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)

As the most predominant excitatory neurotransmitter, glutamate has the potential to influence the function of most neuronal circuits in the central nervous system. To limit receptor activation during signaling and prevent the overstimulation of glutamate receptors that can trigger excitotoxic mechanisms and cell death, extracellular concentrations of excitatory amino acids are tightly controlled by transport systems on both neurons and glial cells. L-Glutamate is a potent neurotoxin, and the inadequate clearance of excitatory amino acids may contribute to the neurodegeneration seen in a variety of conditions, including epilepsy, ischemia, and amyotrophic lateral sclerosis. To establish the contributions of carrier systems to the etiology of neurological disorders, and to consider their potential utility as therapeutic targets, a detailed understanding of transporter function and pharmacology is required. This review summarizes current knowledge of the structural and functional diversity of excitatory amino acid transporters and explores how they might serve as targets for drug design.
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PMID:Excitatory amino acid transporters: a family in flux. 1033 Oct 91

The significance of mild-hypothermia as a treatment of brain ischemia-induced neuronal cell death was investigated by measurement of hippocampul excitatory amino acids, brain lactate and energy-charge just after 10 min of transient forebrain ischemia in a rat model with four vessels occluded. After 10 min of ischemia, cerebral circulation was restored. At that time, in the control group transient increases of hippocampul aspartate and glutamic acid levels were observed. Furthermore, brain lactate levels were also elevated but the energy-charge was reduced. These significant changes were observed in the non-isoflurane anesthesia and mild-hypothermia rats (control group). However, in rats with treatment of either isoflurane or mild-hypothermia, the excessive amount of amino acids and the significant fluctuation of brain metabolic/energy pathway seen in the control group were suppressed. Particularly, in the combined treatment group, these increased and decreased phenomena induced by brain ischemia were significantly inhibited. In a group of pre- and post-treatment of mild-hypothermia, the maximum peak of lactate was significantly less than that seen in the control group, although the sustained increased level of lactate was detected. These results indicate that the combined treatment with isoflurane anesthesia and mild-hypothermia is a suitable treatment for the brain dysfunction induced by ischemia and that the sustained hypothermia may help restore brain lactate levels after brain ischemia because of the lasting anaerobic metabolism.
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PMID:[Changes in brain metabolites under combined mild-hypothermia and isoflurane anesthesia in rat with temporal brain ischemia]. 1079 19

The extracellular glutamate concentration ([glu](o)) rises during cerebral ischemia, reaching levels capable of inducing delayed neuronal death. The mechanisms underlying this glutamate accumulation remain controversial. We used N-methyl-D-aspartate receptors on CA3 pyramidal neurons as a real-time, on-site, glutamate sensor to identify the source of glutamate release in an in vitro model of ischemia. Using glutamate and L-trans-pyrrolidine-2,4-dicarboxylic acid (tPDC) as substrates and DL-threo-beta-benzyloxyaspartate (TBOA) as an inhibitor of glutamate transporters, we demonstrate that energy deprivation decreases net glutamate uptake within 2-3 min and later promotes reverse glutamate transport. This process accounts for up to 50% of the glutamate accumulation during energy deprivation. Enhanced action potential-independent vesicular release also contributes to the increase in [glu](o), by approximately 50%, but only once glutamate uptake is inhibited. These results indicate that a significant rise in [glu](o) already occurs during the first minutes of energy deprivation and is the consequence of reduced uptake and increased vesicular and nonvesicular release of glutamate.
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PMID:Acute decrease in net glutamate uptake during energy deprivation. 1080 15

Glutamic acid, an excitatory amino acid, has been proposed to play a major deleterious influence in cerebral ischemia. However, the neuroprotective activity of various glutamate receptor antagonists is often low or absent, according to the animal model used. In the present study, we examined the effect of several antagonists acting on glutamate receptors of the N-methyl-D-aspartate (NMDA) type in rats submitted to a brief (5 minutes) global cerebral ischemia. The different compounds used were poorly active or inactive on behavioural and histologic alterations induced by ischemia. Our results suggest that, in this model, overactivation of NMDA receptor complex does not play a predominant role in the pathogenesis of ischemic brain damage.
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PMID:[Inefficacy of N-methyl-D-aspartate receptor complex antagonists on behavioral and histologic consequences of global cerebral ischemia in rats]. 1091 75

