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

In the mammalian central nervous system, the N-methyl-D-aspartate (NMDA) subclass of glutamate receptors may play an important role in brain diseases such as stroke, brain or spinal cord trauma, epilepsy, and certain neurodegenerative diseases. Compounds which specifically antagonize the actions of the neurotransmitter glutamate at the NMDA receptor ion-channel site offer a novel approach to treating these disorders. CERESTAT (4, aptiganel CNS 1102) is currently undergoing clinical trial for the treatment of traumatic brain injury and stroke. Previously, we reported that analogues of N-1-naphthyl-N'-(3-ethylphenyl)-N'-methylguanidine (4) bound to the NMDA receptor ion-channel site with high potency and selectivity. Recently, molecules active at both sigma receptors and NMDA receptor sites were investigated. A series of substituted diphenylguanidines 6 which are structurally related to N-1-naphthyl-N'-(3-ethylphenyl)-N'-methylguanidine was prepared. Compounds containing appropriate substitution pattern in one of the phenyl rings of diphenylguanidines displayed high affinity. For example, N-(2,5-dibromophenyl)-N'-(3-ethylphenyl)-N'- methylguanidine (27b, R2 = R5 = Br, R3 = C2H5) exhibited potency at both sigma receptors and NMDA receptor sites; 27b also showed high efficacy in vivo in a neonatal rat excitotoxicity model. Further studies indicated that substituent effects were important in this compound series, and 2,5-disubstituted phenyl was the preferred substitution pattern for high-affinity binding at NMDA receptor sites. Bromo and methylthio were the optimal substituents for the R2 and R5 positions of the 2,5-disubstituted phenyl group, respectively. N-(2-Bromo-5-(methylthio)phenyl)-N'- (3-ethylphenyl)-N'-methylguanidine (34b, R2 = Br, R5 = SMe, R3 = C2H5) was highly active at NMDA receptor sites. We found that the binding affinity of guanidines of type 6 could be further enhanced with the appropriate substitution at R3. Optimal activity in this series are afforded by 43b and 44b (R2 = Cl or Br, R5 = R3 = SCH3). Both 43b and 44b bound to NMDA receptor sites with high potency and selectivity (Ki vs [3H]MK-801: 1.87 and 1.65 nM, respectively); these compounds are active in vivo in various animal models of neuroprotection. The structure--activity relationships for these compounds at the NMDA receptor ion-channel site are discussed.
 ...
PMID:Synthesis and pharmacological evaluation of N-(2,5-disubstituted phenyl)-N'-(3-substituted phenyl)-N'-methylguanidines as N-methyl-D-aspartate receptor ion-channel blockers. 943 97

Ebselen is a selenium compound that have glutathione peroxidase-like activity which is neuroprotective in acute stroke ischemia. The efficacy of ebselen to prevent excitotoxicity provoked by glutamate in cerebellar granule neurons was investigated at various time points and concentrations. Simultaneous addition of ebselen with glutamate decreased neuronal death and was completely reversed by 3 microM of ebselen (3 (4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and propidium iodide assays). However, when 1 microM of ebselen was added with glutamate and remained in the culture medium until 24 or 48 h, the neuronal survival increased to the control. The mechanism proposed for neuroprotection was the ability of ebselen to prevent lipoperoxidation provoked by glutamate. The present findings propose to amplify the use of ebselen in others neurodegenerative disorders involving glutamatergic system.
 ...
PMID:Ebselen prevents excitotoxicity provoked by glutamate in rat cerebellar granule neurons. 1116 74

