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Query: UMLS:C0917798 (cerebral ischemia)
 17,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It has been postulated that a reversal of glutamate reuptake ("uptake reverse") may contribute to glutamate release during cerebral ischemia. We tested this hypothesis by studying the effect of threo-3-hydroxy-DL-aspartic acid (THA), a glutamate uptake inhibitor, on extracellular glutamate accumulation measured by microdialysis during 4-vessel ischemia (20 min). The inhibitory effect of THA on sodium-dependent glutamate uptake was measured in vitro on rat hippocampal slices (Ki = 45 +/- 11 microM). We examined in vivo the effect of THA (400 microM in the dialysis solution) on the extracellular glutamate release from the rat hippocampus, during veratridine depolarization and ischemia. THA decreased the amount of glutamate appearing in the extracellular space during veratridine depolarization (61%). In contrast, the glutamate release induced by ischemia was not affected by THA. We conclude that a reversal of the sodium-dependent uptake contributes to an increase in extracellular glutamate during veratridine depolarization. In contrast, glutamate release occurring during ischemia is not mediated by uptake reverse.
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PMID:Effects of a glutamate uptake inhibitor on glutamate release induced by veratridine and ischemia. 767 Mar 63

The protective effects of Kamikihi-To (KMK), a traditional Chinese medicine, against cerebral ischemia, hypoxia and anoxia were investigated with various experimental models in mice and gerbils. KMK (2.0 g/kg/day, p.o. for 5 days) significantly prolonged the survival time of mice subjected to bilateral common carotid artery occlusion. KMK (0.5 and 2.0 g/kg/day, p.o. for 5 days) also prolonged the survival time of mice injected with N-methyl-D-aspartic acid (NMDA: 80 mg/kg, i.v.). Furthermore, KMK (in a diet containing 8% KMK given orally for 34 days) showed protective effects against delayed neuronal death in CA1 pyramidal cells in the gerbil hippocampus after transient forebrain ischemia. On the other hand, we failed to show any protective effects of KMK (0.5-2.0 g/kg/day, p.o. for 5 days) against normobaric hypoxia and KCN-induced cytotoxic anoxia in mice. These results suggest that KMK may have protective effects against cerebral ischemic disorders, but not against severe hypoxic and anoxic disorders.
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PMID:Protective effects of kamikihi-to, a traditional Chinese medicine, against cerebral ischemia, hypoxia and anoxia in mice and gerbils. 802 19

Although N-methyl-D-Aspartate (NMDA) antagonists protect against focal cerebral ischaemia, there is concern that the high doses necessary for neuroprotection may cause unacceptable adverse effects. We studied the dose response characteristics of the clinically available NMDA antagonist dextromethorphan in a rabbit model of transient focal ischaemia. Thirty-three anaesthetized rabbits underwent occlusion of the left internal carotid and anterior cerebral arteries for 1 h followed by 4.5 h of reperfusion. One hour after the onset of ischaemia, they were treated with an i.v. infusion of varying doses of dextromethorphan or normal saline. Seventeen additional unanaesthetized, nonischaemic rabbits received similar infusions of dextromethorphan to correlate brain with blood levels and to evaluate adverse effects. Rabbits with plasma dextromethorphan levels 500-1500 ng ml-1 had a 64% reduction in ischaemic neuronal damage (p < 0.05); those with levels > 1500 ng ml-1 showed 92% attenuation of neuronal damage and 65% decrease in ischaemic oedema (p < 0.01). Drug levels suggest that dextromethorphan's neuroprotection is not mediated by its active metabolite dextrorphan. Unanaesthetized rabbits with plasma levels > 2500 ng ml-1 demonstrated severe gait ataxia. These results demonstrate that systemic treatment with dextromethorphan after 1 h of focal ischaemia can significantly protect against cerebral damage if adequate plasma and brain levels are achieved. Dextromethorphan was concentrated 7-30 x in brain compared with plasma, and brain levels were highly correlated with plasma levels (r = 0.89). Neuroprotective doses of dextromethorphan were tolerated with only transient side effects.
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PMID:Neuroprotection following focal cerebral ischaemia with the NMDA antagonist dextromethorphan, has a favourable dose response profile. 810 83

The object of this study was to investigate the role of the ventrolateral medullary pressor area in mediating the cardiovascular responses to experimentally induced global cerebral ischemia, and to test if excitatory amino acids or acetylcholine are the transmitters released in this brain region during these responses. The cerebral ischemic response was elicited in pentobarbital-anesthetized, artificially ventilated male Wistar rats by bilateral ligation of vertebral arteries followed by temporary clamping of the common carotid arteries. The pressor area was identified by microinjections of L-glutamate. Inhibition of neurons in this area by microinjections of muscimol, a gamma-aminobutyric acid receptor agonist, abolished the ischemic response, which demonstrated that this area is important in mediating these responses. Microinjections of a broad-spectrum excitatory amino acid receptor blocker (kynurenate), of specific antagonists for N-methyl-D-aspartic acid (NMDA) and non-NMDA receptors (injected alone or in combination), and of atropine failed to block the ischemic responses. These results indicate that: 1) the ventrolateral medullary pressor area mediates pressor responses to cerebral ischemia, and 2) excitatory amino acids or acetylcholine in this area do not mediate the cardiovascular responses to cerebral ischemia.
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PMID:Cardiovascular responses to global cerebral ischemia: role of excitatory amino acids in the ventrolateral medullary pressor area. 848 75

