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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Manipulation of the kynurenine pathway of tryptophan metabolism has yielded a plethora of agents that are now being developed as neuroprotectants and anticonvulsants. This pathway is involved in the production of the excitotoxin quinolinic acid and the neuroprotectant kynurenic acid. Approaches used in the development of therapeutic agents include production of analogues or pro-drugs of kynurenic acid and inhibitors of the enzyme responsible for the synthesis of quinolinic acid. Indeed, analogues of the amino acid receptor antagonist kynurenic acid are now in, or are about to enter, clinical trials for stroke and related disorders. This review summarizes the mechanism of action of these various agents, the development of glutamate receptor antagonists from kynurenic acid and the range of their potential uses in neurology and psychiatry.
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PMID:Development and therapeutic potential of kynurenic acid and kynurenine derivatives for neuroprotection. 1074 Feb 91

Strokes (intracranial thomboses or haemorrhaging) cause death and disability, but effective treatments are lacking. The metabolism of tryptophan leads to the generation of quinolinic acid, an agonist potentially neurotoxic at glutamate receptors, and kynurenic acid, an antagonist at the same population of receptors. The commercial development of the kynurenine pathway has included the use of analogues of kynurenic acid as antagonists at glutamate receptors. A second has been to use prodrugs of kynurenic acid or its analogues. Alternatively, it is proving possible to interfere directly with the kynurenine pathway to block the synthesis of quinolinic acid and promote the formation of kynurenic acid. This change yields neuroprotectant and anticonvulsant compounds.
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PMID:Inhibitors of the kynurenine pathway. 1075 80

In most tissues, including brain, a major proportion of the tryptophan which is not used for protein synthesis is metabolised along the kynurenine pathway. Long regarded as the route by which many mammals generate adequate amounts of the essential co-factor nicotinamide adenine dinucleotide, two components of the pathway are now known to have marked effects on neurones. Quinolinic acid is an agonist at the N-methyl-D-aspartate sensitive subtype of glutamate receptors in the brain, while kynurenic acid is an antagonist and, thus, a potential neuroprotectant. A third kynurenine, 3-hydroxykynurenine, is involved in the generation of free radicals which can also damage neurones. Quinolinic acid is increasingly implicated in neurodegenerative disorders, most especially the AIDS-dementia complex and Huntington's disease, while kynurenic acid has become a standard for the identification of glutamate-releasing synapses, and has been used as the parent for several groups of compounds now being developed as drugs for the treatment of epilepsy and stroke.
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PMID:Endogenous neurotoxins from tryptophan. 1093 23

Kynurenine, a metabolite of tryptophan along the 'kynurenine pathway', is at a branch point of the pathway which can lead to the synthesis of both quinolinic acid (QUIN) and kynurenic acid (KYNA). KYNA is an antagonist of glutamate receptors; however, QUIN is a selective agonist of NMDA receptors, and has been shown to act as an excitotoxic agent. A high QUIN/KYNA ratio has been implicated in a variety of neurological diseases in which excitotoxic neuronal cell death is found, e.g. AIDS-related dementia, stroke, etc. Inhibiting the key enzymes of this pathway (i.e. kynureninase and kynurenine 3-hydroxylase) would lower the QUIN/KYNA ratio, which may potentially have neuroprotective effects. We have developed high through-put assays for kynurenine pathway enzymes which allow us to screen extracts from marine organisms for selective enzyme inhibitors. Active metabolites are purified, isolated and identified by HPLC, high-field NMR and mass spectral techniques. Extracts from a sponge of the Aka species were found to contain a selective inhibitor of kynureninase. We have recently purified and identified the active principal as being serotonin sulfate. Related indoleamines, serotonin and 5-hydroxyindoleacetic acids are inactive. This finding may be suggestive of a novel interaction between the serotoninergic and excitatory amino acid pathways.
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PMID:Screening marine natural products for selective inhibitors of key kynurenine pathway enzymes. 1093 81

In just under 20 years the kynurenine family of compounds has developed from a group of obscure metabolites of the essential amino acid tryptophan into a source of intensive research, with postulated roles for quinolinic acid in neurodegenerative disorders, most especially the AIDS-dementia complex and Huntington's disease. One of the kynurenines, kynurenic acid, has become a standard tool for use in the identification of glutamate-releasing synapses, and has been used as the parent for several groups of compounds now being developed as drugs for the treatment of epilepsy and stroke. The kynurenines represent a major success in translating a basic discovery into a source of clinical understanding and therapeutic application, with around 3000 papers published on quinolinic acid or kynurenic acid since the discovery of their effects in 1981 and 1982. This review concentrates on some of the recent work most directly relevant to the understanding and applications of kynurenines in medicine.
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PMID:Kynurenines in the CNS: from endogenous obscurity to therapeutic importance. 1124 Feb 12

The isoprenoid pathway produces three key metabolites--digoxin (membrane sodium-potassium ATPase inhibitor and regulator of neurotransmitter/aminoacid transport), dolichol (regulates N-glycosylation of proteins) and ubiquinone (free radical scavenger). This was assessed in patients with essential hypertension, familial hypotension, acute coronary artery disease and acute thrombotic strokes. The pathway was also assessed in patients with right hemispheric, left hemispheric and bihemispheric dominance for comparison. In patients with acute coronary artery disease, acute thrombotic stroke, essential hypertension and right hemispheric dominance, there was elevated digoxin synthesis, increased dolichol and glycoconjugate levels and low ubiquinone and high free radical levels. There was also an increase in tryptophan catabolites, reduction in tyrosine catabolites, increase in cholesterol-phospholipid ratio and a reduction in glycoconjugate level of RBC membrane in this group of patients as well as in those with right hemispheric dominance. In patients with familial hypotension and left hemispheric dominance, the patterns were reversed. The role of a dysfunctional isoprenoid pathway and endogenous digoxin in the pathogenesis of essential hypertension and familial hypotension and in thrombotic vascular disease in relation to hemispheric dominance is discussed.
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PMID:Hypothalamic digoxin and neural regulation of blood pressure and vascular thrombosis. 1125 82

