Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glutamate transporters are integral membrane proteins that catalyse the concentrative uptake of glutamate from the synapse to intracellular spaces by harnessing pre-existing ion gradients. In the central nervous system glutamate transporters are essential for normal development and function, and are implicated in stroke, epilepsy and neurodegenerative diseases. Here we present the crystal structure of a eukaryotic glutamate transporter homologue from Pyrococcus horikoshii. The transporter is a bowl-shaped trimer with a solvent-filled extracellular basin extending halfway across the membrane bilayer. At the bottom of the basin are three independent binding sites, each cradled by two helical hairpins, reaching from opposite sides of the membrane. We propose that transport of glutamate is achieved by movements of the hairpins that allow alternating access to either side of the membrane.
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PMID:Structure of a glutamate transporter homologue from Pyrococcus horikoshii. 1548 90

Glutamate is the principal excitatory neurotransmitter in the nervous system. Inactivation of synaptic glutamate is handled by the glutamate transporter GLT1 (also known as EAAT2; refs 1, 2), the physiologically dominant astroglial protein. In spite of its critical importance in normal and abnormal synaptic activity, no practical pharmaceutical can positively modulate this protein. Animal studies show that the protein is important for normal excitatory synaptic transmission, while its dysfunction is implicated in acute and chronic neurological disorders, including amyotrophic lateral sclerosis (ALS), stroke, brain tumours and epilepsy. Using a blinded screen of 1,040 FDA-approved drugs and nutritionals, we discovered that many beta-lactam antibiotics are potent stimulators of GLT1 expression. Furthermore, this action appears to be mediated through increased transcription of the GLT1 gene. beta-Lactams and various semi-synthetic derivatives are potent antibiotics that act to inhibit bacterial synthetic pathways. When delivered to animals, the beta-lactam ceftriaxone increased both brain expression of GLT1 and its biochemical and functional activity. Glutamate transporters are important in preventing glutamate neurotoxicity. Ceftriaxone was neuroprotective in vitro when used in models of ischaemic injury and motor neuron degeneration, both based in part on glutamate toxicity. When used in an animal model of the fatal disease ALS, the drug delayed loss of neurons and muscle strength, and increased mouse survival. Thus these studies provide a class of potential neurotherapeutics that act to modulate the expression of glutamate neurotransmitter transporters via gene activation.
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PMID:Beta-lactam antibiotics offer neuroprotection by increasing glutamate transporter expression. 1563 12

Glutamate receptors play a major role in neural cell plasticity, growth, and maturation. The degree to which ionotropic glutamate receptors (iGluR) conduct current is dependent on binding of extracellular ligands, of which glutamate is the native agonist. Although the glutamate binding site of the GluR2 class of amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) iGluR has been structurally characterized, the allosteric sites attributed to neurosteroid binding have yet to be localized. Here, using intrinsic tryptophan fluorescence spectroscopy, we show that the extracellular glutamate binding core of the GluR2 class of AMPA receptors also binds to two neurosteroids, pregnenolone sulfate (PS) and 3alpha-hydroxy-5beta-pregnan-20-one sulfate, both of which negatively modulate its activity. Interest in these sulfated neurosteroids stems from their differential modulation of other members of the iGluR family and their potential use as endogeneous agents for stroke therapy. In particular, whereas PS inhibits AMPA and other non-N-methyl-D-aspartate (NMDA) family members, it activates the NMDA receptor. In addition to providing evidence for binding of these neurosteroids to the glutamate binding core of the GluR2 class of AMPA receptors, our data suggests that both neurosteroids bind in a similar manner, consistent with their modulation of activity of this class of iGluR. Interestingly, the conformational change induced upon binding of these neurosteroids is distinct from that induced upon glutamate binding.
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PMID:Identification of a neurosteroid binding site contained within the GluR2-S1S2 domain. 1563 52

