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)

MDL 28170, Cbz-(L)-Val-(D,L)-Phe-H, which exists as a mixture of L,L- and L,D-diastereoisomers, is a calpain inhibitor currently investigated as a novel therapeutic agent for the treatment of ischemic stroke and head and spinal trauma. This report describes a capillary electrophoresis (CE) method that uses sodium dodecyl sulfate (SDS) micellar electrokinetic conditions for the separation of the L,L- and L,D-diastereoisomers of MDL 28170. The report also describes the applications of this CE method to the study of epimerization of the L,L- and L,D-diastereoisomers in pH 7.4 phosphate buffered saline solution (PBS), rat and human plasma at 37 degrees C. The relative percent-time courses obtained showed interconversion of the diastereoisomers in all three matrices studied. However, the epimerization process in rat and human plasma was found to be at least 50 times faster than that in PBS. The epimerization half-life of the L,L-diastereoisomer in rat plasma was approximately 30 min, which is about three-fold faster than the observed elimination half-life of the L,L-diastereoisomer reported in a pharmacokinetic study following intravenous bolus dosing.
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PMID:Epimerization study of the L,L- and L,D-diastereoisomers of the calpain inhibitor MDL 28170 by capillary electrophoresis. 1528 90

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

Polycystic ovary syndrome (PCOS), a common endocrinopathy of women of reproductive age, is associated with the early appearance of multiple risk factors for cardiovascular disease, such as abdominal obesity, dyslipidemia, and diabetes mellitus. However, premature atherosclerosis of the carotid artery has not yet been demonstrated in young women with PCOS. Measurement of carotid intima-media thickness (IMT) is considered an easy and reliable index of subclinical atherosclerosis, which is predictive of subsequent myocardial infarction and stroke. To evaluate the cardiovascular risk of PCOS and the participation of the hyperandrogenemic and metabolic pattern, we measured carotid IMT by B-mode ultrasound as well as hormonal and several cardiovascular disease-associated parameters in 75 young women with PCOS and 55 healthy, age- and body mass index-matched women. The PCOS women had significantly increased carotid IMT (0.58 vs. 0.47 mm, P < 0.001) and abdominal adiposity; higher levels of androgens, insulin, homeostasis model assessment score of insulin sensitivity, and total and low-density lipoprotein-cholesterol; and significantly lower levels of SHBG and high-density lipoprotein-cholesterol. In the studied population (n = 130), PCOS status, age, body mass index, and parental history of coronary heart disease were strong positive predictors of carotid IMT, whereas dehydroepiandrosterone sulfate was a strong negative predictor. In PCOS patients lower delta4-androstenedione and high-density lipoprotein-cholesterol levels were additionally strong positive predictors of carotid IMT, whereas in control women only total cholesterol was the additional positive predictor of carotid IMT. In conclusion, young women with PCOS have an early increase of cardiovascular risk factors and greater carotid IMT, both of which may be responsible for subclinical atherosclerosis. The hyperandrogenemic phenotype of the syndrome may attenuate the consequences of the dysmetabolic phenotype on the vascular wall.
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PMID:Association of hyperandrogenemic and metabolic phenotype with carotid intima-media thickness in young women with polycystic ovary syndrome. 1574 Dec 56

The upregulation of extracellular matrix components, especially chondroitin sulfate proteoglycans, after brain injury and stroke is known to accompany the glial reaction, forming repellent scars that hinder axonal growth and the reorganization of the injured neuronal networks. The extracellular matrix associated with perineuronal nets (PNs) in the primarily injured and remote regions has not yet been systematically analyzed. We use the model of permanent middle cerebral artery occlusion (MCAO) to investigate the acute and long-lasting consequences of ischemia for PNs, related to the damage of neurons and reactions of glial cells, in spontaneously hypertensive rats. Extracellular matrix components associated with PNs around cortical interneurons and neurons in thalamic nuclei were characterized 1, 7, 14, and 35 days after MCAO, using Wisteria floribunda agglutinin (WFA) staining and immunocytochemistry. The degradation of PNs in the infarct core was initiated by loss of WFA-binding matrix components, indicating the cleavage of glycosaminoglycan chains of chondroitin sulfate proteoglycans. Immunostaining showed the subsequent removal of proteoglycan core proteins within the extending microglia/macrophage invasion zone lasting for 2 weeks after MCAO. In the cortical periinfarct region, delineated by an astrocytic scar against the infarct core, the number of WFA-stained and proteoglycan core protein-immunoreactive PNs was permanently reduced. In the homolateral ventroposterior thalamus, the delayed decrease in perineuronal matrix was related to the distribution pattern of activated microglia and massive neuronal degeneration. It can be concluded from these results that complementary to the known upregulation of matrix components in the glial scar, deficits in the expression of the neuron-associated extracellular matrix develop in the periinfarct and remote regions. These deficits may contribute to the long-lasting functional impairments after stroke.
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PMID:Decomposition and long-lasting downregulation of extracellular matrix in perineuronal nets induced by focal cerebral ischemia in rats. 1580 66

