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)

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

After ATP binding the myosin head undergoes a large structural rearrangement called the recovery stroke. This transition brings catalytic residues into place to enable ATP hydrolysis, and at the same time it causes a swing of the myosin lever arm into a primed state, which is a prerequisite for the power stroke. By introducing point mutations into a subdomain interface at the base of the myosin lever arm at positions Lys(84) and Arg(704), we caused modulatory changes in the equilibrium constant of the recovery stroke, which we could accurately resolve using the fluorescence signal of single tryptophan Dictyostelium myosin II constructs. Our results shed light on a novel role of the recovery stroke: fine-tuning of this reversible equilibrium influences the functional properties of myosin through controlling the effective rates of ATP hydrolysis and phosphate release.
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PMID:Selective perturbation of the myosin recovery stroke by point mutations at the base of the lever arm affects ATP hydrolysis and phosphate release. 1744 72

Emery-Dreifuss muscular dystrophy (EDMD) is characterized by early-onset contractures, slowly progressive weakness, and muscle wasting in humeroperoneal muscles, and adult-onset cardiomyopathy with conduction block. We analyzed blood samples from an EDMD family, including a mother and two daughters, and found a novel mutation in codon 520 in exon 9 of the lamin A/C (LMNA) gene, resulting in a substitution of tryptophan (W) by glycine (G) in all three patients. The mother died after a stroke-like episode at the age of 43. The elder sister received pacemaker implantation, which improved symptoms of exercise intolerance and dizziness. These cases illustrate the necessity of correct diagnosis, evaluation, and follow-up of cardiac problems due to the wide clinical spectrum and high prevalence of cardiac conduction block in patients with autosomal dominant EDMD.
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PMID:Novel LMNA mutation in a Taiwanese family with autosomal dominant Emery-Dreifuss muscular dystrophy. 1749 93

Inflammation and oxidative stress are involved in brain damage following stroke, and tryptophan oxidation along the kynurenine pathway contributes to the modulation of oxidative stress partly via the glutamate receptor agonist quinolinic acid and antagonist kynurenic acid, and via redox-active compounds such as 3-hydroxyanthranilic acid. We have confirmed that following a stroke, patients show early elevations of plasma neopterin, S100B and peroxidation markers, the latter two correlating with infarct volume assessed from computed tomography (CT) scans, and being consistent with a rapid inflammatory response. We now report that the kynurenine pathway of tryptophan metabolism was also activated, with an increased kynurenine : tryptophan ratio, but with a highly significant decrease in the ratio of 3-hydroxyanthranilic acid : anthranilic acid, which was strongly correlated with infarct volume. Levels of kynurenic acid were significantly raised in patients who died within 21 days compared with those who survived. The results suggest that increased tryptophan catabolism is initiated before or immediately after a stroke, and is related to the inflammatory response and oxidative stress, with a major change in 3-hydroxyanthranilic acid levels. Together with previous evidence that inhibiting the kynurenine pathway reduces brain damage in animal models of stroke and cerebral inflammation, and that increased kynurenine metabolism directly promotes oxidative stress, it is proposed that oxidative tryptophan metabolism may contribute to the oxidative stress and brain damage following stroke. Some form of anti-inflammatory intervention between the rise of S100B and the activation of microglia, including inhibition of the kynurenine pathway, may be valuable in modifying patient morbidity and mortality.
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PMID:Altered kynurenine metabolism correlates with infarct volume in stroke. 1789 81

