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)

Reduction of cerebral edema, an early symptom of ischemia, is one of the most important remedies for reducing subsequent chronic neural damage in stroke. Melatonin, a metabolite of tryptophan released from the pineal gland, has been found to be effective against neurotoxicity in vitro. The present study was aimed to demonstrate the effectiveness of melatonin in vivo in reducing ischemia-induced edema using magnetic resonance imaging (MRI). Rats were subjected to middle cerebral artery (MCA) occlusion/reperfusion surgery. Melatonin was administered twice (6.0 mg/kg, p.o.): just prior to 1 h MCA occlusion and 1 day after the surgery. T2-weighted multislice spin-echo images were acquired 1 day after the surgery. Increases in T2-weighted signals in ischemic sites of the brain were clearly observed after MCA occlusion. The signal increase was found mainly in the striatum and in the cerebral cortex in saline-treated control rats. In the melatonin-treated group, the total volume of cerebral edema was reduced by 45.3% compared to control group (P < 0.01). The protective effect of melatonin against cerebral edema was more clearly observed in the cerebral cortex (reduced by 56.1%, P < 0.01), while the reduction of edema volume in the striatum was weak (reduced by 23.0%). The present MRI study clearly demonstrated that melatonin is effective in reducing edema formation in ischemic animals in vivo, especially in the cerebral cortex. Melatonin may be highly useful in preventing cortical dysfunctions such as motor, sensory, memory, and psychological impairments.
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PMID:Melatonin reduces cerebral edema formation caused by transient forebrain ischemia in rats. 1246 99

Kynurenines are formed as part of the tryptophan metabolism and are known to exhibit pro- and anti-oxidant activities in vitro. The mapping of these biological redox-systems and identification of potential in vivo targets are therefore of great interest in cellular physiology. Here the redox-behavior of different kynurenines and anthranilic acids is evaluated electrochemically and compared to that of simple model compounds. Electrochemical results are correlated with the activity of these compounds in redox-bioassays where 3-hydroxyanthranilic acid and 3-hydroxykynurenine have significant redox-activity. The specific electrochemical redox-behavior of these two compounds, indicating a particular redox-mechanism involving the hydroxyl group, can be used to rationalize these findings. The results indicate that tryptophan metabolites can undergo a range of complex redox-reactions in vivo whose precise nature critically depends on structural details. As a consequence, some of the kynurenines have the potential to contribute to neuronal damage in brain disorders and stroke.
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PMID:Electrochemical and in vitro evaluation of the redox-properties of kynurenine species. 1250 9

Melatonin, a pineal secretory product synthesized from tryptophan, has been found to be effective against neurotoxicity. The present study was aimed at demonstrating the effectiveness of melatonin in vivo in reducing ischemia-induced cerebral edema using magnetic resonance imaging (MRI). Rats were subjected to middle cerebral artery (MCA) occlusion/reperfusion surgery. Melatonin was administered twice (6.0 mg/kg, p.o.) just prior to 1 hr of MCA occlusion and 1 day after the surgery. T2-weighted multislice spin-echo images were acquired 1 day after the surgery. In the saline-treated control rats, increases in T2-weighted signals (water content) were clearly observed in the striatum and in the cerebral cortex. In the melatonin-treated group, total volume of edema was reduced by 51.6% compared with control group (P < 0.01). The protective effect of melatonin against edema was more clearly observed in the cerebral cortex (reduced by 59.8%, P < 0.01) than in the striatum (reduced by 34.2%, P < 0.05). Edema volume in a coronal slice was the greatest at the level of the bregma. Suppression of cerebral edema by melatonin was more effective posterior than anterior to the bregma. Melatonin appeared to reduce the volume of the edematous sites rather than to shift the signal intensity distribution. The present MRI study clearly demonstrates the effectiveness of melatonin against cerebral edema formation in ischemic animals in vivo, especially in the cerebral cortex. Melatonin may be highly useful in preventing cortical dysfunctions such as motor, sensory, memory, and psychological impairments associated with ischemic stroke.
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PMID:Melatonin suppresses cerebral edema caused by middle cerebral artery occlusion/reperfusion in rats assessed by magnetic resonance imaging. 1467 26