N-Methyl-D-aspartate (NMDA) receptor-mediated cell death is complex, probably involving elements of necrosis and apoptosis. The mechanisms underlying this phenomenon are incompletely understood but have been suggested to involve reactive oxygen species such as nitric oxide and superoxide anion (O(2)) and nuclear factor-kappaB (NF-kappaB) signaling. In this study, we used a selective nonpeptidyl superoxide dismutase mimetic (M40403) and SN50, a peptide inhibitor of NF-kappaB translocation, to investigate the role of O(2) and the potential downstream signaling molecules in cell death induced by activation of the NMDA receptor. Application of NMDA to a mixed neuronal/glial forebrain culture resulted in an early increase in the release of cytoplasmic lactate dehydrogenase (LDH), which peaked at 4 h. This was followed by a reduction in mitochondrial metabolism of the dye MTT [3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide] that continued to decrease throughout the 20-h exposure. A substantial increase in DNA fragmentation as measured by an enzyme-linked immunosorbent assay (ELISA) specific for DNA-associated histone proteins (nucleosomes) was observed at 7 and 20 h. M40403 and SN50 blocked NMDA-induced changes in LDH release at 2, 4, and 20 h, MTT metabolism at 4 and 20 h, and DNA fragmentation at 20 h as measured by the ELISA and by an increase in terminal dUTP-nick end labeling. M40403 also prevented NMDA-induced nuclear transport of NF-kappaB and increased expression of Bax relative to Bcl-X(L). SN50 was also able to block NMDA-induced cell death as well as the increased Bax/Bcl-X(L) ratio. Time course studies and experiments with SN50 and M40403 suggest that O(2) production and NF-kappaB translocation may be involved in necrosis and apoptosis, but the latter also requires an increased expression of Bax. The ability of M40403 to prevent NMDA-induced cell death relatively early in this cascade suggests its potential therapeutic utility in central nervous systems diseases such as stroke that are associated with increased NMDA receptor-mediated production of O(2).
 ...
PMID:The role of superoxide and nuclear factor-kappaB signaling in N-methyl-D-aspartate-induced necrosis and apoptosis. 1196 Oct 46

The role of the lipid abnormalities as a risk factor for stroke remains controversial; very likely because only the standard lipid fractions are measured and because different causes of stroke are not considered. LDL phenotype B promotes atherogenesis and is recognized as a risk factor for ischemic heart disease, but its prevalence in ischemic stroke of distinct causes is unknown. Therefore we designed the study to investigate the prevalence of LDL phenotype B in stroke survivors with large vessel disease (LVD) or small vessel disease (SVD) and to establish the relationship between LDL phenotypes and basic lipid fractions in this group of patients. 59 patients (24 patients with LVD and 35 patients with SVD) being at least 3 months after ischemic stroke were included into the study. 30 sex- and age-matched subject served as controls. The concentrations of total cholesterol, HDL- and LDL-cholesterol, as well as triglycerides were measured and the LDL phenotype was determined using the potassium bromide density gradient ultracentrifugation. The LDL phenotype B was more frequent in patients with LVD (67%, p < 0.05) compared to patients with SVD and with controls. LDL phenotype B was also more frequent in patients with SVD (40%) and in all stroke survivors combined (51%), when compared with control group (17%, p < 0.05; chi-square test). Among stroke survivors, controls and studied subjects as a whole, those with LDL phenotype B revealed the lower concentration of HDL-cholesterol (1.19 +/- 0.33 vs. 1.46 +/- 0.42; 1.16 +/- 0.29 vs. 1.53 +/- 0.3 and 1.19 +/- 0.32 vs. 1.49 +/- 0.37, respectively; p < 0.05, Student t-test) when compared with carriers of LDL A phenotype. The LDL phenotype B is more frequent in ischemic stroke survivors compared to controls, and within the group of stroke survivors, LDL B is more prevalent in patients with LVD. The LDL phenotype B is associated with lower concentration of HDL-cholesterol.
 ...
PMID:[LDL phenotype A and B in ischemic stroke]. 1210 52

Patients in status asthmaticus need intensive treatment often in ICU. In last 10 years period 342 patients with this diagnosis treated in ICU at university hospital were enrolled in the study and divided into 4 groups. The groups differ in treatment. In group I therapy included: oxygen supplementation, inhaled beta-agonist and intravenous steroid. In group II treatment was like in group I with i.v. theophylline, in group III like in group II with inhaled ipratropium bromide. Group IV was composed with patients who need mechanical ventilation. This study show that used treatment in groups caused significant improvement in bronchial air flow. The hospitalization time in groups I-III was similar (mean range 9.7-11 days). In group IV was longer (mean 16.4 days). We observed small numbers of complications: 11 deaths, 5 atelectasis, 4 heart insufficiency, 3 nosocomial pneumonia, 2 pleural oedema, 2 mediastinum oedema, 2 exacerbations of ischaemic heart disease and 2 cerebral stroke.
 ...
PMID:[Efficacy of treatment modification in status asthmaticus and complication frequency]. 1236 58

