipase activation, must be involved in the ischemia-evoked release of excitotoxic amino acids.
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PMID:Hyposmotically induced amino acid release from the rat cerebral cortex: role of phospholipases and protein kinases. 1053 55

We tested the hypothesis that the second messenger activated by nitric oxide, cyclic GMP, would reduce the effects of myocyte stunning following simulated ischemia-reperfusion and that this was related to cyclic GMP protein kinase. Ventricular cardiac myocytes were isolated from New Zealand White rabbits (n = 8). Cell shortening was measured by a video edge detector and protein phosphorylation was determined autoradiographically after SDS gel electrophoresis. Cell shortening data were acquired at: (i) baseline followed by 8-Bromo-cGMP 10(-6) M (8-Br-cGMP) and then KT 5823 10(-6) M (cyclic GMP protein kinase inhibitor) and (ii) simulated ischemia (20 min of 95% N(2)-5% CO(2) at 37 degrees C) followed by simulated reperfusion (reoxygenation) with addition of 8-Br-cGMP 10(-6) M followed by KT 5823 10(-6) M, (iii) addition of 8-Br-cGMP prior to ischemia followed by the addition of KT 5823 10(-6) M after 30 min of reoxygenation. In the control group, 8-Br-cGMP 10(-6) M decreased percentage shortening (%short) (5.0 +/- 0.6 vs 3.8 +/- 0. 4) and the maximum velocity (V(max), microm/s) (48.6 +/- 6.9 vs 40.2 +/- 6.4). KT 5823 10(-6) M added after 8-Br-cGMP partially restored %short (4.6 +/- 0.5) and V(max) (46.6 +/- 8.0). After stunning, baseline myocytes had decreased %short (3.4 +/- 0.2) and V(max) (36. 0 +/- 4.2). After the addition of 8-Br-cGMP, the %short (2.7 +/- 0. 2) and V(max) (27.6 +/- 2.5) decreased further. The addition of KT 5823 did not change either the %short or the V(max). The myocytes with 8-Br-cGMP during ischemia had increased %short (4.2 +/- 0.2) and V(max) (37.2 +/- 3.4) when compared to the stunned group. The addition of KT 5823 did not significantly alter %short (3.3 +/- 0.4) or V(max) (29.2 +/- 5.0) in the myocytes pretreated with 8-Br-cGMP. Protein phosphorylation was increased by 8-Br-cGMP in control and stunned myocytes. KT 5823 blocked this effect in control but not stunned myocytes, suggesting some change in the cyclic GMP protein kinase. Ischemia-reperfusion produced myocyte stunning that was reduced when 8-Br-cGMP was added prior to but not after ischemia.
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PMID:Cyclic GMP reduces ventricular myocyte stunning after simulated ischemia-reperfusion. 1063 26

We investigated the function of estrogen receptor-alpha in global myocardial ischemia and reperfusion injury in male estrogen receptor-alpha knockout (ERKO) and wild-type mice. Mouse hearts were subjected to 45 min of global ischemia followed by 180 min of reperfusion. The hearts were excised, cannulated, and maintained in a chilled (4 degrees C) cardioplegia solution until warm (37 degrees C) oxygenated Krebs-Henseleit bicarbonate buffer was perfused through the coronary arteries. ERKO hearts started beating later and had a higher incidence of ventricular fibrillation and/or tachycardia than control hearts. Coronary flow rate was significantly lower in ERKO hearts during the 90- and 120-min periods of reperfusion. Ca(2+) accumulation was significantly greater following 30, 90, 120, 150, and 180 min of reperfusion in ERKO hearts. Nitrite production was significantly less in ERKO hearts following 90, 120, and 150 min of reperfusion. Myocardial reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide was significantly lower in experimental ERKO hearts. Marked interstitial edema and contraction bands were seen in hematoxylin-eosin-stained sections of ischemia-reperfused ERKO hearts but not in control tissues. Hematoxylin-basic fuchsin-picric acid-stained sections from experimental ERKO hearts had fewer viable myocytes compared with controls. Transmission electron microscopy revealed swollen and fragmented mitochondria with amorphous and granular bodies, loss of matrix, and rupture of cristae in experimental ERKO hearts. This is the first demonstration that estrogen receptor-alpha plays a cardioprotective role in ischemia-reperfusion injury in males.
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PMID:Myocardial ischemia-reperfusion injury in estrogen receptor-alpha knockout and wild-type mice. 1077 44

