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 renewed interest in an enzyme first discovered over 25 years ago stems from the potential of inhibitors of this enzyme to treat conditions as diverse as diabetes, Alzheimer's disease, stroke and bipolar disorder, and even to enhance the repopulating capacity of transplanted haematopoietic stem cells. The emergence of the first few potent and specific glycogen synthase kinase-3 (GSK-3) inhibitors will end years of speculation on their potential and finally allow the impact of GSK-3 inhibitors to be evaluated clinically. The next few years are likely to be particularly exciting ones for fans of this old enzyme. This review focuses on the role of GSK-3 in the insulin signalling pathway and highlights the evidence implicating the enzyme in insulin resistance. Pharmacological in vitro and in vivo proof-of-concept studies are also discussed, which establish the therapeutic potential of GSK-3 inhibitors as agents for the treatment of Type 2 diabetes.
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PMID:Targeting glycogen synthase kinase-3 in insulin signalling. 1670 83

Since 2005, the chief residents of the University Outpatient Clinic of Lausanne have established a database of articles chosen from miscellaneous reviews and electronic journals and selected for their scientific value and practical usefulness. This first review is based on articles published in 2006 and covering five topics useful for the primary care physician: chronic daily headaches are frequent in women, isolated vertigo is only exceptionally a sign of stroke and a bipolar disorder must be investigated in case of depression. HIV testing in a medical setting is at present more satisfactory than rapid HIV testing at home and finally watchful waiting of inguinal hernia is possible in asymptomatic or pauci-symptomatic men.
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PMID:[News in internal ambulatory medicine]. 1731 96

The authors determined whether diagnoses of cardiovascular disease (CVD) and CVD-related conditions differed by psychiatric diagnosis among male Veterans Administration patients from the mid-Atlantic region. Among 7,529 patients (mean age: 54.5 years), the prevalence of diagnoses ranged from 3.6% (stroke) to 35.4% (hypertension). Compared with schizophrenia patients, those with bipolar disorder were 19% more likely to have diabetes, 44% more likely to have coronary artery disease, and 18% more likely to have dyslipidemia, after adjustment. Clinical suspicion for CVD-related conditions, as well as risk-modification strategies, in patients with serious mental illness should incorporate differences in prevalence across specific psychiatric diagnoses.
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PMID:Cardiovascular disease and metabolic risk factors in male patients with schizophrenia, schizoaffective disorder, and bipolar disorder. 1787

Involuntary emotional expression disorder (IEED) is underrecognized by clinicians, misdiagnosed as depression or bipolar disorder and undertreated, because clinicians are unfamiliar with the disorder. An important clinical consideration for IEED is that of distinguishing mood from affect. IEED describes a syndrome of relatively stereotypical episodes of uncontrollable crying and/or laughing, resulting from lesions of multiple types, in multiple brain regions, without an apparent stimulus to trigger such responses. This syndrome is common among a number of neurological diseases like patients with a stroke or traumatic brain injury (TBI), patients with amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), as well as dementias such as Alzheimer;s disease (AD), and motor disorders such as Parkinson;s disease (PD). The neuropathological cause and neurochemistry of the disorder remains unclear. There is general agreement that IEED is the result of an injury to the neurological pathways that control the expression of emotions. Adequate treatment can reduce the frequency and improve the quality of life of patients and caregivers.
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PMID:Involuntary emotional expression disorder - new/old disease in psychiatry and neurology. 1791 17

It is just over a quarter of a century since the original identification and characterization of glycogen synthase kinase-3 (GSK-3), a major protein kinase that is involved in the regulation of glucose metabolism. GSK-3 modulates the function of a diverse series of proteins, as well as being associated with a wide variety of human disorders, including neurodegenerative diseases, stroke, bipolar disorder, diabetes and cancer. Not surprisingly, GSK-3 has attracted significant attention as a therapeutic target and as a means to understand the molecular basis of these disorders. Small-molecule GSK-3 inhibitors have now started to reach clinical development for the treatment of various disorders.
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PMID:Glycogen synthase kinase-3 (GSK-3) inhibitors reach the clinic. 1860 May 69