Integrated management of nematodes as well as other soil-borne pests and diseases in horticultural crops in the tropics and subtropics as well as in protected cultivation in temperate climates is often a lopsided approach based on soil fumigation. With the upcoming loss of methyl bromide (Mbr), because of its effects on the ozone layer of the atmosphere, growers will have to make changes in the way they look at the problem of controlling soil-borne nematodes, fungi, insects and weeds. They can no longer rely on eradication of all pest problems with a one-stroke fumigation process. This is a severe problem that requires sound scientific solutions. New control technologies need to be developed and established methods urgently refined that are acceptable to the growers. Alternative fumigants and systemic nematicides still on the market will not provide broad spectrum control equal to Mbr. More disturbing is a provocative statement made by an economist that due to pesticides nematologists have neglected developing suitable alternative IPM measures of control. Some people may agree with this statement, especially if they are not involved in soil-ecosystem research. If you are a nematologist, this thought-provoking statement is at first upsetting but it is not valid. My talk will concentrate on the biological and cultural control methodologies that have been developed by nematologist around the world for use in management systems. These are technologies that can compensate for the loss of methyl bromide to horticultural crops in many countries. Alternatives are available and new methodologies are being developed for restructuring IPM strategies in many crops. The compatibility of these new approaches with general farming practices needs to be assessed on a country by country basis. Mutually interacting technology packages are needed, that are logically structured in "biological system management" programs that stress biocontrol aspects of control and not pesticides as is often the case in standard IPM approaches.
 ...
PMID:Strategies for biological system management of nematodes in horticultural crops: fumigate, confuse or ignore them. 1270 1

Anesthesia during and after off-pump surgery is critical for the outcome of the procedure. Intubation time has been shown to correlate with ICU time and length of stay. This study is to evaluate the extubation time and predictors of prolonged extubation in this institution. One hundred and sixty consecutive patients during Jan 2001-June 2002, excluding pre-operative tracheostomy (n = 1) were retrospectively reviewed. Anesthetic agents include fentanyl, rocuronium Bromide, midazolam and sevoflurane. Phenylephrine and nitroglycerine were used to maintain adequate arterial pressures. Post-operative pain control was mainly with intravenous fentanyl and oral pain medications. The extubation time was divided into 4 groups; 0-2 h, n = 76, mean = 1.11 +/- 0.5 h; 2-4 h, n = 30, mean = 2.91 +/- 0.5 h; 4-24 h, n = 39, mean = 11.44 +/- 7.3 h; > 24 h, n = 5, mean = 33.3 +/- 21 h. The data were collected and analyzed following the guidelines of National STS cardiac surgery database. All pre-operative risk factors included: Age (> 70 yrs vs < or = 70 yrs), gender (male vs female), diabetes (yes vs no), hypertension (yes vs no), morbid obesity (yes vs no), renal insufficiency (yes vs no), chronic obstructive lung disease (yes vs no), history of cerebrovascular accident (yes vs no), smoking (yes vs no), dyslipidemia (yes vs no), history of myocardial infarction (MI) (yes vs no), history of congestive heart failure (CHF) (yes vs no), unstable angina (yes vs no), left ventricular ejection fraction (LVEF) (> 40% vs < or = 40%), left main (LM) lesion (LM > 50% vs LM < or = 50%), intra-aortic balloon pump (IABP) used (yes vs no) and time between operating and closing (> 4.30 h vs < or = 4.30 h) were used to predict failed early extubation (2 h). More than 50 per cent of the patients were extubated in less than 2 h (1.11 +/- 0.5 h) and only 5 patients were extubated after 24 h. Univariate analysis revealed old age, diabetes, MI, CHF, LVEF < or = 0.4 and the use of IABP are the predictors (p < 0.05) of failed early extubation. Multivariate analysis of these variables revealed old age with adjusted odds ratio of 4.6 (95% CI = 1.5-13.7) p < 0.01, diabetes with adjusted odds ratio of 3.2 (95% CI = 1.3-7.5) p < 0.01 and IABP used with adjusted odds ratio of 4.3 (95% CI = 1.3-14.6) p = 0.02 are the predictors of fail early extubation. The findings suggested early extubation is possible in OPCAB surgery and attention should be made when operate in patients who have old age, diabetes, and IABP used.
 ...
PMID:Off-pump coronary artery bypass surgery: evaluation of extubation time and predictors of failed early extubation. 1286 66