We determined the ability of a new benzomorphan derivative [2R-[2 alpha, 3(R*),6 alpha]]-1,2,3,4,5,6-hexahydro-3-(2-methoxypropyl)- 6,11,11-trimethyl-2,6-methano-3-benzazocin-9-ol hydrochloride (BIII 277 CL) to inhibit the N-methyl-D-aspartic acid (NMDA) receptor-channel complex in vitro and in vivo. BIII 277 CL potently displaced [3H]MK-801 binding from the NMDA receptor-channel complex in synaptosomal membrane preparations from rat brain cortex (Ki = 4.49 nmol/l). It was much less effective at displacing [3H]dihydromorphine, [3H]naloxone and [3H]ditolyguanidine binding in similar membrane preparations: the Ki values were 3323, 8031 and 1017 nmol/l, respectively. BIII 277 CL did not exhibit any marked affinities for a variety of other central neurotransmitter receptors. BIII 277 CL antagonized NMDA-induced [3H]noradrenaline release (EC50 = 1.7 mumol/l) and NMDA-induced inhibition of protein synthesis in rat hippocampal slices (EC50 = 3.0 mumol/l). In mice, BIII 277 CL prevented NMDA-induced lethality (ID50 = 0.54 mg/kg s.c.) and, as expected, also caused disturbances in motor coordination in the same dose range (ED50 = 0.47 mg/kg s.c.). The duration of BIII 277 CL was much shorter than than of (+)MK-801 in both tests. Finally, BIII 277 CL (0.3 mg/kg s.c. 5 times over 24 h) reduced the cortical infarct area in mice that had been subjected previously to focal cerebral ischemia by unilateral occlusion of the middle cerebral artery. In summary, these results indicate that BIII 277 CL is a potent and specific ion-channel blocker of the NMDA receptor-channel complex which could be used for the treatment of acute thromboembolic stroke in humans.
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PMID:BIII 277 CL is a potent and specific ion-channel blocker of the NMDA receptor-channel complex. 853 Nov 6

Leukocytes play an important role in the development of ischemia/reperfusion injury. Recent work in our laboratory has demonstrated that a mixture of synthetic fibronectin peptides to leukocyte adhesion molecules reduces ischemic brain damage after transient focal cerebral ischemia. The purpose of this study was to evaluate the efficacy of the individual peptides on leukocyte accumulation, infarct size, and neurological outcome in rats subjected to 1 h of cerebral ischemia and 48 h of reperfusion. Thirty-five animals were divided into five groups: transient ischemia without treatment (Group I), treatment with arginyl-glycyl-aspartic acid (RGD) peptide (Group II), connecting segment (CS)-1 peptide (Group III), fibronectin (FN)-C/H-V peptide (Group IV), and scrambled FN-C/H-V peptide (Group V). Groups III and IV showed a significant decrease in the degree of leukocyte infiltration in the lesion and in the infarct size (p < 0.05) when compared to Groups I, II, and V. The neurological grade of Groups III and IV was significantly better than in Groups I, II, and V at 48 h after reperfusion (p < 0.01). Thus, in addition to demonstrating the potential efficacy of synthetic peptides as therapeutic agents for ischemia-reperfusion, these results also offer new insights into the mechanisms of leukocyte arrest and recruitment in ischemia/reperfusion injury.
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PMID:Neuronal protection from cerebral ischemia by synthetic fibronectin peptides to leukocyte adhesion molecules. 889 83

Glutamate receptor antagonists are protective in animal models of focal cerebral ischemia. Lamotrigine (3,5-diamino-6-[2,3-dichlorophenyl]-1,2, 4-triazine) is an anticonvulsant drug that blocks voltage-gated sodium channels and inhibits the ischemia-induced release of glutamate. Experiments in primary neuronal cultures implicate nitric oxide (NO) as a mediator of glutamatergic neurotoxicity acting via N-Methyl-D-Aspartate (NMDA) receptors. The effect of glutamate release inhibitor, Lamotrigine upon NO and cGMP production has been examined in focal cerebral ischemia in rats. Focal cerebral ischemia was produced by the permanent occlusion of right middle cerebral artery (MCA) in urethane anesthetized rats. A number of indicators of brain NO production (nitrite, cGMP) were determined in ipsilateral and contralateral cerebral cortex and cerebellum after 0, 10, 60 min of focal cerebral ischemia. The same parameters were measured in rats treated with Lamotrigine (20 mg/kg, i.p.) 30 min before or just after the occlusion of the right MCA.
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PMID:Effects of Lamotrigine on brain nitrite and cGMP levels during focal cerebral ischemia in rats. 908 81

