Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The three-vessel occlusion model of Kameyama et al. (Kameyama, M., Suzuki, J., Shirane, R. and Ogawa, A. (1985) Stroke 16, 489-493) was adapted with modifications to induce complete reversible rat forebrain ischemia. A fast and simple procedure for the isolation and purification of rat brain mitochondria, which provides high yield, is described. Mitochondria isolated from ischemic brain (12-30 min ischemia) exhibited decreases in State 3 respiratory rates of approx. 70% with NAD-linked respiratory substrates. Less effect was observed with succinate and rotenone. The State 4 respiratory activity remained near control levels except at 15 min of ischemia (25% increase) with NAD-linked substrates. Similarly, with succinate and rotenone, an approx. 30% increase in State 4 activity was observed at 20 min of ischemia. Consequently, the respiratory control indices (RCIs) were decreased. Both the respiratory rates and RCIs could be restored to near control levels upon the addition of EGTA(EDTA) or ruthenium red to the assay mixture. Analysis employing fura-2 as a Ca2+ probe, indicated a great decrease in the first order rate constant for Ca2+ uptake of ischemic mitochondria and a significant increase in Ca2+ homeostasis with an increase in the cytosolic Ca2+ concentration which results in excessive association of Ca2+ on the mitochondrial membrane and an inhibition of the respiratory chain-linked oxidative phosphorylation and Ca(2+)-transport activity of forebrain mitochondria. These deficits are proportional to the duration of ischemia.
 ...
PMID:Ischemic injury to rat forebrain mitochondria and cellular calcium homeostasis. 155 46

Heat stroke was induced in intact rats in a thermal chamber (45 degrees C) and simultaneously a group of animals was subjected to overheating for the same time but was given intraperitoneal injections of ionol (120 mg/kg) for 2 days and 30 minutes before exposure in the chamber. Significant increase of the concentration of intermediates--lactate, pyruvate, malate, glutamate, ammonia--and decrease of the alpha-ketoglutarate content occurred in the renal tissue in animals of both groups. The NAD/NADH ratio in the cytoplasm and mitochondria reduced essentially, to a greater degree in animals given ionol injections. The last named were distinguished by higher survival and lower degree of hyperthermia.
 ...
PMID:[The effect of ionol on oxidative-reductive processes in the kidney during heat stroke]. 261 12

The effect of the ganglioside GM1 was studied in a focal cerebral ischemia model in 30 cats consisting of 2 hours of middle cerebral artery occlusion followed by 4 hours of recirculation. The cerebrocortical electrical activity, extracellular potassium activity, and microcirculation indicated by NAD/NADH fluorescence were measured during occlusion as well as during recirculation in the core of the middle cerebral artery territory, while the cerebral metabolic rate for glucose (ICMRgl) was measured at the end of recirculation. The cats were classified into either mildly or moderately severe stroke groups based on the depression of the cerebrocortical electrical activity on the occluded side. Of 12 cats with only a mild stroke, six were administered GM1 intravenously 30 minutes after occlusion, while six cats were not treated. Of 12 cats with a moderate stroke, six were treated and six were left untreated. In six additional cats, only a sham insult was undertaken. In the cats with mild stroke, GM1 treatment significantly increased lCMRgl in the peripheral middle cerebral artery territory compared with the untreated cats; for the six treated cats, lCMRgl was normalized toward the control level, whereas it was depressed in the six untreated cats. There were no other significant effects of GM1 treatment on the other measured parameters. A potential protective effect of anesthesia is discussed.
Stroke 1989 Jun
PMID:Effect of GM1 ganglioside after focal cerebral ischemia in halothane-anesthetized cats. 272 48

An increase in cytosolic free calcium concentration ([Ca2+]i) may trigger irreversible cell injury following cerebral ischemia. We have measured changes in [Ca2+]i in cat cortex in vivo during ischemia produced by 1 hour of middle cerebral artery occlusion and during 30 minutes of reperfusion. Indo-1, a fluorescent Ca2+ indicator, was loaded into the exposed cortex by superfusion, and changes in the [Ca2+]i signal (400/506 nm ratio) were measured microfluorometrically during ultraviolet excitation (340 nm). The nicotinamide adenine dinucleotide/reduced nicotinamide adenine dinucleotide (NAD/NADH) redox state and hemodynamic changes were measured simultaneously. The animals showing severe deterioration in their electroencephalograms (EEG) showed a progressive increase in the [Ca2+]i signal during ischemia (baseline: 1.46 +/- 0.05; 60 minutes after occlusion: 2.99 +/- 0.37; n = 7). At 30 minutes following reperfusion, the animals showing little recovery in their EEG exhibited a further increase in [Ca2+]i (4.71 +/- 0.87, n = 3), whereas animals showing significant recovery in their EEG also showed recovery of [Ca2+]i (1.55 +/- 0.09, n = 4). By contrast, the moderate or mild stroke animals with less deterioration in their EEGs showed no increase in [Ca2+]i during either ischemia or reperfusion. These data suggest that the increase in [Ca2+]i might be closely related not only to deterioration of brain function during ischemia but also to poor recovery during the reperfusion period.
 ...
PMID:In vivo measurement of cytosolic free calcium during cerebral ischemia and reperfusion. 314 14