The rate-limiting step of the myosin basal ATPase (i.e. in absence of actin) is assumed to be a post-hydrolysis swinging of the lever arm (reverse recovery step), that limits the subsequent rapid product release steps. However, direct experimental evidence for this assignment is lacking. To investigate the binding and the release of ADP and phosphate independently from the lever arm motion, two single tryptophan-containing motor domains of Dictyostelium myosin II were used. The single tryptophans of the W129+ and W501+ constructs are located at the entrance of the nucleotide binding pocket and near the lever arm, respectively. Kinetic experiments show that the rate-limiting step in the basal ATPase cycle is indeed the reverse recovery step, which is a slow equilibrium step (k(forward) = 0.05 s(-1), k(reverse) = 0.15 s(-1)) that precedes the phosphate release step. Actin directly activates the reverse recovery step, which becomes practically irreversible in the actin-bound form, triggering the power stroke. Even at low actin concentrations the power stroke occurs in the actin-attached states despite the low actin affinity of myosin in the pre-power stroke conformation.
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PMID:The mechanism of the reverse recovery step, phosphate release, and actin activation of Dictyostelium myosin II. 1821 92

Matrix metalloproteinases (MMPs) have been implicated in the pathophysiology of ischemic stroke. In particular, the gelatinases MMP-2 and MMP-9 contribute to disruption of the blood-brain barrier and hemorrhagic transformation following ischemic injury. In addition to extracellular matrix degradation, MMPs may directly regulate neuronal cell death through mechanisms that are not completely understood. Here we describe the spatio-temporal distribution of activated MMP-2 and MMP-9 in the brain of rats subjected to 2 h middle cerebral artery occlusion (MCAo) followed by different periods of reperfusion (15 min, 2 h, 6 h and 22 h). By in situ zymography we have observed that gelatinases become activated 15 min and 2 h after the beginning of reperfusion in the ischemic core and penumbra, respectively. In situ zymography signal broadly co-localized with NeuN-positive cells, thus suggesting that proteolysis mainly occurs in neurons. Gelatinolytic activity was mainly detected in cell nuclei, marginally appearing in the cytosol only at later stages following the insult; we did not detect variations in gelatinolysis in the extracellular matrix. Finally, we report that pharmacological inhibition of MMPs by N-[(2R)-2-(hydroxamidocarbonyl-methyl)-4-methylpenthanoyl]-L-tryptophan methylamide (GM6001) significantly reduces brain infarct volume induced by transient MCAo. Taken together our data underscore the crucial role of gelatinases during the early stages of reperfusion and further extend previous observations documenting the detrimental role of these enzymes in the pathophysiology of brain ischemia.
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PMID:Brain regional and cellular localization of gelatinase activity in rat that have undergone transient middle cerebral artery occlusion. 1825 36

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a genetic disease characterized by ischemic stroke with early onset, migraine, seizures, and vascular dementia. CADASIL is associated with mutations within NOCT3 gene, mainly clustered in exons 3 and 4. We report a case of CADASIL presenting progressive subcortical dementia in the sixth decade. Neither family history, nor acute ischemic events were present. MRI findings were typical for CADASIL. NOTCH3 analysis disclosed a new missense mutation within exon 7, leading to the substitution of cysteine 366 with a tryptophan (Cys366Trp). Our finding suggests CADASIL diagnosis must be considered in patients with vascular dementia also in absence of stroke-like events and of family history.
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PMID:Sporadic vascular dementia as clinical presentation of a new missense mutation within exon 7 of NOTCH3 gene. 1849 32