DHEA, together with DHEAS, is the most abundant steroid in the blood of young adult humans. Levels in humans decline with age and during certain types of illness or stress. We have found that DHEA(S) can prevent or reduce the neurotoxic actions in the hippocampus of the glutamate agonists N-methyl-D-aspartic acid (NMDA) both in vitro and in vivo or alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainic acid in vitro. Pre-treatment with DHEA (10-100 nM for 6-8 h) protected primary hippocampal cultures from embryonic day 18 (E18) embryos against NMDA-induced toxicity (0.1, 1, 10, and 50 mM). DHEA added either with NMDA (1 mM) or 1 h later had lesser, but still significant, protective actions. DHEAS also reduced NMDA-induced toxicity (1 mM), although the lowest effective dose of DHEAS (100 nM) was higher than that of DHEA (10 nM). DHEA (100 nM) protected cultured neurons against the neurotoxic actions of either AMPA (25 microM) or kainic acid (1 mM) as well. In vivo, s.c. pellets of DHEA, which resulted in plasma levels that resembled those in young adult humans, protected hippocampal CA1/2 neurons against unilateral infusions of 5 or 10 nmol of NMDA. Because the release of glutamate has been implicated in the neural damage after cerebral ischemia and other neural insults, these results suggest that decreased DHEA levels may contribute significantly to the increased vulnerability of the aging or stressed human brain to such damage.
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PMID:Dehydroepiandrosterone (DHEA) and DHEA-sulfate (DHEAS) protect hippocampal neurons against excitatory amino acid-induced neurotoxicity. 946 6

Although various neuroprotective and fibrinolytic drugs are currently under evaluation in the acute stages of ischaemic stroke, their therapeutic potential is likely to be limited by unwanted side effects and a narrow time window of opportunity for intervention. Proteolytic enzymes are involved in the catabolism of peptide neurotransmitters and structural cellular proteins in normal brain and have been implicated in the pathogenesis of neurodegenerative disorders. We hypothesised that activation of these enzymes might also play a crucial role in effecting ischaemic neuronal injury, thereby providing a potential site for therapeutic intervention in human stroke. Focal cerebral ischaemia was induced by thermocoagulation of the left middle cerebral artery in aged (30 month) male Wistar rats who were pre-treated with saline or the competitive N-methyl-D-Aspartate antagonist D-CPP-ene, which has been shown to be neuroprotective in young animal models of stroke. Major protease activities were analysed in the left (ischaemic) and right (non-ischaemic) hemispheres, following tissue homogenisation. Data have been analysed using Mann-Whitney tests and are presented as means +/- standard errors. Enzyme activity decreased in ischaemic brain; for example, the mean activity of dipeptidyl aminopeptidase I was 23 +/- 3 and 43 +/- 6 nmol substrate/hour/ml brain extract in the left and right hemispheres respectively (n = 10, p < 0.05). Ischaemic neuronal injury is not effected by the early activation of proteolytic enzymes and protease inhibitors are therefore unlikely to be of benefit in human stroke.
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PMID:The role of proteolytic enzymes in focal ischaemic brain damage. 1145 20

Transforming growth factor-alpha (TGF-alpha), a ligand of the epidermal growth factor receptor, reduces the infarct size after focal cerebral ischemia in rat, but the molecular basis underlying the protection is unknown. Excitotoxicity and global inhibition of translation are acknowledged to contribute significantly to the ischemic damage. Here we studied whether TGF-alpha can rescue neurons from excitotoxicity in vitro and how it affects calcium homeostasis, protein synthesis, and the associated Akt and extracellular signal-regulated kinase 1/2 (Erk1/2) intracellular signaling pathways in mixed neuron-glia cortical cultures. We found that 100 ng/ml TGF-alpha attenuated neuronal cell death induced by a 30-min exposure to 35 microM N-methyl-D-aspartic acid (NMDA) (as it reduced lactate dehydrogenase release, propidium iodide staining, and caspase-3 activation) and decreased the elevation of intracellular Ca2+ elicited by NMDA. TGF-alpha induced a prompt and sustained phosphorylation of Erk1/2 and prevented the loss of Akt-P induced by NMDA 3 h after exposure. The protective effect of TGF-alpha was completely prevented by PD 98059, an inhibitor of the Erk1/2 pathway. Studies of incorporation of [3H]leucine into proteins showed that NMDA decreased the rate of protein synthesis, and TGF-alpha attenuated this effect. TGF-alpha stimulated the phosphorylation of the eukaryotic initiation factor 4E (eIF4E) but did not affect eIF2 alpha, two proteins involved in translation regulation. PD 98059 abrogated the TGF-alpha effect on eIF4E. Our data demonstrate that TGF-alpha exerts a neuroprotective action against NMDA toxicity, in which Erk1/2 activation plays a key role, and suggest that the underlying mechanisms involve recovery of translation inhibition, mediated at least in part by eIF4E phosphorylation.
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PMID:Transforming growth factor-alpha attenuates N-methyl-D-aspartic acid toxicity in cortical cultures by preventing protein synthesis inhibition through an Erk1/2-dependent mechanism. 1277 Nov 52


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