Local cerebral glucose utilization (lCMRgl), NADH fluorescence, cerebral blood flow (CBF), electrocortical activity (ECoG) and histology were studied during a 4 hr recovery period following 2 hrs of left middle cerebral artery (MCA) occlusion in cats. Changes in relative reduced pyridine nucleotides and CBF were measured by fluororeflectometry, ECoG was obtained from the left middle ectosylvian gyrus (MEG), and lCMRgl was measured at the end of the recovery period autoradiographically with 14-C-2-deoxyglucose. A sham group was comprised of 4 cats. The ten animals subjected to the stroke were classified into 3 groups based on the mean amplitude of the ECoG at the end of the ischemic period. At the end of the recovery period, the relative reduced pyridine nucleotides showed a 22.5% oxidation (oxidation of NADH), a 66.2% reduction (reduction of NAD) and a 3.0% reduction compared to the sham group in the severe, moderate and mild groups, respectively. LCMRgl of the left MEG in the severe group was 64.2% of the corresponding sham value, whereas lCMRgl in the moderate and mild groups were 124.8% and 132.0% of the sham, respectively. CBF at the end of the recovery period ranged from 28.1% to 83.0% of the sham value, although there was no significant difference among these groups. Histologically, a large portion of the neurons in the left MEG in the severe group showed ischemic neuronal changes, while the damage was less severe in the moderate and mild groups. On the basis of these data, it is suggested that a relative substrate deficiency and/or a loss of mitochondrial enzymatic pool size may occur in the animals comprizing the severe group. Conversely, anaerobic glycolysis may be activated in the moderate group, while the mild group exhibits an increase in glucose metabolism that is most likely aerobic. A gradient in the magnitude of changes in lCMRgl was noted from the central MCA territory to the surrounding brain regions in the ischemic hemisphere. In addition, there was a mild, but statistically significant (p less than 0.05), depression in lCMRgl with no histological damage in the non-ischemic hemisphere of the severe group.
Stroke
PMID:Cerebral glucose metabolism during the recovery period after ischemia--its relationship to NADH-fluorescence, blood flow, EcoG and histology. 376 74

Cerebral ischemia was induced in cats using bilateral carotid artery occlusion coupled with hemorrhagic hypotension. Thirty minutes of ischemia, which depleted levels of ATP and phosphocreatine throughout the cerebral cortex, was followed by 2-4 hours of recirculation. During the recovery period, cortical perfusion and NADH fluorescence were monitored through a cranial window. Postischemic perfusion, as indicated by transit time, was initially higher than control, but declined to subnormal levels by 60 minutes. NADH fluorescence transients, induced by brief anoxia, also decreased steadily during recirculation, indicating a failure of oxidation-reduction capability. The disappearance of anoxic-NADH transients usually preceded the decline of flow, suggesting that O2 delivery was not the factor limiting redox reactions. Furthermore, tissue levels of NADH, which were nearly normal after 2-4 hours of recirculation, did not indicate tissue hypoxia. In spite of normalization of NADH, resynthesis of high energy phosphates were severely impaired. The degree of ATP recovery varied widely in different cortical regions; however, there were two general groups of ATP values--one at 5% and the other at 70% of control levels. In the energy-depleted areas, NADH levels were normal, but the total pool of NAD (NADH + NAD+) and the tissue content of K+ were 43% lower than control. In contrast, the NAD pool and K+ content were only slightly diminished in the regions with greater ATP restitution. The results suggest that postischemic resynthesis of ATP may be limited not by inadequate delivery of O2, but rather by defective production of NADH.
Stroke
PMID:Factors limiting regeneration of ATP following temporary ischemia in cat brain. 706 95