Experimental studies have shown the role of excitotoxicity in the pathogenesis of ischemic brain lesions, and glutamate levels have been found to be elevated in CSF and plasma from patients, early after stroke. In this study, we investigated whether platelets could be involved in the mechanism of altered plasma glutamate levels after stroke. Forty four patients, from 6 hours to 9 months after ischemic stroke, 15 age-related healthy controls and 15 controls with stroke risk factors or previous transient ischemic attack were enrolled. Glutamate plasma levels, platelet glutamate release after aggregation and platelet glutamate uptake were assessed. Plasma glutamate levels were increased up to 15 days after the ischemic event in stroke patients, and the levels at day 3 were inversely correlated with the neurologic improvement between day 3 and 15. Ex vivo platelet glutamate release was decreased by 70% in stroke patients, suggesting previous in vivo platelet activation. Moreover, platelet glutamate uptake in these patients was decreased by 75% up to 15 days and was still reduced 90 days after stroke. Our data show a prolonged increase of glutamate in plasma after stroke, which might presumably be linked to altered platelet functions, such as excessive release of the amino acid or impaired uptake.
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PMID:Increased plasma glutamate in stroke patients might be linked to altered platelet release and uptake. 1566 99

Diabetes with hypertension is characterized by increased cerebrovascular pathology and poorer outcomes following stroke. In this study we evaluated the effect of global brain ischemia on brain metabolic parameters in normal and diabetic rats treated with a dihydropyridine calcium antagonist, felodipine. Normal and diabetic rats were treated daily with felodipine (5 mg/kg) or saline. After 4 wk global ischemia was produced by occluding the carotid arteries for 1 h. In other groups the occlusion was removed and the animals were allowed to reperfuse for an additional 2 h. Following 1 h global ischemia, with or without reperfusion, the animals and controls were killed by decapitation. Cerebral water, lactate, ATP, and glutamate were measured. Glo-bal ischemia with or without reperfusion increased cerebral water and lactate, but decreased ATP. Treatment with felodipine decreased lactate, but increased water content. Ischemia in diabetics with or without reperfusion decreased water and lactate. Treated diabetics had higher ATP levels after reperfusion. Glutamate levels were increased in diabetics and were further increased by treatment. We conclude that the enhanced CNS damage following cerebral ischemia in diabetes is not correlated with ATP or lactate levels and may be mediated in part by increased glutamate. Calcium channel antagonist may augment this process.
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PMID:The effect of global brain ischemia in normal and diabetic animals: the influence of calcium channel blockers. 1571 Oct 20

Glutamate transporters remove glutamate from the synaptic cleft to maintain efficient synaptic communication between neurons and to prevent glutamate concentrations from reaching neurotoxic levels. Glutamate transporters play an important role in ischemic neuronal death during stroke and have been implicated in epilepsy and amytropic lateral sclerosis. However, the molecular structure and the glutamate-uptake mechanism of these transporters are not well understood. The most recent models of glutamate transporters have three or five subunits, each with eight transmembrane domains, and one or two membrane-inserted loops. Here, using fluorescence resonance energy transfer (FRET) analysis, we have determined the relative position of the extracellular regions of these domains. Our results are consistent with a trimeric glutamate transporter with a large (>45 A) extracellular vestibule. In contrast to other transport proteins, our FRET measurements indicate that there are no large-scale motions in glutamate transporters and that glutamate uptake is accompanied by relatively small motions around the glutamate-binding sites. The large extracellular vestibule and the small-scale conformational changes could contribute to the fast kinetics predicted for glutamate transporters. Furthermore, we show that, despite the multimeric nature of glutamate transporters, the subunits function independently.
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PMID:Small-scale molecular motions accomplish glutamate uptake in human glutamate transporters. 1571 9

Glutamate is the main excitatory neurotransmitter in the central nervous system and it plays a significant role not only in synaptic transmission but also in acute and chronic neuropathologies including stroke. Presently, four receptors for glutamate have been identified and the NMDA receptor family is the most intensively studied. A number of NMDA receptor antagonists have been developed and used for treatment of neurological diseases in patients. However, all of these drugs have been failed in clinical trials either because of intolerable side effects or lack of medical efficacy. Recently, the understanding of molecular structure of NMDA receptors has been advanced and this finding thus provides information for designing subtype-selective antagonists. Using NR2B subunit selective antagonists, ifenprodil and eliprodil, as basic structure models, second and third generation congeners have been developed. Several NR2B-selective compounds showed neuroprotective actions at doses that did not produce measurable side effects in preclinical studies. Some of NR2B subunit selective antagonists have also been tested for the treatment of ischemic brain injury. The present review describes the role of glutamate in ischemic brain injury with an emphasis on the NR2B containing NMDA receptors.
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PMID:NMDA/NR2B selective antagonists in the treatment of ischemic brain injury. 1585 99