Oxygen-sensing and reactivity to changes in the concentration of oxygen is a fundamental property of cellular physiology. This central role is determined, mainly, by, to the fact that oxygen represents the final acceptor of electrons, derived from the normal cellular metabolism, at the end of the mitochondrial respiratory chain. Despite significant advances in molecular characterization of various oxygen-sensitive processes, the nature of the oxygen-sensor molecules and the mechanisms that link sensors to effects remains unclear. One such controversy is about the role and nature of reactive oxygen species (ROS) changes during hypoxia. Irrespective of the mechanisms of oxygen sensing, one of the constant early responses to hypoxia in almost all cell types is an increase in intracellular Ca2+ ([Ca2+]i). In many instances, this increase is mediated by the activation of various plasma membrane Ca2+ conductances. Some of these channels have specific Ca2+ permeability (e.g. voltage-operated Ca2+ channels), whereas others have non-specific cation conductances and are activated by a variety of ligands (ligand-operated channels). In the last decade, a large superfamily of channels with significant Ca2+ permeability has been progressively identified and characterised: the TRP channels. Through their properties, some groups of the TRP channels provide a link to the other hypoxia-activated mechanism of [Ca2+]i increase: the release of Ca2+ from intracellular Ca2+ stores. Since the [Ca2+]i signals, depending on their localization and intensity, are important regulators of the subsequent cellular responses to hypoxia, a deeper understanding of the mechanisms through which hypoxia regulate the activity of these pathways that increase intracellular Ca2+ could point the way towards the development of new therapeutic approaches to reduce or suppress the pathological effects of cellular hypoxia, such as those seen in stroke or myocardial ischemia.
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PMID:Hypoxia sensing and pathways of cytosolic Ca2+ increases. 1526 75

The fluorescence properties of Dictyostelium discoideum (Dd) myosin II constructs containing a single tryptophan residue have revealed detailed information regarding nucleotide binding and hydrolysis steps. Here we extend these studies to investigate the influence of actin on nucleotide-induced fluorescence transients. The fluorescence from native actin tryptophan residues is not significantly perturbed on binding to myosin, although an apparent signal is detected as a consequence of a light scatter artifact. Actin has a minor effect on the response of W129, located at the entrance to the nucleotide-binding pocket, and reduces the forward rate constants for the isomerization(s) associated with binding of ATP, ATPgammaS, and ADP by 3-fold or less. The isomerization detected by W129 clearly precedes the dissociation of actin in the case of ADP and ATPgammaS binding. The fluorescence from the conserved W501 residue, located at the distal end of the relay helix, is very sensitive to the switch 2 and/or lever arm disposition. Consequently, the observed fluorescence emission intensity can be used to estimate the equilibrium constant between the pre- and post-power stroke conformations. Actin modulates this equilibrium by no more than 2-fold in the presence of nucleoside triphosphate. These data have implications for the mechanism of product release and suggest that actin activates another process in the mechanism, such as switch 1 movement and Pi release, rather than influencing the switch 2 equilibrium and lever arm position directly.
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PMID:The effect of F-actin on the relay helix position of myosin II, as revealed by tryptophan fluorescence, and its implications for mechanochemical coupling. 1558 52

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

Kynurenine (KYN) is an intermediate in the pathway of the metabolism of tryptophan to nicotinic acid. KYN is formed in the mammalian brain (40%) and is taken up from the periphery (60%), indicating that it can be transported across the blood-brain barrier (BBB). In the brain, KYN can be converted to two other components of the pathway: the neurotoxic quinolinic acid (QUIN) and the neuroprotective kynurenic acid (KYNA). QUIN is probably the most widely studied metabolite of KYN, because it may cause excitotoxic neuronal cell loss and convulsions by interacting with the N-methyl-D-aspartate (NMDA) receptor complex, a type of glutamate receptor. KYNA is another metabolite of KYN; its synthesis is catalysed by KYN aminotransferases. This is the only known endogenous NMDA receptor inhibitor, which can act at the glycine site on the receptor complex. Furthermore, KYNA non-competitively inhibits alpha7 nicotinic acetylcholine presynaptic receptors (nAChRs), inhibiting glutamate release, and regulates the expression of alpha4beta2 nAChR. It is well-known that the activation of excitatory amino acid (EAA) receptors can play a role in a number of neurodegenerative disorders, such as Parkinson's disease, Alzheimer's disease, stroke and epilepsy. Various studies have been made of whether the EAA receptor antagonist KYNA can exert a therapeutic effect in these neurological disorders. It has been established that KYNA has only a very limited ability to cross the BBB. Other KYNA derivatives have been synthesised (e.g. glucosamine-KYNA, 4-chloro-KYNA and 7-chloro-KYNA), which are well transported across the BBB and act on the glutamate receptors. Moreover, it has been demonstrated that probenecid, a known inhibitor of the transport of organic acids (e.g. KYNA), increases the cerebral concentration of KYNA. There is another new perspective to the maintenance of a high level of KYNA in the brain: the use of enzyme inhibitors, which can block the synthesis of the neurotoxic QUIN. These are some of the most promising possibilities as novel therapeutic strategies for the treatment of neurodegenerative diseases, in which the hyperactivation of amino acid receptors could be involved. The presence and importance of KYN derivatives in the periphery are also discussed in the light of recent publications.
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PMID:Role of kynurenines in the central and peripheral nervous systems. 1618 Nov 18