The kynurenine pathway accounts for the metabolism of around 80% of non-protein tryptophan metabolism. It includes both an agonist (quinolinic acid) at NMDA receptors and an antagonist (kynurenic acid). Since their discovery, there has been a major development of kynurenic acid analogues as neuroprotectants for the treatment of stroke and neurodegenerative disease. Several prodrugs of kynurenic acid or its analogues that can be hydrolysed within the CNS are also available. More recently, the pathway itself has proved to be a valuable drug target, affected by agents which reduce the synthesis of quinolinic acid and increase the formation of kynurenic acid. The change in the balance of these, away from the excitotoxin and towards the neuroprotectant, has anticonvulsant and neuroprotective properties.
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PMID:Kynurenic acid antagonists and kynurenine pathway inhibitors. 1128 14

Myosin subfragment 1 (S1) is the ATP catalyzing motor protein in muscle. It consists of three domains that catalyze ATP and bind actin (catalytic), conduct energy transduction (converter), and transport the load (lever arm). These domains interface in two places identified as interface I, containing the reactive thiol (SH1) and ATP-sensitive tryptophan (Trp510), and interface II, containing the reactive lysine residue (RLR). Two crystal structures of S1 were extrapolated to working "in solution" or oriented "in tissue" forms, using structure-sensitive optical spectroscopic signals from extrinsic probes located in the interfaces. Observed signals included circular dichroism (CD) and absorption originating from S1 in solution in the presence and absence of actin and fluorescence polarization from cross-bridges in muscle fibers. Theoretical signals were calculated from S1 crystal structure models perturbed with lever arm movement from swiveling at three conserved glycines, 699, 703, and 710 (chicken skeletal myosin numbering). Structures giving the best agreement between the computed and observed signals were selected as the representative forms. Both interfaces undergo dramatic conformational change during ATPase and force development. Changes at interface I suggest the molecular basis for the collisional quenching sensitivity of Trp510 to nucleotide binding. The probe conformation at SH1 suggests how it alters S1 ATPases. At interface II, the spatial relationship of the lever arm and the extrinsic probe at RLR suggests how the probe alters S1 ATPases and that it should inhibit lever arm movement during the power stroke. The latter possibility, if true, establishes a part of the corridor through which the lever arm swings during the power stroke. Global structural changes in actomyosin are discussed in the accompanying paper [Burghardt et al. (2001) Biochemistry 40, 4821-4833].
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PMID:Conformation of myosin interdomain interactions during contraction: deductions from proteins in solution. 1129 51

Variant human cystatin C (L68Q) is an amyloidogenic protein. It deposits in the cerebral vasculature of Icelandic patients with cerebral amyloid angiopathy, leading to stroke. Wild-type and variant cystatin C are cysteine proteinase inhibitors which form concentration dependent inactive dimers; however, variant cystatin C dimerizes at lower concentrations and has an increased susceptibility to a serine protease. We studied the effect of the L68Q amino acid substitution on cystatin C properties, utilizing full length cystatin C purified in mild conditions from media of cells stably transfected with either the wild-type or variant cystatin C genes. The variant cystatin C forms fibrils in vitro detectable by electron microscopy in conditions in which the wild-type protein forms amorphous aggregates. We also show by circular dichroism, steady-state fluorescence and Fourier-transformed infrared spectroscopy that the amino acid substitution modifies cystatin C structure by destabilizing alpha-helical structures and exposing the tryptophan residue to a more polar environment, yielding a more unfolded molecule. These spectral changes demonstrate that variant cystatin C has a three-dimensional structure different from that of the wild-type protein. The structural differences between variant and wild-type cystatin C account for the susceptibility of the variant protein to unfolding, proteolysis and fibrillogenesis.
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PMID:Distinct properties of wild-type and the amyloidogenic human cystatin C variant of hereditary cerebral hemorrhage with amyloidosis, Icelandic type. 1129 25

A simple, sensitive and reproducible isocratic high-performance liquid chromatography (HPLC) method has been developed for the determination of amino acids in human serum. The method involves precipitation of the serum proteins with methanol followed by pre-column derivatization of amino acids with o-phthalaldehyde-2-mercaptoethanol or o-phthalaldehyde-sodium sulfite. HPLC separation of the derivatives was performed using an ODS column with an isocratic mobile phase system and electrochemical detection (+0.75 V). The response was linear over the range 5-300 microM for all amino acids. The method allows quantitative determination of glutamic acid, asparagine, serine, glutamine, histidine, taurine, alanine, arginine, methionine, isoleucine, ornithine, leucine, phenylalanine, lysine and tryptophan at concentrations as low as 0.5-5.0 pmol (signal-to-noise ratio=2). Using this method, the levels of amino acids in serum from healthy donors and patients with ischemic stroke were determined.
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PMID:Analysis of amino acids in human serum by isocratic reversed-phase high-performance liquid chromatography with electrochemical detection. 1135 26


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