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)

Increased extracellular concentrations of glutamate during episodes of cerebral ischemia may be due in part to a positive glutaminergic feedback loop. We evaluated the effect of selective AMPA or NMDA receptor antagonists on hippocampal extracellular concentrations of excitatory amino acids during ischemia and reperfusion. Thirteen New Zealand white rabbits were subjected to 10 min of global cerebral ischemia produced by neck tourniquet inflation (20 psi) combined with systemic hypotension during halothane (1-1.5%) anesthesia. Hippocampal extracellular concentrations of glutamate, aspartate, and glycine were monitored using in vivo microdialysis. NBQX (a selective AMPA receptor antagonist), MK801 (a noncompetitive NMDA receptor antagonist), or 5% dextrose was administered starting 1 h before ischemia. The NBQX group (n = 4) received 5 mg.kg-1 of NBQX intravenously (dissolved in 5% dextrose) over 5 min followed by an infusion of 5 mg.kg-1.h-1. The 5% dextrose group (n = 4) received an equivalent volume of 5% dextrose. The peak concentrations of glutamate, aspartate, and glycine in the early reperfusion period were 5-8-fold, 9-10-fold, and 4-5-fold higher than preischemic values, respectively. There were no significant differences, however, among the three groups in the concentrations of glutamate, aspartate, or glycine at any time during the study. These results do not support the existence of a positive feedback loop for glutamate mediated via AMPA or NMDA autoreceptors in the hippocampus during transient global ischemia or reperfusion.
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PMID:AMPA and NMDA receptor antagonists do not decrease hippocampal glutamate concentrations during transient global ischemia. 135 5

We have administered antagonists acting competitively or noncompetitively at the N-methyl-D-aspartate receptor after a short period of incomplete ischaemia and evaluated selective neuronal loss in the CA1 region of the rat hippocampus. The competitive antagonists D-(-)-2-amino-7-phosphonoheptanoate (2APH); 100 or 330 mg/kg; 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonate (CPP); 3.3 or 10 mg/kg; and CGS 19755 (cis-4-phosphonomethyl-2-piperidine carboxylate) 3.3 or 10 mg/kg; and the noncompetitive antagonists MK801 [+)5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate), 0.3, 1, or 3 mg/kg, and dextrorphan, 2, 6, 18, or 54 mg/kg, were administered intraperitoneally 15 min and 5 h after a 10-min incomplete ischaemia period; additionally MK801 (1 or 3 mg/kg) and CGS 19755 (10 or 30 mg/kg) were administered 5 and 10 h postischaemia. Seven days after ischaemia, the brains were fixed by perfusion. CA1 pyramidal cell counts were performed on Nissl-stained sections using an ocular grid piece. Ventilated (no ischaemia) control animals had a mean of 406 +/- 13 CA1 neurones/3 grid lengths. Ischaemia reduced this mean to 157 +/- 23. A significant protective effect against this cell loss was seen after two injections (at 15 min and 5 h postischaemia) of 2APH, CPP (10 mg/kg), CGS 19755 (10 mg/kg), MK801 (1 mg/kg), and dextrophan (54 mg/kg). Delayed injection (5 and 10 h postischaemia) of CGS 19755 (10 and 30 mg/kg) and MK801 (1 and 3 mg/kg) did not provide any protection against pyramidal cell loss.
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PMID:Protection by NMDA antagonists against selective cell loss following transient ischaemia. 215 99