One challenge in the molecular diagnosis of mitochondrial DNA (mtDNA) disorders is detection of a low percentage of mutant heteroplasmy. We report a patient who had a delayed molecular diagnosis of mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome due to the complication of an extensive family history of another neuromuscular disease, Duchenne muscular dystrophy, and the failure to detect a low proportion of mutant A3243G mtDNA with a polymerase chain reaction (PCR)/restriction fragment length polymorphism (RFLP)/ethidium bromide detection method. Using an improved, more sensitive allele-specific oligonucleotide (ASO) radioactive dot-blot hybridization method, a low degree of A3243G heteroplasmy was detected in several tissues from this patient. This case underscores the importance of a sensitive mutation detection method and the need for a search for mtDNA mutations if the patient's clinical symptoms suggest a mitochondrial disorder despite the family background of another neuromuscular disease.
 ...
PMID:A mitochondrial DNA mutation in a patient with an extensive family history of Duchenne muscular dystrophy. 1522 88

The purpose of this study was to compare the hemodynamic effects of pentobarbital and propofol and their effects on cardiovascular adaptation to an abrupt increase in left ventricular afterload. Experiments were performed in 12 open-chest pigs instrumented for measurement of aortic pressure and flow, and left ventricular pressure and volume. In one group (n = 6), anesthesia was obtained with sodium pentobarbital (3 mg x kg(-1) x h(-1)), and, in the second group B (n = 6), with propofol (10 mg x kg(-1) x h(-1)). Both groups received sufentanil (0.5 microg x kg(-1) x h(-1)) and pancuronium bromide (0.1 mg x kg(-1)). Left ventricular function was assessed by the slope of end-systolic pressure-volume relationship and stroke work. After baseline recordings, left ventricular afterload was increased by aortic banding. The cardiovascular adaptations triggered by the aortic banding, such as tachycardia, vasoconstriction, and augmentation of myocardial contractility were prevented with propofol, suggesting interference with the baroreflex. Increase in left ventricular afterload decreased mechanical efficiency, regardless of anesthetic agent. These results showed that pentobarbital at 3 mg x kg(-1) x h(-1) has less deleterious hemodynamic effects than propofol at 10 mg x kg(-1) x h(-1).
 ...
PMID:Comparison of the effects of propofol and pentobarbital on left ventricular adaptation to an increased afterload. 1547 25

Bone morphogenetic proteins play a key role in astrocytic differentiation. Astrocytes express the gap junctional protein connexin-43, which permits exchange of small molecules in brain and enhances synaptic efficacy. Bone marrow stromal cells produce soluble factors including bone morphogenetic protein 2 and bone morphogenetic protein 4 (bone morphogenetic protein 2/4) in ischemic brain. Here, we tested whether intra-carotid infusion of bone marrow stromal cells promotes synaptophysin expression and neurological functional recovery after stroke in rats. Adult male Wistar rats were subjected to 2 h of right middle cerebral artery occlusion. Rats were treated with or without bone marrow stromal cells at 24 h after middle cerebral artery occlusion via intra-arterial injection (n=8/group). A battery of functional tests was performed. Immunostaining of 5-bromo-2-deoxyuridine, Ki67, bone morphogenetic protein 2/4, connexin-43, synaptophysin, glial fibrillary acidic protein, neuronal nuclear antigen, and double staining of 5-bromo-2-deoxyuridine/glial fibrillary acidic protein, 5-bromo-2-deoxyuridine/neuronal nuclear antigen, glial fibrillary acidic protein/bone morphogenetic protein 2/4 and glial fibrillary acidic protein/connexin-43 were employed. Rats treated with bone marrow stromal cells significantly (P<0.05) improved functional recovery compared with the controls. 5-Bromo-2-deoxyuridine and Ki67 positive cells in the ipsilateral subventricular zone were significantly (P<0.05) increased in bone marrow stromal cell treatment group compared with the controls, respectively. Administration of bone marrow stromal cells significantly (P<0.05) promoted the proliferating cell astrocytic differentiation, and increased bone morphogenetic protein 2/4, connexin-43 and synaptophysin expression in the ischemic boundary zone compared with the controls, respectively. Bone morphogenetic protein 2/4 expression correlated with the expression of connexin-43 (r=0.84, P<0.05) and connexin-43 expression correlated with the expression of synaptophysin (r=0.73, P<0.05) in the ischemic boundary zone, respectively. Administration of bone marrow stromal cells via an intra-carotid route increases endogenous brain bone morphogenetic protein 2/4 and connexin-43 expression in astrocytes and promotes synaptophysin expression, which may benefit functional recovery after stroke in rats.
 ...
PMID:Bone marrow stromal cells upregulate expression of bone morphogenetic proteins 2 and 4, gap junction protein connexin-43 and synaptophysin after stroke in rats. 1673 Sep 12


<< Previous 1 2 3 4 5 6 7 8 9 Next >>