During ischemic stroke, massive neural damage occurs due to excess release of glutamate which acts mainly through N-methyl-D-aspartate (NMDA) receptors. Activation of the NMDA receptor stimulates nitric oxide (NO) production by NO synthase (NOS). NO mediates glutamate neurotoxicity as inhibitors of NOS prevent neuronal death. FK506, an immunosuppressant drug, binds to FK506 binding protein (FKBP). One target of the FK506/FKBP complex is the calcium/calmodulin-dependent protein phosphatase calcineurin, whose activity is inhibited upon interaction with FK506/FKBP. FK506 treatment increases phosphorylation level of calcinurin substrates including NOS. As a potent neuroprotective agent in vitro and in vivo, FK506 increases NOS phosphorylation and decreases NO production. NO activates poly(ADP-ribose) synthetase (PARS), a nuclear enzyme that synthesizes poly(ADP-ribose) from NAD. Prolonged activation of PARS depletes NAD and lowers cellular energy levels. Inhibition of PARS also prevents NO toxicity. NOS inhibitors, immunosuppressants and PARS inhibitors may be useful agents to prevent neuronal damage during stroke.
 ...
PMID:Nitric oxide synthase, immunophilins and poly(ADP-ribose) synthetase: novel targets for the development of neuroprotective drugs. 747 44

Experiments were conducted on male albino rats to study some intracellular metabolites (lactate, pyruvate, malate, glutamate, alpha-ketoglutarate, ammonia) and the redox process in the tissues of the liver, kidneys, myocardium, and skeletal muscles during hyperthermia (40 degrees C for one hour and 45 degrees C for one hour). Changes of the metabolite content and shifts in the redox process in the direction of oxidation in the liver and kidneys at both levels of hyperthermia are evidence of the development of tissue hypoxia of circulatory character in these organs. The mitochondrial NAD/NADH ratio in the myocardium reduced in moderate hyperthermia and increased during a heat stroke. There were no signs of cellular hypoxia in the skeletal muscles. It is concluded on basis of the results that changes of the blood flow in the organs play the leading role in the origin of thermal hypoxia.
 ...
PMID:[Intracellular oxidative-reductive processes in tissues in hyperthermia]. 805 76

We focus our attention in this presentation to the extracellular ionic changes during and after local ischemia and in repetitive versus single global ischemia. In the cat stroke model of MCA occlusion a considerable variability in the severity of ischemia was observed. This was demonstrated in electrical activity (ECoG), NAD/NADH fluoro-reflectometry and extracellular ionic changes. A striking experience was, that the K+ recovery is rather fast even after two hours of ischemia, and this is partly due to maintained activity of the sodium-potassium pump. After the MCA release a secondary acidosis occurs, which is the result of excess lactic acid production. This lactacidosis is certainly contributes to the late morphological damage. The repeated acidotic insult (in gerbil model of global cerebral ischemia) could be the cause of the more severe morphological and blood-brain-barrier damage in the repetitive ischemia too. The acidosis in many cases is even more pronounced after relieving the carotid arteries. This secondary acidosis causes endothelial damage and vasogenic oedema.
 ...
PMID:Ion and metabolic disturbances after global and focal cerebral ischemia. 857 39

Decreased activity of complex I (NAD:ubiquinone oxidoreductase) is the most frequent biochemical finding associated with mutation at the base pair 3243 of the mitochondrial DNA. The mutation has been previously shown to lead to a defective translation. We hypothesized that due to an imperfect assembly of complex I subunits the substrate affinity of this enzyme may be lowered and this may be counteracted by increasing the mitochondrial NAD+NADH concentration. Therefore, we studied the effect and mechanism of action of nicotinamide treatment in a MELAS patient with the base pair 3243 mutation. Nicotinamide treatment was initiated after his first stroke-like episode. The blood NAD concentration (representing the intracellular concentration in erythrocytes) increased linearly being 24-fold at 6 weeks of treatment. Blood lactate and pyruvate concentration decreased by 50% within three days and 24 h urine lactate content within 2 weeks and we observed a clinical improvement together with a decrease in the lesion volume in magnetic resonance imaging within the first month. The cellular NAD increase upon nicotinamide administration was probably universal, because it occurred in a time and dose-dependent manner in cultured fibroblasts from both the patient and the controls. Alleviation of the lactate accumulation during the nicotinamide treatment suggests that an increase in the cellular NAD+NADH concentration leads to enhancement of the oxidation of reducing equivalents. However, the Km of complex I for NADH in skeletal muscle from the patient was similar to that of controls. This may indicate that physiologically mitochondrial complex I operates at non-saturating substrate concentration, and this may explain the effect of nicotinamide treatment.
 ...
PMID:Increase of blood NAD+ and attenuation of lactacidemia during nicotinamide treatment of a patient with the MELAS syndrome. 859 19


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