Amyloid beta-peptide-binding alcohol dehydrogenase (ABAD) is a member of the family of short chain dehydrogenase/reductases whose distinctive properties include the capacity to bind amyloid beta-peptide and enzymatic activity toward a broad array of substrates including n-isopropanol and beta-estradiol. In view of the wide substrate specificity of ABAD and its high activity on l-beta-hydroxyacyl-CoA derivatives, we asked whether it might also catalyze the oxidation of the ketone body d-3-hydroxybutyrate. This was indeed the case, and oxidation proceeded with K(m) of approximately 4.5 mm and V(max) of approximately 4 nmol/min/mg protein. When placed in medium with d-beta-hydroxybutyrate as the principal energy substrate, COS cells stably transfected to overexpress wild-type ABAD (COS/wtABAD) better maintained 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide reduction, cellular energy charge, and morphologic phenotype compared with COS/vector cells. Using a severe model of metabolic perturbation, transgenic mice with targeted neuronal expression of ABAD subjected to transient middle cerebral artery occlusion showed strokes of smaller volume and lower neurologic deficit scores in parallel with increased brain ATP and decreased lactate, compared with nontransgenic controls. These data suggest that ABAD contributes to the protective response to metabolic stress, especially in the setting of ischemia.
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PMID:Amyloid beta -peptide-binding alcohol dehydrogenase is a component of the cellular response to nutritional stress. 1086 39

Na(+) influx has been implicated to play an important role in the mechanisms of neuronal cell damage under ischemia as well as in neurodegenerative disorders. Thus far, however, the effects of Na(+) influx on astrocytic damage have not been studied extensively. In the present study, we have examined the effects of Na(+) influx induced by veratridine (Na(+) channel opener), monensin (Na(+) ionophore), and glutamate (co-transportation with Na(+)) on rat cultured astroglial damage. Cells were incubated with bicarbonate buffer with 25 mM glucose containing either 100 microM veratridine, 10 microM monensin, or 1 mM glutamate with or without 1 mM ouabain for 20 h. Cellular damage was evaluated quantitatively by lactate dehydrogenase (LDH) release or 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) reduction. Veratridine, monensin, or glutamate alone did not induce significant astroglial damage. Veratridine and monensin co-incubated with ouabain, which inhibits active extrusion of Na(+) by Na(+),K(+)-ATPase, thereby enhances intracellular Na(+) accumulation, caused significant cell death (P<0. 001, approximately 50% cell damage), whereas glutamate did not. Na(+)-free solution substituted by choline (impermeable cation) attenuated cell damage induced by veratridine and monensin markedly, while Li(+) substitution (permeable cation) rather exacerbated. Nifedipine (100 microM), a blocker of L-type Ca(2+) channel, reduced veratridine-induced glial damage by 50%. Neither bepridil nor benzamil, a blocker of Na(+)-Ca(2+) exchanger, had any protection. Cyclosporin A (1 or 10 microM), an inhibitor of mitochondrial permeability transition or 10 microM N-benzyloxycarbonyl-Val-Ala-Asp-(O-methyl)fluoromethyl ketone (zVAD-fmk), which inhibits a broad range of caspases, did not show protective effects.
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PMID:Astroglial cell death induced by excessive influx of sodium ions. 1108 May 18