The purpose of the present study was to test whether the anticonvulsant, memantine (1-amino-3,5-dimethyladamantane), can protect neurons against hypoxic or ischemic damage. To this end, we used a rat model of transient forebrain ischemia and cultured neurons from chick embryo cerebral hemispheres. Ischemia was induced for 10 min by clamping both carotid arteries and lowering the mean arterial blood pressure to 40 mm Hg; the rats were allowed to recover for 7 days. Cultured neurons were made hypoxic with 1 mmol/l NaCN added to the incubation medium for 30 min followed by a recovery period of 3 days. The possible effects of memantine were compared with those produced by a typical non-competitive NMDA antagonist, dizocilpine. Similar effects were obtained with both drugs. The drugs reduced the damage caused by transient ischemia to neurons of the hippocampal CA1 subfield. Memantine (10 and 20 mg/kg) had a dose-dependent effect when administered intraperitoneally to the rats 1 h before ischemia. Dizocilpine was active in this model at a dosage of 1 mg/kg. When administered after ischemia, 10 mg/kg memantine significantly protected CA1 neurons against ischemic damage. Furthermore, the drugs protected cultured neurons against hypoxic damage. The lowest effective concentration was 0.1 mumol/l for dizocilpine and 1 mumol/l for memantine. Thus, memantine possesses neuroprotective activity but is less potent than dizocilpine.
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PMID:Neuroprotective effect of memantine demonstrated in vivo and in vitro. 222 32

The N-methyl-D-aspartate receptor antagonist MK801 has been reported to prevent neuronal change in models of ischemia in adult animal systems. We studied the hypothesis that blockade of the N-methyl-D-aspartate receptor would prevent the depression of cerebral high-energy phosphates found in perinatal asphyxia without producing alterations in cerebral blood flow, and thus prevent neuropathologic damage. Newborn beagle puppies were anesthetized, tracheotomized, ventilated, and randomized to asphyxial insult (I = discontinuation of ventilatory support for 5 min) or no insult (NI) and drug treatment with MK801 (10 mg/kg intravenously) or an equal volume of saline (S). Puppies received MK801 or saline 15 min prior to I/NI. In S/I pups during insult, blood flow increased to brainstem structures but decreased elsewhere. MK801 had no effect on cerebral blood flow in either control or insulted puppies. 1H NMR studies demonstrated no effect of the MK801 on NI brains. Phosphocreatine levels were 1.7 +/- 0.1, 0.6 +/- 0.1, and 0.9 +/- 0.1 mmole/kg (mean: +/- S.D.) for the S/NI, S/I, and MK801/I pups, respectively. Cerebral lactate was 1.3 +/- 0.2, 3.0 +/- 0.7, and 2.0 +/- 0.4, respectively. The pH fell 0.8 units in the S/I puppies, compared to 0.4 units in the MK801/I puppies. We conclude that pretreatment with the N-methyl-D-aspartate receptor antagonist MK801 in part protects the developing brain against severe metabolic insult.
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PMID:Beagle puppy model of perinatal asphyxia: blockade of excitatory neurotransmitters. 255 28

The hippocampus is among those brain regions which are selectively vulnerable to ischemic damage. Hippocampal damage due to transient cerebral ischemia is mainly of the delayed, non-necrotic type which may arise after disruption or activation of specific cellular systems, including transmitter release through excitatory amino acid receptors. We investigated the contribution of L-type voltage dependent calcium channels (VDCCs) to glycine (GLY) potentiated N-methyl-D-aspartate (NMDA) receptor- and potassium-stimulated [3H]norepinephrine (NE) release in a canine model of global cerebral ischemia and reperfusion. Tissue was collected from four experimental groups: non-arrested controls (NA), global cerebral ischemia induced by 10 minute cardiac arrest (CA), and CA followed by 30 min or 24 hours reperfusion after restoration of spontaneous circulation. Brain slices prepared from all groups accumulated approximately equivalent amounts of [3H]NE. The sensitivity of [3H]NE release to stimulation by NMDA/GLY or elevated potassium was unchanged after ischemia and reperfusion. About 30% of release stimulated by the addition of 20 mM potassium was inhibited by the NMDA receptor-operated channel antagonist MK801 in all groups except CA in which only 4% of release was inhibited by MK801. The ability of 1 microM nitrendipine (NTP) to block stimulated release indicated that the contribution of the L-type VDCC to potassium or NMDA/GLY-stimulated release was significant only in NA and 24 hour reperfused animals.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The role of L-type voltage dependent calcium channels in stimulated [3H]norepinephrine release from canine hippocampal slices following global cerebral ischemia and reperfusion. 760 36

