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)

Flunarizine, a class IV Ca++ antagonist non-selective for slow Ca++ channels, has been shown to be beneficial in the prophylactic treatment of migraine, the treatment of vertigo, and as add-on treatment in therapy-resistant forms of epilepsy. Flunarizine protects the brain against functional and/or structural neuronal damage in various animal models of cerebral ischemia. In addition to its cerebrovascular effect, flunarizine has also direct neuroprotective actions. New data have emerged on flunarizine with regard to Ca++ and Na+ channels in neuronal cells. There are several possible mechanisms involved in the mode of action of flunarizine. Flunarizine may block Ca++ and Na+ channels, both of which may flux Ca++ as well as Na+. A decrease in Ca++ influx may prevent further release of glutamate, and activation of NMDA receptor gated Ca++ channels at physiological pH. A decrease in Na+ influx may prevent cytotoxicity secondary to a large gain in intracellular Ca++, by reverse operation of the Na+/Ca++ exchanger. This mechanism may be important when the glycolytic rate is increased with concomitant acidosis, and phospholipids are broken down as occurs typically during ischemia. Given the complexity of biochemical events leading to cell death, blocking exclusively one channel subtype is not likely to yield sufficient protection. Hence, it may be useful to develop anti-ischemic compounds which act on a series of pathways involved in Ca++ overload, rather than selectively block one such channel.
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PMID:Ca++ and Na+ channels involved in neuronal cell death. Protection by flunarizine. 185 Aug 15

Glutamate is an important factor in the mechanisms of neuronal damage following cerebral ischemia. Blockade of one type of glutamate receptor, the N-methyl-D-aspartate (NMDA) receptor, decreases brain infarct size in experimental models of permanent focal ischemia, but protection in models of transient reversible ischemia is ambiguous. We investigated the effect of the noncompetitive NMDA receptor antagonist dizocipiline (MK-801) on neuronal damage in the CA1 region of the rat hippocampus, using two models of reversible cerebral ischemia: 10 or 15 min of bilateral common carotid occlusion combined with hypotension, or 6-8.5 min of cardiac arrest. Histopathologic evaluation of neuronal damage was performed 7 days after the ischemic insults. Thirteen groups of rats (a total of 129 animals) were treated with saline or dizocilpine in single or multiple doses ranging from 0.1 to 5 mg.kg-1, given intravenously or intraperitoneally prior to and/or after the ischemic insult. In none of the dizocilpine-treated groups could neuronal protection be demonstrated in the CA1 region of the septal as well as dorsotemporal hippocampus, compared to a corresponding saline-treated group. We conclude that systemically administered noncompetitive NMDA receptor antagonists do not provide a marked protection against neuronal damage after a transient period of severe forebrain ischemia.
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PMID:Lack of protection by the N-methyl-D-aspartate receptor blocker dizocilpine (MK-801) after transient severe cerebral ischemia in the rat. 185 15

Release of glutamate from brain cells is increased during ischemia and is thought to be involved in ischemic damage. In rat hippocampal slices the release of glutamate during 'in vitro ischemia' (anoxia without glucose) is shown to be blocked by two groups of compounds: non-competitive N-methyl-D-aspartate (NMDA) antagonists and sigma ligands. The effects are selective for the ischemic glutamate release, which is independent of extracellular Ca2+. High K+, Ca2+ dependent, induced release of glutamate is not inhibited. NMDA receptor blockade normally does not prevent ischemic transmission damage in the rat hippocampal slice. However, when ischemic glutamate release is attenuated, NMDA receptor antagonists do prevent the damage. This indicates that high levels of glutamate may cause damage via non-NMDA as well as NMDA receptors.
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PMID:Sigma-ligands and non-competitive NMDA antagonists inhibit glutamate release during cerebral ischemia. 196 13