Glutamate is the predominant excitatory neurotransmitter in the central nervous system. The receptors that bind glutamate, including N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor subtypes, are strongly implicated in higher cognitive processes, especially learning and memory. Loss of glutamate receptor function impairs the ability to acquire and retain information in some patients subsequent to stroke or brain injury, and positive allosteric modulators of glutamate receptors can restore learning and memory in some of these patients. Here we demonstrate that kynurenic acid (KYNA), an endogenous tryptophan metabolite, acts upon heterologous AMPA receptors via two distinct mechanisms. Low (nanomolar to micromolar) concentrations of KYNA facilitate AMPA receptor responses, whereas high (millimolar) concentrations of KYNA competitively antagonize glutamate receptors. Low concentrations of KYNA appear to increase current responses through allosteric modulation of desensitization of AMPA receptors. These findings suggest the possibility that low concentrations of endogenous KYNA acting at AMPA receptors may be a positive modulator of excitatory synaptic transmission.
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PMID:Kynurenic acid has a dual action on AMPA receptor responses. 1664 24

Kynurenine 3-monooxygenase (KMO) is an NADPH-dependent flavoprotein hydroxylase that catalyzes the conversion of l-Kynurenine (L-Kyn) to 3-hydroxykynurenine (3OHKyn). The reaction is central to the tryptophan degradative pathway and takes place within microglial cells defining cellular concentrations of the N-methyl-d-aspatate (NMDA) receptor agonist quinolinate and antagonist kynurenate. The influence over the cellular concentrations of these NMDA receptor effectors makes KMO an attractive target for the treatment of ischemic stroke. Pseudomonas fluorescens str 17400, expresses five activities of tryptophan catabolism including that of KMO. The KMO gene from P. fluorescens was cloned into the pET-17b plasmid using incorporated NdeI and XhoI restriction sites. This construct yielded PfKMO to 20% of total cell protein after 12h of expression at 22 degrees C without induction by isopropyl-beta-thiogalactopyranoside (IPTG). The enzyme could be readily purified using ammonium sulfate fractionation and ion exchange chromatography, resulting in pure KMO with a turnover number of 5.0 s(-1). PfKMO activity was dependent on the reduction state of the enzyme. Preparation and storage benefited from the presence of a reductant such as dithiothreitol or beta-mercaptoethanol. The loss of activity was found to be directly related to the oxidation of thiols as measured by dinitrothiobenzoate assay. Steady-state assays monitoring the consumption of dioxygen were used to measure apparent kinetic parameters and ligand perturbation of flavin fluorescence was used to determine a Kd value for both L-Kyn and the inhibitor m-nitrobenzoylalanine. PfKMO is offered as prototypical bacterial form of the enzyme to serve as a viable platform on which to base future KMO studies.
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PMID:Heterologous expression and purification of kynurenine-3-monooxygenase from Pseudomonas fluorescens strain 17400. 1697 76

The kynurenine pathway is the main pathway of tryptophan metabolism. L-kynurenine is a central compound of this pathway since it can change to the neuroprotective agent kynurenic acid or to the neurotoxic agent quinolinic acid. The break-up of these endogenous compounds' balance can be observable in many disorders. It can be occur in neurodegenerative disorders, such as Parkinson's disease, Huntington's and Alzheimer's disease, in stroke, in epilepsy, in multiple sclerosis, in amyotrophic lateral sclerosis, and in mental failures, such as schizophrenia and depression. The increase of QUIN concentration or decrease of KYNA concentration could enhance the symptoms of several diseases. According to numerous studies, lowered KYNA level was found in patients with Parkinson's disease. It can be also noticeable that KYNA-treatment prevents against the QUIN-induced lesion of rat striatum in animal experiments. Administrating of KYNA can be appear a promising therapeutic approach, but its use is limited because of its poorly transport across the blood-brain barrier. The solution may be the development of KYNA analogues (e.g. glucoseamine-kynurenic acid) which can pass across this barrier and disengaging in the brain, then KYNA can exert its neuroprotective effects binding at the excitatory glutamate receptors, in particular the NMDA receptors. Furthermore, it seems hopeful to use kynurenine derivatives (e.g. 4-chloro-kynurenine) or enzyme inhibitors (e.g. Ro-61-8048) to ensure an increased kynurenic acid concentration in the central nervous system.
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PMID:Kynurenines, Parkinson's disease and other neurodegenerative disorders: preclinical and clinical studies. 1701 44


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