Non-competitive N-methyl-D-aspartate receptor antagonists, including phencyclidine, ketamine, and MK801, produce vacuoles and induce the hsp 70 stress gene in layer III pyramidal neurons of the rat cingulate cortex. This study shows that phencyclidine (50 mg/kg) induces hsp 70 messenger RNA and HSP70 stress protein primarily in pyramidal neurons in posterior cingulate and retrosplenial cortex, neocortex, insular cortex, piriform cortex, hippocampus, and in the basal nuclei of the amygdala. Several neurotransmitter receptor antagonists inhibited induction of HSP70 produced by phencyclidine (50 mg/kg): haloperidol (ED50 = 0.8 mg/kg), clozapine (ED50 = 1 mg/kg), valium (ED50 = 1 mg/kg), SCH 23390 (ED50 = 7 mg/kg) and muscimol (ED50 = 3 mg/kg). Baclofen had no effect. Nifedipine blocked the induction of HSP70 produced by phencyclidine in some regions (cingulate, neocortex, insular cortex) but only partially blocked HSP70 induction in other regions (piriform cortex, amygdala). These results suggest that phencyclidine injuries pyramidal neurons via dopamine D1, D2, D4, sigma and other receptors. Several factors appear to contribute to this unusual multi-receptor mediated injury. (1) Phencyclidine blocks N-methyl-D-aspartate receptors on GABAergic interneurons resulting in decreased inhibition of pyramidal neurons. This may help to explain why multiple excitatory receptors mediate the injury and why GABAA agonists decrease the injury produced by phencyclidine. (2) Phencyclidine blockade of an amine transporter helps explain why dopamine receptor antagonists ameliorate injury. (3) Phencyclidine depolarizes neurons and produces high, potentially damaging intracellular calcium levels probably by blocking K+ channels that may be linked to sigma receptors. Since nifedipine prevents injury in cingulate, insula, and neocortex, it appears that calcium entry through L-type voltage gated calcium channels plays a role in the pyramidal neuronal injury produced by phencyclidine in these regions. There are similarities between the cingulate neurons injured by phencyclidine and circuits recently hypothesized to explain receptor changes in cingulate gyrus of schizophrenic patients. The present and previous studies also provide approaches for decreasing the clinical side effects of N-methyl-D-aspartate receptor antagonists to facilitate their possible use in the treatment of ischemia and other disorders.
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PMID:Phencyclidine induction of the hsp 70 stress gene in injured pyramidal neurons is mediated via multiple receptors and voltage gated calcium channels. 784 88

Neuronal damage induced by ischemia involves various changes in neurotransmission. Nitric oxide (NO), a putative neurotransmitter and/or neuromodulator has some role in this neuronal damage. In the present study, the effect of NO on the terminal site of dopamine (DA) neurons in the rat striatum was examined using the microdialysis technique. First perfusion with sodium nitroprusside (SNP) as an NO donor increased extracellular DA (10 mM, 460%; 1 mM, 140%) in the striatum and decreased its metabolites. Pretreatment with tetrodotoxin (TTX, 5 microM), (+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imine hydrogen maleato (MK801, 1 microM) or muscimol (1 microM) inhibited SNP-induced increases in extracellular DA and decreases in DOPAC (TTX, complete block; MK801, 75% inhibition; muscimol, 80% inhibition). Second, extracellular NO, DA and DOPAC were measured in the gerbil striatum following 10 minutes of forebrain ischemia produced by occluding both carotid arteries. Occlusion of the carotid arteries also caused increases in extracellular NO and DA in the gerbil striatum (NO, 3000%; DA, 2800%). These findings suggest that NO-facilitated DA release occurs via interaction between glutamatergic and dopaminergic neurons. These changes are probably partially involved in the neurodegenerative phenomena following ischemia. It is also shown that simultaneous measurements of NO and DA using this technique may be useful in assessing ischemic changes in vivo.
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PMID:[Effect of nitric oxide on central dopaminergic neurons]. 789 32