Opipramol, a potent sigma ligand and a tricyclic antidepressant compound, provided significant neuronal protection (P less than 0.0001) against ischemia-induced neuronal cell loss in the hippocampus in Mongolian gerbils, at a dose of 50 mg/kg (30 min pretreatment). However, opipramol did not offer protection when given 60 min after the ischemic insult. Opipramol decreased basal levels of cGMP in the cerebellum of the mouse and harmaline-induced increases in levels of cGMP, with approximate ED50 values of 4 and 27 mg/kg. Opipramol antagonized methamphetamine- and pentylenetetrazol-induced increases in levels of cGMP. Parenteral administration of opipramol also antagonized the increases in levels of cGMP in the cerebellum of the mouse after the local administration of D-serine, an agonist at the N-methyl-D-aspartate (NMDA)-associated, strychnine-insensitive glycine receptor. These results indicate that opipramol attenuates responses mediated through the NMDA receptor complex. These results further support the functional modulation of the NMDA receptor complex by sigma ligands and provide a neurochemical correlate for the observed anti-ischemic properties of opipramol.
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PMID:Opipramol, a potent sigma ligand, is an anti-ischemic agent: neurochemical evidence for an interaction with the N-methyl-D-aspartate receptor complex in vivo by cerebellar cGMP measurements. 196 77

Acute neurological injury from hypoxia-ischemia, hypoglycemia, and trauma is thought to be predominantly mediated by activation of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor in the brain and the subsequent influx of calcium ions through receptor-operated channels. Several chronic degenerative diseases, such as Huntington's disease and the amyotrophic lateral sclerosis-Parkinsonism-dementia complex found on Guam, may share a similar pathogenesis due to a glutamate-like toxin. This laboratory recently reported that exposure to a reducing agent, such as dithiothreitol (DTT), selectively increases ionic current flow through NMDA-activated channels in several types of central neurons; conversely, oxidizing agents reverse this effect. To investigate the novel influence of redox modulation on NMDA neurotoxicity, in the present in vitro study we monitored survival of an identified central neuron, the retinal ganglion cell, approximately 24 h after a brief exposure to DTT. To determine the degree of killing specifically related to activation of the NMDA receptor, 2-amino-5-phosphonovalerate (APV, a selective NMDA antagonist) was added to sibling cultures. APV-preventable, glutamate-induced death was increased 70 +/- 9% with DTT treatment. This effect was totally blocked by the concomitant addition of an oxidizing agent, 5,5-dithiobis-2-nitrobenzoic acid (DTNB). These findings suggest that the enhanced killing following chemical reduction with DTT is mediated at the NMDA receptor site, and that the redox state of the NMDA receptor is crucial for the survival of neurons facing glutamate-related injury.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Redox modulation of NMDA receptor-mediated toxicity in mammalian central neurons. 197 Jan 45

Degeneration of hippocampal CA1 neurons occurs following transient complete ischemia produced by raised intracranial pressure. Both systemic injection of MK-801 and profound cerebral hypothermia produced by cisternal infusion of room temperature (22-25 degrees C) fluids protect vulnerable CA1 neurons from degeneration. Hypothermia appears to decrease hippocampal extracellular levels of glutamate during and after ischemia but provides only relative protection from ischemia as CA1 degeneration does occur with prolonged (30 min) periods of ischemia. Elevated intracranial pressure appears to produce ischemic degeneration in the hippocampus via an NMDA receptor mediated excitotoxic process which is highly temperature dependent.
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PMID:Degeneration of hippocampal CA1 neurons following transient ischemia due to raised intracranial pressure: evidence for a temperature-dependent excitotoxic process. 197 Sep 44

Excitotoxicity is believed to underlie the selective loss of vulnerable neurons after transient ischemia, while lactic acidosis seems to be the principal feature and probable cause of tissue infarcts. Primary hippocampal cultures containing both neurons and astrocytes derived from fetal rats were used to examine the relative contributions of and interactions between excitotoxic and acidotic cell injury. Hypoxia-induced damage was energy dependent and involved the N-methyl-D-aspartate (NMDA) receptor. Glucose above 1 mM could completely protect against hypoxia-induced injury in a pH range of 7.4-6.5, while the NMDA receptor antagonist D,L-2-amino-5-phosphonovaleric acid (500 microM) during the posthypoxic period provided only partial protection in the absence of glucose. Astrocyte cultures were undamaged by ischemic-like treatment in this pH range, suggesting that hypoxia-induced cell death in mixed cultures was restricted to neurons. Lowering the extracellular pH to 7.0 and 6.5 caused no neuronal damage in normoxic controls, but in each case provided significant protection against hypoxic neuronal injury. In contrast, a second type of neurotoxicity was observed after a 6-h exposure to pH 6.0, while exposure to pH 5.5 was required to kill astrocytes. This acidotic damage appeared to be energy independent and did not involve the NMDA receptor. These results suggest that excitotoxic neuron death has an energetic component and that acidosis may produce both protective and damaging effects in the hippocampus during ischemic insults.
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PMID:Mechanistic distinctions between excitotoxic and acidotic hippocampal damage in an in vitro model of ischemia. 197 25