This study was designed to determine the role of altered cAMP and K(+) channel-dependent mechanisms in impaired pial artery dilation to the newly described opioid, nociceptin/orphanin FQ (NOC/oFQ) following hypoxia/ischemia in newborn pigs equipped with a closed cranial window. Recent studies have observed that NOC/oFQ elicits pial dilation via release of cAMP, which, in turn, activates the calcium sensitive (K(ca)) and the ATP-dependent K(+) (K(ATP)) channel. Global cerebral ischemia (20 min) was induced via elevation of intracranial pressure, while hypoxia (10 min) decreased pO(2) to 35+/-3 mm Hg with unchanged pCO(2). Topical NOC/oFQ (10(-8), 10(-6) M) induced vasodilation was attenuated by ischemia/reperfusion (I+R) and reversed to vasoconstriction by hypoxia/ischemia/reperfusion (H+I+R) at 1 h of reperfusion (control, 9+/-1 and 16+/-1%; I+R, 3+/-1 and 6+/-1%; H+I+R, -7+/-1 and -12+/-1%). Such altered dilation returned to control values within 4 h in I+R animals and within 12 h in H+I+R animals. NOC/oFQ dilation was associated with elevated CSF cAMP in control animals but such biochemical changes were attenuated in I+R animals and reversed to decreases in cAMP concentration in H+I+R animals (control, 1037+/-58 and 1919+/-209 fmol/ml; I+R, 1068+/-33 and 1289+/-30 fmol/ml; H+I+R, 976+/-36 and 772+/-27 fmol/ml for absence and presence of NOC/oFQ 10(-6) M, respectively). Topical 8-Bromo cAMP (10(-8), 10(-6) M) pial dilation was unchanged by I+R but blunted by H+I+R (control, 10+/-1 and 20+/-1%; I+R, 11+/-1 and 20+/-2%; H+I+R, 0+/-1 and 0+/-2%). Pituitary adenylate cyclase activating polypeptide and cromakalim, adenylate cyclase and K(ATP) channel activators, respectively, elicited dilation that was blunted by both I+R and H+I+R while NS1619, a K(ca) channel activator, elicited dilation that was unchanged by I+R but blunted by H+I+R. These data indicate that impaired NOC/oFQ dilation following I+R results form altered adenylate cyclase and K(ATP) channel-dependent mechanisms. These data further indicate that impaired NOC/oFQ dilation following H+I+R results not only from altered adenylate cyclase and K(ATP) channel but also from altered cAMP and K(ca) channel-dependent mechanisms.
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PMID:Role of cAMP and K(+) channel-dependent mechanisms in piglet hypoxic/ischemic impaired nociceptin/orphanin FQ-induced cerebrovasodilation. 1108 86

The role of the L-arginine/nitric oxide (NO) pathway in myocardial ischaemic/reperfusion injury remains controversial in experimental animal models. The aim of the present studies was to investigate the role of this pathway in the human myocardium. Myocardial specimens from right atrial appendages of patients undergoing elective coronary bypass graft surgery were incubated in crystalloid buffer at 37 degrees C and subjected to 120 min of simulated ischaemia followed by 120 min of reoxygenation. Tested drugs were added 15 min before ischaemia, and maintained during ischaemia and throughout reoxygenation. Ischaemia resulted in severe myocardial damage, as assessed by the leakage of lactate dehydrogenase (LDH) into the incubation medium and by the capacity of the tissue to reduce 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) to formazan product. L-Arginine (10 mM), a precursor of NO, significantly decreased LDH leakage (from 9.0+/-0.6 to 5.3+/-0.3 units/g wet wt; P<0.05), but had no effect on MTT reduction or oxygen consumption. D-Arginine (10 mM), N(G)-nitro-L-arginine methyl ester (L-NAME; 0.5 mM), an NO synthase inhibitor, and S-nitroso-N-acetylpenicillamine (at 1, 100, 500 and 1000 microM), an NO donor, had no significant effects on the measured indices, and L-NAME did not reverse the protection afforded by L-arginine against LDH leakage. In addition, the formation of nitrotyrosine was not influenced by ischaemia/reoxygenation alone or by the agents investigated. In conclusion, these data suggest that L-arginine affords modest protection against ischaemic/reoxygenation injury of the human myocardium, an action that is NO-independent, and that NO metabolism does not play a significant role in this model.
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PMID:Role of the L-arginine/nitric oxide pathway in ischaemic/reoxygenation injury of the human myocardium. 1109 92


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