Signal transduction via ionotropic glutamate receptors is found in many life forms, from protozoa to mammals. Glutamate is the main excitatory neurotransmitter in the mammalian CNS, were fast postsynaptic depolarisation is induced by the activation of AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors. In addition to their important physiological role, excessive AMPA receptor stimulation is also a hallmark of excitotoxicity-related diseases, like ischaemic stroke. Conversely, AMPA receptor inhibitors were proposed to be useful neuroprotective drugs. First generation AMPA receptor blockers were competitive antagonists, like NBQX, which showed robust neuroprotection in a variety of disease-related animal models. Its clinical use, however, was restricted by the very low solubility, inducing kidney precipitaton in vivo. Second generation competitive antagonists are available, which do not possess this property. None of those, however, up to now is in clinical use. Competitive AMPA receptor antagonists are not the first choice for neuroprotective drugs, since due to receptor kinetics they preferently suppress the physiological relevant component of the postsynaptic glutamate response. Non-competitive blockers, like 2,3-benzodiazepines or the novel neuroprotectant BIIR 561 should be suited better for the treatment of stroke. The latter compound is also described as blocker of voltage-gated sodium channels. Targetting more than one mechanism in the excitotoxicity cascade might be a fruitful approach for the development of neuroprotective drugs.
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PMID:AMPA receptor antagonists for the treatment of stroke. 1585

Excitotoxicity is an important mechanism involved in perinatal brain injuries. Glutamate is the major excitatory neurotransmitter, and most neurons as well as many oligodendrocytes and astrocytes possess receptors for glutamate. Perinatal insults such as hypoxia-ischemia, stroke, hypoglycemia, kernicterus, and trauma can disrupt synaptic function leading to accumulation of extracellular glutamate and excessive stimulation of these receptors. The activities of certain glutamate receptor/channel complexes are enhanced in the immature brain to promote activity-dependent plasticity. Excessive stimulation of glutamate receptor/ion channel complexes triggers calcium flooding and a cascade of intracellular events that results in apoptosis and/or necrosis. Recent research suggests that some of these intracellular pathways are sexually dimorphic. Age dependent expression of different glutamate receptor subtypes with varying abilities to flux calcium has been associated with special patterns of selective vulnerability at different gestational ages. For example, selective injury to the putamen, thalamus and cerebral cortex from near total asphyxia in term infants may be related to excessive activation of neuronal NMDA and AMPA type glutamate receptors, while brainstem injury may be related primarily to stimulation of neuronal AMPA/kainate receptors. In contrast, periventricular leukomalacia in premature infants has been linked to expression of AMPA/kainate receptors on immature oligodendrocytes. Insight into the molecular pathways that mediate perinatal brain injuries could lead to therapeutic interventions.
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PMID:Excitotoxicity in perinatal brain injury. 1619 90

Glutamate-mediated damage to oligodendrocytes contributes to mental or physical impairment in periventricular leukomalacia (pre- or perinatal white matter injury leading to cerebral palsy), spinal cord injury, multiple sclerosis and stroke. Unlike neurons, white matter oligodendrocytes reportedly lack NMDA (N-methyl-d-aspartate) receptors. It is believed that glutamate damages oligodendrocytes, especially their precursor cells, by acting on calcium-permeable AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid)/kainate receptors alone or by reversing cystine-glutamate exchange and depriving cells of antioxidant protection. Here we show that precursor, immature and mature oligodendrocytes in the white matter of the cerebellum and corpus callosum exhibit NMDA-evoked currents, mediated by receptors that are blocked only weakly by Mg2+ and that may contain NR1, NR2C and NR3 NMDA receptor subunits. NMDA receptors are present in the myelinating processes of oligodendrocytes, where the small intracellular space could lead to a large rise in intracellular ion concentration in response to NMDA receptor activation. Simulating ischaemia led to development of an inward current in oligodendrocytes, which was partly mediated by NMDA receptors. These results point to NMDA receptors of unusual subunit composition as a potential therapeutic target for preventing white matter damage in a variety of diseases.
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PMID:NMDA receptors are expressed in oligodendrocytes and activated in ischaemia. 1637 11


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