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)

Intracellular calcium toxicity appears to play a major role in cell death during cerebral ischemia. Such calcium enters the cell mainly through the N-methyl-D-aspartate subclass of the postsynaptic glutamate receptor. Increased extracellular hydrogen ion concentration has been shown recently to reduce N-methyl-D-aspartate-activated divalent cation currents. Therefore, we studied the effect of induced brain acidosis, via hypercarbic ventilation, as a potential therapeutic modality in focal cerebral ischemia. Brain acidosis reduced infarct volume in a biphasic manner, with maximal protection at approximately brain pH 6.8. The effect was lost at pH 6.5, presumably due to the effect of acidosis on glial glutamate uptake.
 ...
PMID:Brain acidosis induced by hypercarbic ventilation attenuates focal ischemic injury. 826 4

A novel series of octahydrophenanthrenamines and their heterocyclic analogues have been synthesized as potential noncompetitive antagonists of the N-methyl-D-aspartate (NMDA) receptor complex. The compounds were evaluated for their affinity at the phencyclidine (PCP) binding site by determining their ability to displace [3H]TCP from crude rat brain synaptic membranes. A wide range of affinities were observed, with the most potent analogs possessing IC50's equivalent to that of the reference agent MK-801 (3, dizocilpine). NMDA antagonist activity was demonstrated by prevention of glutamate-induced accumulation of [45Ca2+] in cultured rat cortical neurons. Selected compounds were also studied in vivo to determine their ability to prevent the lethal effects of systemically injected NMDA in the mouse. In general, the SAR of the phenanthrenamine series may be summarized as follows: (a) for the amino group at C4a, NHMe > NH2 > NHEt >> NC5H10; (b) for the B-ring substitution, X = CH2 > S > O; (c) unsaturation of the C ring decreases receptor affinity; (d) cis-ring fusion between the B and C rings is desirable; (e) 6-hydroxy or 6-methoxy substitution of the phenanthrenamine system identified an additional hydrogen bonding interaction that substantially increased receptor affinity; (f) spiro analogues (such as 55, IC50 = 3400 nM), which altered the point of attachment of the C ring, caused a substantial reduction in PCP-site affinity. Molecules from this series were useful for refining a pharmacophore model consistent with previous models of the PCP site. In this model, the (R)-(+)-phenanthrenamine 13 superimposes closely onto MK-801 (3), and the angular 4a-amino group is believed to hydrogen bond with a putative receptor site atom. In the phenanthrenamine and thiaphenanthrenamine series, the (R)-(+)-enantiomers (9, 13, and 44) are more potent by approximately 5-10-fold than their corresponding (S)-(-)-enantiomers with respect to their affinity for the PCP site, their ability to prevent accumulation of [45Ca2+] in cultured neuronal cells, and their protection against the lethal effects of NMDA in mice. In general, there was no separation between the dose that prevented NMDA lethality and the dose that produced ataxia in mice, except in the case of the thiaphenanthrenamines 41 and 43. We have not yet obtained evidence that this small separation in activity offers a therapeutic advantage in the treatment of cerebral ischemia or other neurodegenerative disorders.
 ...
PMID:Synthesis and pharmacological evaluation of 4a-phenanthrenamine derivatives acting at the phencyclidine binding site of the N-methyl-D-aspartate receptor complex. 833 37

This study was designed to better define a protocol for hypervolemic hemodilution in acute cerebral ischemia and investigate the mechanism of action of this therapy. Anesthetized rats (n = 40) were subjected to 6 h of middle cerebral artery (MCA) occlusion. At 45 min after MCA occlusion, each rat received one of the following treatment modalities: (1) control, (2) isovolemic hemodilution, (3) hypervolemic nonhemodilution (whole blood), (4) hypervolemic hemodilution (normal saline), and (5) hypervolemic hemodilution (hetastarch). Local cerebral blood flow (CBF) was determined with hydrogen clearance technique, and cardiac output was assessed by measuring the descending aorta blood flow (DAF). Infarction volume was estimated by 2,3,5-triphenyltetrazolium chloride staining method. Hetastarch infusion increased both DAF and local CBF more than the other treatments, by 98% and by 89%, respectively. Hetastarch also reduced infarction volume the most to 71 +/- 19 mm3 (p < 0.01 versus control 117 +/- 32 mm3). A significant correlation between percent (%) changes in local CBF and % changes in DAF existed in ischemic brain regions, and the hetastarch infusion improved local CBF more prominently in profoundly ischemic regions in contrast to isovolemic hemodilution. These data demonstrated the superiority of hypervolemic hemodilution with hetastarch as compared to other similar treatment modalities for acute cerebral ischemia, and indicate that cardiac output augmentation may be more responsible than decreased blood viscosity for the beneficial effect of hypervolemic hemodilution on local CBF in profoundly ischemic regions, as such ischemic brain tissue can severely lose its regulatory control of CBF to alterations in cardiac output.
 ...
PMID:Role of hypervolemic hemodilution in focal cerebral ischemia of rats. 834 73