Glycogen synthase kinase-3, a serine/threonine kinase, has been implicated in a wide variety of pathological conditions such as diabetes, Alzheimer's disease, stroke, bipolar disorder, malaria and cancer. Herein we report 3D-QSAR analyses using CoMFA and CoMSIA and molecular docking studies on 3-anilino-4-phenylmaleimides as GSK-3alpha inhibitors, in order to better understand the mechanism of action and structure-activity relationship of these compounds. Comparison of the active site residues of GSK-3alpha and GSK-3beta isoforms shows that all the key amino acids involved in polar interactions with the maleimides for the beta isoform are the same in the alpha isoform, except that Asp133 in the beta isoform is replaced by Glu196 in the alpha isoform. We prepared a homology model for GSK-3alpha, and showed that the change from Asp to Glu should not affect maleimide binding significantly. Docking studies revealed the binding poses of three subclasses of these ligands, namely anilino, N-methylanilino and indoline derivatives, within the active site of the beta isoform, and helped to explain the difference in their inhibitory activity.
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PMID:Glycogen synthase kinase-3 inhibition by 3-anilino-4-phenylmaleimides: insights from 3D-QSAR and docking. 1883 67

In this study, the authors performed deep brain stimulation (DBS) of the subgenual anterior cingulate cortex (SACC) in a patient with a history of bipolar disorder. After a right thalamic stroke, intractable depression without mood elevation or a mixed state developed in this patient. He underwent bilateral SACC DBS and died 16 months afterwards. Anatomical connections were studied in this patient preoperatively and postmortem using diffusion tractography (DT). A comparison of in vivo and high resolution ex vivo connectivity patterns was performed as a measure of the utility of in vivo DT in presurgical planning for DBS. Diagnostic measures included neuropsychological testing, preoperative and ex vivo DT, and macroscopic neuropathological assessment. Post-DBS depression rating scores did not improve. In vivo and ex vivo DT revealed markedly reduced limbic projections from the thalamus and SACC to the amygdala in the right (stroke-affected) hemisphere. A highly selective right mediothalamic lesion was associated with the onset of refractory depression. Reduced amygdalar-thalamic and amygdalar-SACC connections could be a contraindication to DBS for depression. Correspondence between preoperative and higher resolution ex vivo DT supports the validity of DT as a presurgical planning tool for DBS.
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PMID:Reduced limbic connections may contraindicate subgenual cingulate deep brain stimulation for intractable depression. 1928 30

Clinicians have long used lithium to treat manic depression. They have also observed that lithium causes granulocytosis and lymphopenia while it enhances immunological activities of monocytes and lymphocytes. In fact, clinicians have long used lithium to treat granulocytopenia resulting from radiation and chemotherapy, to boost immunoglobulins after vaccination, and to enhance natural killer activity. Recent studies revealed a mechanism that ties together these disparate effects of lithium. Lithium acts through multiple pathways to inhibit glycogen synthetase kinase-3beta (GSK3 beta). This enzyme phosphorylates and inhibits nuclear factors that turn on cell growth and protection programs, including the nuclear factor of activated T cells (NFAT) and WNT/beta-catenin. In animals, lithium upregulates neurotrophins, including brain-derived neurotrophic factor (BDNF), nerve growth factor, neurotrophin-3 (NT3), as well as receptors to these growth factors in brain. Lithium also stimulates proliferation of stem cells, including bone marrow and neural stem cells in the subventricular zone, striatum, and forebrain. The stimulation of endogenous neural stem cells may explain why lithium increases brain cell density and volume in patients with bipolar disorders. Lithium also increases brain concentrations of the neuronal markers n-acetyl-aspartate and myoinositol. Lithium also remarkably protects neurons against glutamate, seizures, and apoptosis due to a wide variety of neurotoxins. The effective dose range for lithium is 0.6-1.0 mM in serum and >1.5 mM may be toxic. Serum lithium levels of 1.5-2.0 mM may have mild and reversible toxic effects on kidney, liver, heart, and glands. Serum levels of >2 mM may be associated with neurological symptoms, including cerebellar dysfunction. Prolonged lithium intoxication >2 mM can cause permanent brain damage. Lithium has low mutagenic and carcinogenic risk. Lithium is still the most effective therapy for depression. It "cures" a third of the patients with manic depression, improves the lives of about a third, and is ineffective in about a third. Recent studies suggest that some anticonvulsants (i.e., valproate, carbamapazine, and lamotrigene) may be useful in patients that do not respond to lithium. Lithium has been reported to be beneficial in animal models of brain injury, stroke, Alzheimer's, Huntington's, and Parkinson's diseases, amyotrophic lateral sclerosis (ALS), spinal cord injury, and other conditions. Clinical trials assessing the effects of lithium are under way. A recent clinical trial suggests that lithium stops the progression of ALS.
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PMID:Review of lithium effects on brain and blood. 1952 43

