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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

One of the crucial factors affecting mortality and morbidity after circulatory arrest the ischemic neuronal damage following complete cessation of cerebral blood-flow. To date, no accepted pharmacologic neuroprotective therapy has emerged. Cerebral ischemia causes a rapid shift of Ca++ from the extracellular spaces into cells and it is assumed that this excessive entry of Ca++ is the final pathway of cell death. In addition, Ca++ is involved in the diffuse vasospasm which occurs after global cerebral ischemia. Therefore, calcium entry blockers such as dihydropyridines derivatives have sparked considerable interest especially because of their preferential cerebrovasodilating effects. In vivo studies have demonstrated protection from brain ischemia with calcium entry blockers. However no direct protective effect of these drugs has been shown on neurons. More recent results have underscored the importance of excitatory amino acid neurotransmitters and receptors (particularly N-Methyl-D-Aspartate receptors) in causing intracellular calcium overload and neuronal death after ischemia. Blockade of these receptors or their associated channels may be an interesting way to protect the brain against ischemic damage.
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PMID:[Feasibility of calcium inhibitors in the treatment of brain disease following cardiac arrest]. 281 43

Oxygen-derived free radicals have been shown to be important mediators in ischemia-reperfusion injury to skin flaps. Agents that reduce the level of these free radicals have been used to improve flap survival in model systems. An in vitro study of the interactions between amino acids and hydroxyl radicals by electron spin resonance spectroscopy suggests an intrinsic radical scavenging activity of certain amino acids. The ability of these amino acids to improve acute axial-random skin flap survival was examined in a rat model. Cysteine, methionine, proline, hydroxyproline, histidine, and phenylalanine, given intravenously, significantly improved flap survival over saline controls; alanine gave an intermediate result, while aspartic acid showed no improvement. The in vitro data were generally a good predictor of free radical scavenging ability as manifested by improved flap survival in vivo. Biochemical mechanisms and clinical applications are described.
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PMID:Improved survival of acute skin flaps with amino acids as free radical scavengers. 319 Aug 67

Coronary occlusion was carried out in 58 dogs in an acute experiment and the content of ammonia and urea was studied in venous blood draining directly from the zone of ischemia. Early increase in the concentration of free ammonia in the zone of ischemia was revealed. The administration of l-aspartic acid, potassium asparaginate, magnesium asparaginate, and glutamic acid led to intensification of urea-producing processes in the myocardium and reduction in hyperammoniemia and the degree of ischemic damage to the myocardium.
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PMID:[Correction of nitrogen metabolic disorders in the myocardium in experimental ischemia]. 741 82

2-Amino-N-(1,2-diphenylethyl)-acetamide hydrochloride (FPL 13950) has been demonstrated to have good anticonvulsant efficacy and a relative lack of acute side effects in rodents. Similar in structure to remacemide hydrochloride, it was also shown to possess weak potency as an uncompetitive antagonist of N-methyl-D-aspartic acid (NMDA) receptors. In our study FPL 13950 was profiled preclinically as a potential neuroprotective agent with respect to lengthening the survival time of rodents exposed to hypoxia, as well as for ability to protect the vulnerable CA1 pyramidal neurons of the rat and dog from the consequences of global ischemia. Under conditions of hypoxia, pretreatment of rodents with FPL 13950 resulted in an extension in the time to loss of the righting reflex (rats) and mortality (rats and mice). This occurred whether the rats were maintained at ambient body temperature or made hyperthermic. When administered after 30 min of four-vessel occlusion global ischemia for periods of either 7 (b.i.d.) or 14 days (s.i.d.), FPL 13950 exhibited protection of the vulnerable CA1 hippocampal neurons in rat. In the 14-day treatment study the CA3 neurons were evaluated and FPL 13950 was found to prevent the lesser degree of ischemic-induced damage to this hippocampal region. In ischemic rats treated with FPL 13950 for 7 days, electrophysiological responses of CA1 neurons (orthodromic and antidromic population spikes, in vitro) were also preserved after FPL 13950 treatment. FPL 13950 was administered i.v. at 30 min after 8 min of clamping the ascending aorta in dogs, followed by a b.i.d./s.i.d. dosing regimen for 1 wk. Neuronal damage to CA1 was considerable in the saline-treated ischemic animals but significantly protected in dogs receiving FPL 13950. FPL 13950 continues to serve as a potential backup candidate for remacemide HCl which is currently in clinical trials for patients with stroke and epilepsy.
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PMID:Neuroprotective actions of 2-amino-N-(1,2-diphenylethyl)-acetamide hydrochloride (FPL 13950) in animal models of hypoxia and global ischemia. 763 64