Stroke induces axonal sprouting in peri-infarct cortex. A set of growth-associated genes important in axonal sprouting in peripheral nervous system regeneration and cortical development has recently been defined. The expression profiles of these growth-associated genes were defined during the post-stroke axonal sprouting response using a model of stroke in barrel field cortex. Stroke induces sequential waves of neuronal growth-promoting genes during the sprouting response: an early expression peak (SPRR1), a mid expression peak (p21, Ta1 tubulin, L1, MARCKS), a late peak (SCG10, SCLIP), and an early/sustained pattern (GAP43, CAP23, c-jun). These expression peaks correspond to specific time points in the sprouting response. The expression of the growth-inhibiting chondroitin sulfate proteoglycans aggrecan, brevican, versican, and phosphacan are induced late in the sprouting process; except neurocan, which is increased during the peak of the growth-promoting gene expression. The developmentally associated growth inhibitors ephrin-A5, ephB1, semaphorin IIIa, and neuropilin 1 are also induced in the early phases of the sprouting response. At the cellular level, chondroitin sulfate proteoglycans, in the form of peri-neuronal nets, are reduced in the region of axonal sprouting, during the peak of growth-promoting gene expression. These results identify a unique profile of growth-promoting gene expression in adult cortex after stroke, the inhibitory molecules that are present during the sprouting response, and a region in which growth-promoting genes are increased, growth-inhibitory proteins are diminished and axonal sprouting occurs. This region may be a growth-promoting zone after stroke.
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PMID:Growth-associated gene expression after stroke: evidence for a growth-promoting region in peri-infarct cortex. 1586 33

IBT 9302 (heparinase III, EC 4.2.2.8), purified from Flavobacterium heparinum, selectively cleaves heparan sulfate proteoglycans (HSPGs) from cellular surfaces and extracellular matrices. HSPGs serve as binding sites for P- and L-selectins, as well as for pro-inflammatory chemokines, such as interleukin (IL)-8. IBT 9302 reversibly removes these binding sites and inflammatory mediators, thereby limiting tissue damage following reperfusion of ischaemic areas by reducing leukocyte rolling, adhesion and extravasation. In models of myocardial ischaemia/reperfusion injury, infusion of IBT 9302 the time of transport and reperfusions, reduces the area of necrosis/area at risk ratios relative to vehicle-treated animals. Cardioprotection is accompanied by a reduction in serum creatine kinase levels and neutrophil adherence to coronary vessels, and the preservation of endothelial relaxation responsiveness to acetylcholine. HSPGs also serve as accumulation sites for most growth factors and IBT 9302 limits both proliferation and migration of vascular smooth muscle cells to platelet-derived growth factor (PDGF), basic fibroblast growth factor (bFGF) and endothelial growth factor (EGF). In vivo, the application of IBT 9302 at the time of vascular injury significantly reduces arterial medial proliferation. External application of IBT 9302 to wounds in a steroid-impaired wound healing model increases tensile strength by releasing mitogenic growth factors and HSPGs from the surrounding extracellular matrix. Pharmacokinetic studies show a simple monoexponential decay following iv. bolus dosing of IBT 9302, with a half-life of 5 - 6 min. The majority of [(125)I]-IBT 9302 goes to the liver (60%) and kidneys (25%), following iv. dosing. Preliminary toxicology studies in rats following single iv. bolus (10 mg/kg) or infusion (10 mug/kg/min) dosing show no untoward effects. These results suggest that IBT 9302 may have therapeutic utility in treating myocardial ischaemia/reperfusion injury, ischaemic stroke, restenosis or in healing diabetic ulcer wounds, by virtue of its ability to selectively cleave HSPGs.
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PMID:IBT 9302 (Heparinase III): a novel enzyme for the management of reperfusion injury-related vascular damage, restenosis and wound healing. 1599 12

17alpha-estradiol (17alpha-E2) differs from its isomer, the potent feminizing hormone 17beta-estradiol (17beta-E2), only in the stereochemistry at one carbon, but this is sufficient to render it at least 200-fold less active as a transactivating hormone. Despite its meager hormonal activity, 17alpha-E2 is as potent as 17beta-E2 in protecting a wide variety of cell types, including primary neurons, from a diverse array of lethal and etiologically relevant stressors, including amyloid toxicity, serum withdrawal, oxidative stress, excitotoxicity, and mitochondrial inhibition, among others. Moreover, both estradiol isomers have shown efficacy in animal models of stroke, Alzheimer's disease (AD), and Parkinson's disease (PD). Data from many labs have yielded a mechanistic model in which 17alpha-E2 intercalates into cell membranes, where it terminates lipid peroxidation chain reactions, thereby preserving membrane integrity, and where it in turn is redox cycled by glutathione or by NADPH through enzymatic coupling. Maintaining membrane integrity is critical to mitochondrial function, where loss of impermeability of the inner membrane initiates both necrotic and apoptotic pathways. Thus, by serving as a mitoprotectant, 17alpha-E2 forestalls cell death and could correspondingly provide therapeutic benefit in a host of degenerative diseases, including AD, PD, Friedreich's ataxia, and amyotrophic lateral sclerosis, while at the same time circumventing the common adverse effects elicited by more hormonally active analogues. Positive safety and pharmacokinetic data from a successful phase I clinical study with oral 17alpha-E2 (sodium sulfate conjugate) are presented here, and several options for its future clinical assessment are discussed.
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PMID:Development of 17alpha-estradiol as a neuroprotective therapeutic agent: rationale and results from a phase I clinical study. 1602 55