Reactive oxygen species (ROS) are produced at low levels in mammalian cells by various metabolic processes, such as oxidative phosphorylation by the mitochondrial respiratory chain, NAD(P)H oxidases, and arachidonic acid oxidative metabolism. To maintain physiological redox balance, cells have endogenous antioxidant defenses regulated at the transcriptional level by Nrf2/ARE. Oxidative stress results when ROS production exceeds the cell's ability to detoxify ROS. Overproduction of ROS damages cellular components, including lipids, leading to decline in physiological function and cell death. Reaction of ROS with lipids produces oxidized phospholipids, which give rise to 4-hydroxynonenal, 4-oxo-2-nonenal, and acrolein. The brain is susceptible to oxidative damage due to its high lipid content and oxygen consumption. Neurodegenerative diseases (AD, ALS, bipolar disorder, epilepsy, Friedreich's ataxia, HD, MS, NBIA, NPC, PD, peroxisomal disorders, schizophrenia, Wallerian degeneration, Zellweger syndrome) and CNS traumas (stroke, TBI, SCI) are problems of vast clinical importance. Free iron can react with H(2)O(2) via the Fenton reaction, a primary cause of lipid peroxidation, and may be of particular importance for these CNS injuries and disorders. Cholesterol is an important regulator of lipid organization and the precursor for neurosteroid biosynthesis. Atherosclerosis, the major risk factor for ischemic stroke, involves accumulation of oxidized LDL in the arteries, leading to foam cell formation and plaque development. This review will discuss the role of lipid oxidation/peroxidation in various CNS injuries/disorders.
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PMID:Lipid oxidation and peroxidation in CNS health and disease: from molecular mechanisms to therapeutic opportunities. 1962 72

Cerebral ischemia is a major cause of death and long-term disability worldwide. Ischemic penumbra, the electrically silent but metabolically viable perifocal brain tissue, is the target for the much elusive stroke therapy. To characterize the molecular events of the dynamic penumbra, we applied an iTRAQ-based shotgun proteomic approach in an in vitro neuronal model, using the rat B104 neuroblastoma cell line. Various functional and cytometric assays were performed to establish the relevant time-point and conditions for ischemia to recapitulate the pathology of the penumbra. Two replicate iTRAQ experiments identified 1796 and 1566 proteins, respectively (<or=1.0% false discovery rate). Mining of proteomic data indicated the up-regulation of proteins involved in ammoniagenesis, antiapoptotic, anti-inflammatory and mitochondrial heat shock response and down-regulation of proteins pertaining to antioxidative defense and protein metabolism. Additionally, many proteins (for instance, park7 and VAP-A) involved in the chronic neurological disorders (such as Alzheimer's disease, Parkinson's disease or Bipolar disorder) were also regulated in this model of acute neuronal injury. Our results also provide preliminary evidence about the presence of a relative glucose paradox under in vitro conditions indicating possible application of this cell system to study the mechanisms of transient protection induced by concomitant glucose deprivation under hypoxia. In conclusion, our study shows the potential application of iTRAQ-based quantitative proteomics for the elucidation of pathophysiology and the discovery of novel therapeutic targets in the field of neuroproteomics.
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PMID:Phenotyping of an in vitro model of ischemic penumbra by iTRAQ-based shotgun quantitative proteomics. 1991 22


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