Effects of aging on monoamine metabolism in transient cerebral ischemia were studied using adult and aged female spontaneously hypertensive rats (SHRs). Tissue monoamine contents in discrete brain areas were quantified after 20 min of cerebral ischemia with or without 30-min recirculation. Cerebral blood flow (CBF) was determined with a hydrogen clearance method in separate experiments. Dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) contents in the striatum, nucleus accumbens and septum decreased in ischemic aged SHRs, compared with those in ischemic adult SHRs. After 30-min recirculation, DA contents were actually unchanged with inconsistently increased DOPAC levels. Ischemic CBF decreased to < 20% of the resting CBF in the striatum and cortex, which was not different between the two age groups of SHRs. These results indicate that aging is primarily responsible for more severely impaired DA metabolism during cerebral ischemia in aged SHRs.
 ...
PMID:Ischemia-induced changes in brain monoamine metabolism in aged spontaneously hypertensive rats. 840 55

1H magnetic resonance spectroscopy (MRS) has attracted much attention in recent years. Since the proton is the most sensitive stable nucleus for MRS, and since almost all metabolites contain hydrogen atoms, it is possible to perform a noninvasive chemical analysis on tissues deep within the body of a subject. Technical solutions to the elimination of water and lipid signals as well as resolution of the large number of potential metabolite peaks have been found. Most current work is on the brain, much of it in humans. This review begins with a consideration of these technical problems and also localization, editing, quantitation, and interpretation of spectra. Two diseases are considered in detail: cerebral ischemia (including stroke and neonatal ischemic/hypoxic injury) and cancer; a further section briefly reviews studies on other diseases. In the immediate future, 1H MRS is likely to benefit from a number of technical advances: higher field magnets, better control of gradients and eddy currents, more sophisticated radiofrequency (RF) pulses, and 1H-observe/13C-edited spectroscopy all offer potential improvements. Another major improvement will come from increased user-friendliness of clinical spectrometers and use of automated objective methods for spectroscopic data analysis.
 ...
PMID:Proton spectroscopy in vivo. 851 31

It is generally thought by neurosurgeons that when temporary clipping of a major cerebral vessel is necessary during aneurysm surgery, repeated short periods of cerebral ischemia are safer for the brain than a single long episode. This study was performed to investigate whether repetitive short episodes of cerebral ischemia would alter the resulting brain injury as compared with a single long period of ischemia in a rat model for focal cerebral ischemia. Middle cerebral artery occlusion and reperfusion were performed by the intraluminal thread technique. The experimental design consisted of a single 90-minute occlusion period in the continuous ischemia group versus three 30-minute occlusion periods with 15-minute reperfusion periods in the repetitive group. Local cerebral blood flow was measured by the hydrogen clearance technique. During the ischemic period, local cerebral blood flow values significantly decreased in both the continuous and the repetitive groups. Cerebral blood flow restoration was demonstrated after each episode of reperfusion in both groups. The neurological status scores 2 hours after surgery in the rats subjected to repetitive insults were significantly better compared with those in the rats of the continuous ischemia group. However, the scores on Days 1, 3, and 7 did not show a significantly better difference. The animals were killed 7 days after the induction of ischemia for the measurement of the infarction area under the microscope. The total area of infarction was significantly reduced (4.05 +/- 4.56 versus 47.2 +/- 37.3 mm2, P < 0.001) by interruption of the ischemic time period.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Interrupted arterial occlusion reduces ischemic damage in a focal cerebral ischemia model of rats. 855 5

Cerebral ischemia can result in varying degrees of tissue damage. Conditions of severe ischemia can produce extensive areas of irreversible injury, whereas in conditions of moderate ischemia, tissue damage may be reversible, as in the region of the ischemic penumbra. The reversibility of tissue damage in the penumbral region is of clinical interest, because the characterization of conditions underlying this reversible state may provide information needed for the development of new therapeutic approaches for treatment. Our previous studies demonstrated neurochemical alterations in the levels of dopamine (DA) within the striatum after cerebral ischemia. In the present study, we postulate that these changes may be caused, in part, by alterations in transmitter release and reuptake. To test this hypothesis, forebrain ischemia was induced in Sprague-Dawley rats (Harlan, Indianapolis, IN) by means of bilateral common carotid artery occlusion and hemorrhagic hypotension. Cerebral blood flow (CBF) in the striatum was measured by the method of hydrogen clearance, and the extracellular DA ([DA]e) levels were measured by in vivo microdialysis. Varied reductions of CBF were induced and maintained for 5 hours. Three subgroups were established retrospectively according to the degree of CBF reduction: 67.7, 35.6, and 13.2% of normal CBF in the mild, moderate, and severe ischemic groups, respectively. The induction of ischemia resulted in 1.9-, 9.3-, and 122.3-fold increases in [DA]e above baseline in the mild, moderate, and severe ischemia groups, respectively. At 3 hours after the induction of ischemia, high potassium (100 mmol/L) or Nomifensin (Sigma, St. Louis, MO) (10 mmol/L), a DA uptake blocker, was administrated via a microdialysis probe to stimulate DA release while reductions in CBF were maintained continuously. Thirteen rats were used in the study of the release of DA by potassium or Nomifensin in nonischemic conditions. The administration of high potassium or Nomifensin stimulated DA release in conditions of mild and moderate ischemia. The increase in DA release by potassium stimulation was higher in rats with mild ischemia (106.6-fold) than that in normal rats (22.3-fold). This suggests a hyperexcitability of DA terminals under mild ischemia, as compared with nonischemic conditions. On the other hand, Nomifensin increased [DA]e levels more in moderately ischemic brains than in control brains, suggesting that DA uptake is up-regulated in the former case. The increased release of DA by potassium and Nomifensin was sustained after stimulation in conditions of mild and moderate ischemia. The high level of [DA]e with severe ischemia after ischemic induction was sustained throughout the period of study and was not stimulated by potassium or Nomifensin. We conclude that under conditions of mild and moderate ischemia, DA terminals become highly excitable and reuptake mechanisms are compromised. These changes of DA metabolism during mild and moderate ischemia may explain the sustainability of neurons in the "penumbra" condition of cerebral ischemia and the transformation of the ischemic penumbra to a necrotic core.
 ...
PMID:Alterations in striatal dopamine release and reuptake under conditions of mild, moderate, and severe cerebral ischemia. 855 44