The efficacy of pre-, intra-, and postoperative prevention of hemodynamic disorders by creatinine phosphate, cytochrome C, and glutamic acid was evaluated in 61 coronary patients with decreased myocardial contractility. All these agents exerted a positive inotropic effect in coronary patients with ejection fraction below 0.4, increasing the stroke volume and left-ventricular ejection fraction without modifying heart rate. Glutamic acid is not recommended for preoperative treatment, because it increases oxygen consumption by the myocardium above the reserve potential of the coronary bed. Cytochrome C is the most effective drug for preoperative treatment. Intraoperative preischemic protection of the myocardium by cytochrome C in coronary patients during high risk operations prevents the development of unfavorable hemodynamic complications during induction and maintenance of anesthesia before artificial circulation, provides favorable recovery of cardiac activity, decreases the incidence of severe arrhythmias, promotes a rapid and full-value recovery of myocardial contractile function after ischemia, and decreases the incidence of acute heart failure.
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PMID:[Prevention of disorders of myocardial contractile function in patients with ischemic heart disease during aortocoronary shunting]. 1145 65

A rat model of gastric ischemia-reperfusion injury (GI-RI) was established by clamping the celiac artery for 30 min and allowing reperfusion for 1 h, on which the regulatory effect of the paraventricular nucleus (PVN) and its neural mechanisms were investigated. The results were: 1. Electrical stimulation of the PVN obviously attenuated the GI-RI. Microinjection of L-glutamic acid into PVN produced an effect similar to that of PVN stimulation. 2. Electrolytic ablation of the PVN aggravated the GI-RI. 3. Nucleus tractus solitarius (NTS) ablation could eliminate the protective effect of electrical stimulation of PVN on GI-RI. 4. Hypophysectomy did not alter the effect of electrical stimulation of PVN. 5. Vagotomy or sympathectomy both could increase the effect of PVN stimulation on GI-RI. These results indicate that the PVN participates in the development of GI-RI as a specific area in the CNS, exerting protective effects on the GI-RI. The NTS and vagus and sympathetic nerve may be involved in the regulative mechanism of PVN on GI-RI, but the PVN mechanism here is independent of the PVN-hypophyseal pathway.
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PMID:Neuroregulative mechanism of hypothalamic paraventricular nucleus on gastric ischemia-reperfusion injury in rats. 1212 5

The effects of electrical and chemical stimulation and electrolytic lesion of lateral hypothalamic area (LHA) on gastric ischemia-reperfusion injury (GI-RI) were investigated in rats whose celiac arteries were clamped for 30 min and reperfused for 60 min by removal of the clamp. The results are as follows. (1) Electrical stimulation of LHA could aggravate GI-RI in an intensity-dependent manner by using 0.2, 0.4 or 0.6 mA current respectively. Microinjection of L-glutamic acid into LHA resulted in a similar effect to that of electrical stimulation of LHA on GI-RI. After electrolytic lesion of bilateral LHA, the area of gastric mucosal injury induced by gastric ischemia-reperfusion (GI-R) was smaller than that by electrical stimulation of LHA plus GI-R. (2) Dorsal vagal complex (DVC) lesion or vagotomy could eliminate the effect of electrical stimulation of LHA on GI-RI. (3) Electrical stimulation of LHA increased the content of malondialdehyde (MDA) but decreased the activity of superoxide dismutase (SOD) of ischemia-reperfusion (I-R) gastric mucosa. (4) Electrical stimulation of LHA plus gastric I-R increased gastric juice volume and total acid output, but there were no significant changes in acidity, pepsin activity and gastric barrier mucus. These results indicate that the LHA is an area in the CNS exerting aggravate effects on GI-RI. The DVC and vagus may be involved in the regulative effects of LHA on GI-RI. These effects are associated with increases in gastric mucosal MDA content, gastric juice volume, and total acid output, and a decrease in SOD activity.Acidity, pepsin activity and gastric barrier mucus do not seem to play an important role.
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PMID:[Effects of electrical stimulation of lateral hypothalamic area on gastric ischemia-reperfusion injury in rats]. 1239 27