Kynurenine 3-monooxygenase (KMO) is a flavin-dependent hydroxylase that catalyzes the conversion of l-kynurenine (l-Kyn) to 3-hydroxykynurenine (3OHKyn) in the pathway for tryptophan catabolism. KMO inhibition has been widely suggested as an early treatment for stroke and other neurological disorders that involve ischemia. We have investigated the reductive and the oxidative half-reactions of a stable form of KMO from Pseudomonas fluorescens (KMO). The binding of l-Kyn by the enzyme is relatively slow and involves at least two reversible steps. The rate constant for reduction of the flavin cofactor by NADPH increases by a factor of approximately 2.5 x 10(3) when l-Kyn is bound. The rate of reduction of the KMO.l-Kyn complex is 160 s(-1), and the K(d) for the NADPH complex is 200 microM with charge-transfer absorption bands for the KMO(RED).l-Kyn.NADP(+) complex accumulating after reduction. The reduction potential of KMO is -188 mV and is unresponsive to the addition of l-Kyn or other inhibitory ligands. KMO inhibitors whose structures are reminiscent of l-Kyn such as m-nitrobenzoylalanine and benzoylalanine also stimulate reduction of flavin by NADPH and, in the presence of dioxygen, result in the stoichiometric liberation of hydrogen peroxide, diminishing the perceived therapeutic potential of inhibitors of this type. In the presence of the native substrate, the oxidative half-reaction exhibits triphasic absorbance data. A spectrum consistent with that of a peroxyflavin species accumulates and then decays to yield the oxidized enzyme. This species then undergoes minor spectral changes that, based on flavin difference spectra defined in the presence of 3OHKyn, can be correlated with product release. The oxidative half-reaction observed in the presence of saturating benzoylalanine or m-nitrobenzoylalanine also shows the accumulation of a peroxyflavin species that then decays to yield hydrogen peroxide without hydroxylation.
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PMID:Kynurenine 3-monooxygenase from Pseudomonas fluorescens: substrate-like inhibitors both stimulate flavin reduction and stabilize the flavin-peroxo intermediate yet result in the production of hydrogen peroxide. 1895 92

Changes regarding the immune system and specifically the cytokine system, of which tumor necrosis factor-alpha (TNF-alpha) is a part, have been shown to be involved in the development of neurological and psychiatric disorders such as multiple sclerosis, Parkinson's and Alzheimer's disease, depression, schizophrenia or narcolepsy. Besides, there is evidence that the risk of stroke correlates with the serum concentrations of different cytokines. Additionally, body weight, age and neuroendocrinological mechanism have a strong influence upon plasma levels of TNF-alpha and its soluble receptors (sTNF-Rs). TNF-alpha might contribute to the pathogenesis of these diseases by an activation of the hypothalamo-pituitary-adrenocortical (HPA) axis, an activation of neuronal serotonin transporters, the stimulation of the indoleamine 2,3-dioxygenase which leads to tryptophan depletion, by immunologically mediated destruction of neurons, or neurotoxic release of glutamate. Psychotropic drugs influence the TNF-alpha system, too. During psychopharmacological treatment of schizophrenia, some antipsychotics might act on neurotransmitter metabolism via inducing the proinflammatory cytokine system. Hopefully, these hypotheses may lead to new therapeutical strategies for psychiatric patients in the near future.
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PMID:[The relevance of the TNF-alpha system in psychiatric disorders]. 1941 85

The study compares the single dose histidine-tryptophan-ketoglutarate (HTK) cardioplegia to the repeatedly delivered St Thomas' Hospital Solution (STHS) with respect to preservation of left ventricular mechanoenergetics and leakage of troponin T in a porcine experimental model. Fourteen pigs were randomized to a single infusion of 30 ml/kg HTK cardioplegia (n=7) or 500 ml STHS (n=7) followed by 200 ml after 20 and 40 min. After 1 h of aortic cross-clamping on cardiopulmonary bypass (CPB), the pigs were weaned and the hearts reperfused for 4 h. Stroke work (SW) was determined by a conductance catheter in the left ventricle. Myocardial oxygen consumption (MvO(2)) was measured as a function of coronary blood flow and arterial-to-coronary sinus oxygen saturation difference. Troponin T was sampled from the coronary sinus. The slope of the SW-MvO(2) relationship increased by 1.09 (+/-0.53) in the HTK group compared with 0.33 (+/-0.70) in the STHS group following ischemia and 4 h of reperfusion (P=0.04). Troponin T was significantly higher in the HTK group compared with the STHS group (P=0.04). Repeatedly delivered STHS gives better preservation of postischemic mechanoenergetic function and lower troponin T release compared with single dose HTK cardioplegia, indicating improved cardioprotection with STHS.
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PMID:Mechanoenergetic function and troponin T release following cardioplegic arrest induced by St Thomas' and histidine-tryptophan-ketoglutarate cardioplegia--an experimental comparative study in pigs. 1962 29


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