The changes in the spontaneous excitatory postsynaptic currents (sEPSCs) after transient cerebral ischemia were studied using whole-cell recording from CA1 pyramidal neurons in the gerbil. In neurons recorded 1-2 days after ischemia, sEPSCs had a slowed time course with the decay time constant fitted by a single exponential and it progressively increased after ischemia. Frequency and amplitude distribution of sEPSCs in ischemic neurons were not significantly different from those in the control neurons. The results support the view that abnormal non-N-methyl-D-aspartic acid currents originate at the degenerated postsynaptic site, unrelated to the presynaptic releasing mechanisms.
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PMID:Spontaneous excitatory postsynaptic currents in hippocampal CA1 pyramidal neurons of the gerbil after transient ischemia. 765 1

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 CA1 region of hippocampus is selectively vulnerable to a variety of insults, including hypoxia-ischemia and Alzheimer's disease, but the basis of this regional susceptibility is poorly understood. We examined the regional hippocampal sensitivity to mitochondrial metabolic disruption induced by malonate, an inhibitor of succinate dehydrogenase. The CA1 region was exquisitely sensitive to malonate and the dentate gyrus was extremely resistant; the CA3 region had intermediate sensitivity. This pattern of vulnerability is reminiscent of hypoxic-ischemic damage. Malonate damage was blocked by the N-methyl-D-aspartic acid (NMDA) antagonist, MK-801, but regional susceptibility to malonate did not correlate with the density of NMDA receptors. Instead, malonate toxicity was inversely correlated with activity of succinate dehydrogenase. Our results suggest that regional metabolic capacity may help to determine sensitivity to metabolic/excitotoxic insults such as hypoxia-ischemia.
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PMID:Selective vulnerability of the CA1 region of hippocampus to the indirect excitotoxic effects of malonic acid. 767 3

Glucocorticoids (GCs), the adrenal steroid hormones secreted during stress, exacerbate neuronal death in the hippocampus during ischemia. Since ischemia brain damage is ascribed to an elevated level of extracellular excitatory amino acids (EAAs), this study was undertaken to investigate the effect of GCs on EAA homeostasis in hippocampal cell cultures during the insult of cyanide exposure. Using D-[2,3-3H]aspartic acid ([3H]D-Asp) as a tracer, we found that corticosterone (CORT, the physiological GC in rats) increased the accumulation of extracellular [3H]D-Asp by 25% in hippocampal cultures during cyanide-induced ischemia. CORT had no effect on the release of [3H]D-Asp. Instead, analysis of [3H]D-Asp uptake kinetics indicates that CORT decreased the maximum uptake rate and the Michaelis constant by 44% and 50%, respectively, in cells treated with cyanide. It is concluded that, during cyanide-induced ischemia, CORT might enhance extracellular overflow of [3H]D-Asp by decreasing its uptake, thereby endangering neurons.
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PMID:Glucocorticoids increase extracellular [3H]D-aspartate overflow in hippocampal cultures during cyanide-induced ischemia. 798 1

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

Recently, we reported the synthesis of 3-(sulfonylamino)-2(1H)-quinolones, a new series of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainate and N-methyl-D-aspartic acid (NMDA)/glycine antagonists. By exploring the structure-activity relationships (SAR) in this series, we were able to identify the 6,7-dinitro derivative 6 as a potent and balanced antagonist at both receptors. Unfortunately, compound 6 was devoid of in vivo activity in mice anticonvulsant testing. To overcome this critical limitation, new compounds bearing various acidic moieties at the 3-position of the quinolone skeleton were synthesized and evaluated. The SAR of these new analogues indicated that not all acidic groups are acceptable at the 3-position: A rank order of potency going from carboxylic approximately phosphonic > tetrazole > mercaptoacetic > hydroxamic >> other heterocyclic acids was defined. In addition, the selectivity between the AMPA/kainate and NMDA/glycine sites is dependent on the nature of the substitution (nitro > chloro for AMPA selectivity), its position (5,7- > 6,7-pattern for glycine selectivity), and the distance between the quinolone moiety and the heteroatom bearing the acidic hydrogen (the longer the distance the more AMPA selective the compound). Among these new AMPA antagonists, we have identified 6,7-dichloro-2(1H)-oxoquinoline-3-phosphonic acid (24c) as a water soluble and selective compound endowed with an appealing pharmacological profile. Compared with the reference AMPA antagonist NBQX, the phosphonic acid 24c is much less potent in vitro but almost equipotent in vivo in the audiogenic seizures model after intraperitoneal administration. Moreover, unlike NBQX, compound 24c is also active after oral administration. In the gerbil global ischemia model, compound 24c shows a neuroprotective effect at 10 mg/kg/ip, equivalent to the reference NBQX.
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PMID:Structure-activity relationships in a series of 2(1H)-quinolones bearing different acidic function in the 3-position: 6,7-dichloro-2(1H)-oxoquinoline-3-phosphonic acid, a new potent and selective AMPA/kainate antagonist with neuroprotective properties. 856 8


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