In the present study we investigated the relative vulnerability of neuronal subsets in the striatum to ischemia that was induced by bilateral transient ligation of the common carotid arteries in gerbils. After 4 days of survival, brains were evaluated using histochemical methods (NADPH-diaphorase and silver degeneration procedures) and neurochemical methods with radioimmunoassays for somatostatin-, neuropeptide Y-, and substance P-like immunoreactivity and measurements of amino acids using high-pressure liquid chromatography with electrochemical detection. NADPH-diaphorase-positive neurons were strikingly preserved in the ischemic dorsolateral portion of the striatum, in which there was severe neuronal loss. There was no significant depletion of NADPH-diaphorase-positive neurons in the striatum or cerebral cortex. Concentrations of neuropeptide Y-like and somatostatin-like immunoreactivity were unchanged despite a significant 25% depletion of substance P-like immunoreactivity and gamma-aminobutyric acid. Ischemic brain damage may be mediated by a neurotoxic effect of glutamate acting at the N-methyl-D-aspartate (NMDA) receptor. Previous studies of NMDA excitotoxin lesions in rat striatum have shown a sparing of neurons containing NADPH-diaphorase, somatostatin, and neuropeptide Y. The similar sparing of these neurons following ischemic lesions in gerbil striatum provides further evidence that NMDA receptor activation may play a role in ischemic injury.
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PMID:Selective sparing of NADPH-diaphorase-somatostatin-neuropeptide Y neurons in ischemic gerbil striatum. 197 76

Amino acids such as L-glutamate und L-aspartate are major excitatory neurotransmitters in the mammalian central nervous system (CNS) and potential neurotoxins (excitotoxins), which can destroy central neurons by excessive activation of respective receptors. In the last three decades evidence has accumulated that excitatory amino acids (EAA) are involved in many neurological diseases and that pharmacological intervention offers prospects of novel and more effective therapies. Three different receptor types for EAA have been identified, each being named by the selective agonist to which it is preferentially sensitive, i.e. N-methyl-D-aspartate- (NMDA), kainate- and quisqualate-receptors. In this review interest is focused primarily on the NMDA-receptor, whose structure has been subject of numerous electrophysiological and biochemical studies. Today, it is well established that the NMDA-receptor-ionophore complex has an agonist binding site for glutamate, NMDA and related EAAs which is coupled with an ion channel permeable to Na+, K+, Cl- and Ca2+. Four other binding sites for glycine, phencyclidine, Mg2+ and Zn2+ have been identified which can differentially modulate the function of the NMDA receptor. An additional polyamine binding site has recently been reported. Numerous studies on experimental animals demonstrate that modulators of NMDA-mediated neurotransmission may have antiepileptic, anxiolytic, muscle-relaxant and memory-enhancing effects. Particular interest has gained the possible neuroprotective efficacy of NMDA-receptor antagonists in neurological diseases such as hypoxia/ischemia, hypoglycemia, epilepsy and chronic neurodegenerative disorders (Huntington's, Alzheimer's and Parkinson's disease, amyotrophic lateral sclerosis, and AIDS encephalopathy).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[The N-methyl-D-aspartate receptor complex. Various sites of regulation and clinical consequences]. 197 26

The NMDA receptor is intimately involved an a wide range of pathophysiological processes in the mammalian brain, including epilepsy and ischemia-induced neurodegeneration. The widespread distribution of NMDA receptors places almost every area of the brain at risk from NMDA receptor over-activity. However, it is clear that the central nervous system can function effectively without imminent danger of self-destruction. The focus of this review is the processes that control NMDA receptor responsiveness in vivo. The review will cover the modulation of the receptor by Mg2+, glycine, Zn2+ and polyamines that is believed to occur by virtue of interaction with distinct ligand binding sites on the NMDA receptor complex. Studies suggesting a role for receptor phosphorylation and for redox modulation will be discussed. Finally, some evidence for indirect regulation of cellular responses to NMDA receptor activation by other neurotransmitters will be presented.
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PMID:Modulation of NMDA receptor responsiveness by neurotransmitters, drugs and chemical modification. 197 53


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