It has been documented that increased intake of polyphenols may provide protection against coronary heart disease and stroke. Blueberries (Vaccinium angustifolium) are one of the richest sources of antioxidants among fruits and vegetables. Phenolic compounds from berry extracts inhibit human low density lipoprotein and liposome oxidation. Glycosaminoglycans (GAGs) and proteoglycans (PGs) are structural components of aortas with great structural diversity. Their interaction with compounds such as enzymes, cytokines, growth factors, proteins and lipoproteins and their subsequent role in degenerative diseases has been documented. We investigated the effects of a diet rich in blueberries on the content and structure of GAGs. Sprague-Dawley rats were fed either a control (C) or a blueberry (B) diet for 13 weeks. Aortic tissue GAGs were isolated with papain digestion, alkaline borohydride treatment and anion-exchange chromatography. Cellulose acetate electrophoresis and treatment of the fractions with specific lyases revealed the presence of three GAG populations, i.e. hyaluronan (HA), heparan sulfate (HS) and galactosaminoglycans (GalAGs). Disaccharide composition was determined by high-performance capillary electrophoresis following enzymatic degradation. A 13% higher amount of total GAGs in aortas of B-fed rats was attributed to a higher content of GalAGs (67%). Determination of the sulfated disaccharides showed an overall lower concentration of oversulfated disaccharides in both HS and GalAG populations in the aortas of the B group. Our results demonstrate for the first time that a diet rich in blueberries results in structural alterations in rat aortic tissue GAGs. These changes may affect cellular signal transduction pathways and could have major consequences for the biological function of GAG molecules within the vascular environment.
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PMID:Wild blueberry (Vaccinium angustifolium) consumption affects the composition and structure of glycosaminoglycans in Sprague-Dawley rat aorta. 1611 74

Based on the results of preclinical models, magnesium sulfate (MgSO4) has gained attention as a putative neuroprotective agent. The negative results of a large-scale, randomized clinical trial using MgSO4 in acute stroke have tempered the initial enthusiasm for a neuroprotective benefit of the ion. Additional, large-scale clinical trials in stroke and other forms of brain injury are underway. This article reviews the central nervous system (CNS) physiology of Mg++, disordered Mg++ homeostasis in acute brain injury, preclinical and preliminary clinical foundations of current clinical trials, and the data regarding the CNS bio-availability of MgSO4 an important requisite for neuroprotective therapy. Although human studies have confirmed that moderate hypermagnesemia is well-tolerated and feasible, only modest elevation of cerebrospinal fluid (CSF) [Mg++] occurs. This modest increment of CSF [Mg++] in brain-injured humans occurs in the range of 10 to 19%. However, experimental evidence has yet to establish whether this modest elevation is sufficient for neuroprotection. Because of the limited CNS passage of the ion, further experimental work is needed to define the neuroprotective threshold of [Mg++] in the injured brain.
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PMID:Magnesium neuroprotection is limited in humans with acute brain injury. 1615 86

Abnormal zinc and lipid plasma levels occur more frequently in metabolically uncontrolled diabetic patients. These lipid alterations are key factors in the emergence of microvascular complications, which lead to death in those patients. Yet, zinc sulfate supplementation may be a therapeutical resource to recover some functioning and improve life span. This article reports the assessment of lipid profile from type 2-diabetes mellitus patients treated with hypoglycemic therapy drugs, who additionally presented zinc levels lower than average in Mexican reference. The patients received a 100 mg zinc sulfate treatment in a crossover double-blind design of clinically controlled study with starch as placebo. The diabetic patients had changes in their lipid profile after a 12-week zinc treatment as compared with placebo treatment. The 100 mg zinc sulfate treatment was well tolerated, significantly reduced total cholesterol and triglyceride concentrations, and increased those corresponding to zinc as well as HDL cholesterol in the bloodstream. Thus, using this treatment the cardiovascular involvement is expected to decrease in the type 2-diabetes mellitus patients, especially those with myocardial infarction and stroke, which are the main death causes in Mexico.
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PMID:Effect of zinc replacement on lipids and lipoproteins in type 2-diabetic patients. 1663 97


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