We examined the effect of interleukin-6 (human recombinant) on glutamate-induced neuronal death of cultured 20-day fetal rat hippocampal neurons. After 7 days in culture, the hippocampal neurons were markedly degenerated by the addition of L-glutamate and also N-methyl-D-aspartate. The neuronal death was prevented by the addition of MK801, a potent N-methyl-D-aspartate antagonist. Interleukin-6 at the concentration of 50 ng/ml has a significant preventive effect on the glutamate-induced neuronal death. Basic fibroblast growth factor at the concentration of 100 ng/ml gave also significant protective effect on hippocampal neurons, but nerve growth factor was ineffective in preventing the toxicity. It has been postulated that glutamate plays an important role in the pathogenesis of neuronal death such as ischemia and the various neurological diseases. Interleukin-6 might have somewhat physiological or pathological role in these events.
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PMID:Interleukin-6 protects cultured rat hippocampal neurons against glutamate-induced cell death. 791 97

Recently, diffusion-weighted magnetic resonance imaging (DWI) has been shown to visualize acute ischemic lesions in the brain before changes are observable with conventional magnetic resonance imaging. However, the underlying mechanisms of these acute DWI changes are unclear and may include both reversible and irreversible damage. In this study, we demonstrate that acute DWI lesions may be reversed with MK801 therapy postischemia. Sprague-Dawley rats (n = 12) were subjected to middle cerebral artery occlusion and DWI scans were obtained beginning 60 min postocclusion. Distinct regions of hyperintensity were observed in the basal ganglia and cortex, corresponding with the expected distribution of ischemia in this model. After the first scan, animals were treated with MK801 (0.5 mg/kg i.v.) or normal saline and subsequently scanned again 30 and 60 min after treatment. In the control group, the area of hyperintense lesions continued to increase, by 55% in the cortex and 57% in the basal ganglia. MK801 therapy significantly (p < 0.01) reduced the area of damage by the third DWI scan at 60 min posttreatment (-50% cortex, -22% basal ganglia, -41% total hemisphere) compared to pretreatment scans. Tetrazolium (TTC) stains at 24 h confirmed that MK801 significantly reduced the volumes of infarction (p < 0.05). These results demonstrate that significant portions of the acute ischemic lesion on DWI are reversible with pharmacologic intervention.
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PMID:Pharmacologic reversal of acute changes in diffusion-weighted magnetic resonance imaging in focal cerebral ischemia. 801 6

Excitatory amino acids and their receptors have been postulated to be involved in mediating ischemic neuronal damage. We occluded the bilateral carotid arteries for 5 min in gerbils to examine the effect of FR115427, a novel N-methyl-D-aspartate (NMDA) antagonist, on ischemic neuronal damage. FR115427 prevented hippocampal CA1 cell damage at a dose of 10 mg/kg and reduced spontaneous locomotor hyperactivity in gerbils after the development of ischemia at a dose of 32 mg/kg. The effective doses of MK801 were 3.2 mg/kg for preventing hippocampal CA1 cell damage and 1 mg/kg for reducing spontaneous locomotor hyperactivity. Moreover, we monitored the changes in body temperature of ischemic gerbils for 24 hr. The body temperature of ischemic gerbils significantly increased 1 hr after reperfusion. The pretreatment with FR115427 or MK801 prevented the hyperthermia provoked 1 hr after reperfusion in ischemic gerbils. In addition, the hypothermia was developed in gerbils treated with MK801 24 hr after reperfusion. However, FR115427 did not show hypothermia at any time. These results indicate that FR115427 has a protective effect against ischemic hippocampal CA1 cell damage after systemic administration, and this protective effect appears to be due to anti-NMDA activity.
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PMID:Protective effect of FR115427 against ischemic hippocampal damage in gerbils. 802 20


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