The neuroprotective effects of theanine and catechins contained in green tea are discussed. Although the death of cultured rat cortical neurons was induced by the application of glutamic acid, this neuronal death was suppressed with exposure to theanine. The death of hippocampal CA1 pyramidal neurons caused by transient forebrain ischemia in the gerbil was inhibited with the ventricular preadministration of theanine. The neuronal death of the hippocampal CA3 region by kainate was also prevented by the administration of theanine. Theanine has a higher binding capacity for the AMPA/kainate receptors than for NMDA receptors, although the binding capacity in all cases is markedly less than that of glutamic acid. The results of the present study suggest that the mechanism of the neuroprotective effect of theanine is related not only to the glutamate receptor but also to other mechanisms such as the glutamate transporter, although further studies are needed. One of the onset mechanisms for arteriosclerosis, a major factor in ischemic cerebrovascular disease, is probably the oxidative alteration of low-density lipoprotein (LDL) by active oxygen species. The oxidative alterations of LDL were shown to be prevented by tea catechins. Scavenging of *O(2)(-) was also exhibited by tea catechins. The neuroprotective effects of theanine and catechins contained in green tea are a focus of considerable attention, and further studies are warranted.
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PMID:Neuroprotective effects of the green tea components theanine and catechins. 1249 31

L-Glutamate is the major excitatory neurotransmitter in mammalian central nervous system, and excitatory amino acid transporters (EAATs) are essential for terminating synaptic excitation and for maintaining extracellular glutamate concentration below toxic levels. Although the structure of these channel-like proteins has not been yet reported, their membrane topology has been hypothesised based on biochemical and protein sequence analyses. In the case of an inadequate clearance from synaptic cleft and from the extrasynaptic space, glutamate behaves as a potent neurotoxin, and it may be related to several neurodegenerative pathologies including epilepsy, ischemia, amyotrophic lateral sclerosis, and Alzheimer disease. The recent boom of glutamate is demonstrated by the enormous amount of publications dealing with the function of glutamate, with its role on modulation of synaptic transmission throughout the brain, mainly focusing: i). on the structure of its receptors, ii). on molecular biology and pharmacology of Glu transporters, and iii). on the role of glutamate uptake and reversal uptake in several neuropathologies. This review will deal with the recent and most interesting published results on Glu transporters membrane topology, Glu transporters physiopathological role and Glu transporters medicinal chemistry, highlighting the guidelines for the development of potential neuroprotective agents targeting neuronal high-affinity sodium-dependent glutamate transporters.
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PMID:Neuronal high-affinity sodium-dependent glutamate transporters (EAATs): targets for the development of novel therapeutics against neurodegenerative diseases. 1257 Jul 95

The upregulation of TIMP-1 following an excitotoxic injury has recently been hypothesized to be part of a general neuronal response that mediates long-lasting changes involved in tissue reorganization and possibly neuroprotection. In this study we have shown for the first time that within hours of applying TIMP-1 in recombinant form or by adenovirus-mediated gene transfer, neurons are highly protected against excitotoxic injury. Neither TIMP-3 nor a nonsecretable form of TIMP-1 protected neurons. TIMP-1 conferred highly significant protection to hippocampal cells exposed to a wide range of glutamic acid concentrations in both dissociated and organotypic hippocampal cultures. TIMP-1 did not prevent apoptotic cell death or death mediated by chemical ischemia. The observed neuroprotection may be explained by a decrease in calcium influx into neurons following stimulation with glutamate. These findings have a fundamental implication for our understanding of the physiological role of secreted TIMP-1 in the central nervous system.
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PMID:Tissue inhibitor of metalloproteinase 1 inhibits excitotoxic cell death in neurons. 1259 42


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