The possibility that cortical spreading depression (CSD) may have neuroprotective action during subsequent focal cerebral ischemia was examined in rats. Three days before the imposition of focal cerebral ischemia CSDs were elicited by applying potassium chloride (KC1) for 2 h through a microdialysis probe implanted in the occipital cortex. Control animals were handled identically except that saline was infused instead of KC1. Focal ischemia was produced by the intraluminal suture method and cortical and subcortical infarct volumes were measured 7 days later. Neocortical infarct volume was reduced from 124.8 +/- 49.5 mm(3) in the controls to 62.9 +/- 59.5 mm(3) in the animals preconditioned with CSD (p = 0.012). There was no difference between the two groups in the subcortical infarct volume or in CBF, measured by the hydrogen clearance method, during or immediately after the ischemic interval. Our data indicate that preconditioning CSD applied 3 days before middle cerebral artery occlusion may increase the brain's resistance to focal ischemic damage and may be used as a model to explore the neuroprotective molecular responses of neuronal and glial cells.
 ...
PMID:Cortical spreading depression protects against subsequent focal cerebral ischemia in rats. 859 53

A new model of transient cerebral ischemia in 10-day- old rats is described. Under microscopic guidance, the right external and internal carotid arteries were electrically coagulated. A solid 0.47 mm diameter nylon thread was inserted into the right common carotid artery toward the ascending aorta up to 10-12 mm from the upper edge of the sternomastoid muscle (preischemic rats). A 60-min cerebral ischemia was induced by clamping the left external and internal carotid arteries (ischemic rats), followed by 3-h recirculation. 31P magnetic resonance (MRS) spectroscopic studies revealed that severe intracellular acidosis occurred and ATP disappeared completely for a least the last 20 min of ischemia. Cerebral blood flow (CBF), measured by the hydrogen clearance technique, decreased to approximately 11% of the preischemic level in the frontal cortex soon after the induction of ischemia. On resuscitation, ATP recovered completely and the preischemic intracellular pH level was restored within 180 min. CBF has recovered to approximately 30% of the preischemic level at 5 min after resuscitation. The CBF recovery was not compete even at 180 min after resuscitation. With this model, the effects of pure ischemia without hypoxia on the neonatal brain and the process of recovery from transient ischemia can be studied.
 ...
PMID:A new model of transient cerebral ischemia in neonatal rats. 859 55

Effects of L-arginine, 300 mg/kg, i.p., on the regional cerebral blood flow (rCBF), brain metabolism, and infarct volume were examined in spontaneously hypertensive rats subjected to occlusion of both left middle cerebral artery and left common carotid artery. Rats treated with L-arginine had higher rCBF, determined by hydrogen clearance method, in the ischemic core (7 +/- 1 ml/100 g/min, mean +/- S.E.M.) and penumbral regions (16 +/- 2) than did rats treated with saline (5 +/- 0 and 7 +/- 1, respectively). Simultaneously, L-arginine attenuated metabolic derangement in the ischemic tissue at 60 min, i.e. well maintained adenosine triphosphate (ATP) in ischemic region (1.29 +/- 0.07 mmol/kg in L-arginine group vs. 1.05 +/- 0.06 in saline group), and also close to normal levels in ATP (2.61 +/- 0.02 mmol/kg vs. 2.45 +/- 0.05), glucose (2.29 +/- 0.12 mmol/kg vs. 1.80 +/- 0.17) and lactate (1.63 +/- 0.10 mmol/kg vs. 2.24 +/- 0.21) in periischemic region. In another experiment, the effects of L-arginine on rCBF in the subcortical regions and on infarct volume were evaluated. L-arginine, compared with saline, increased rCBF by 8 ml/100 g/min in the ischemic side and reduced infarct volume by 29% at 24 h of ischemia. These findings support that L-arginine may be potentially useful for the treatment of acute cerebral ischemia.
 ...
PMID:L-arginine ameliorates cerebral blood flow and metabolism and decreases infarct volume in rats with cerebral ischemia. 861 23


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