Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0917798 (cerebral ischemia)
 17,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A considerable body of information supports the occurrence and pathophysiological importance of oxygen radical-mediated lipid peroxidation in acute cerebral damage secondary to traumatic or ischemic injury. Moreover, peroxidative mechanisms have been implicated in chronic neurodegenerative (e.g., Alzheimer's and Parkinson's diseases) and demyelinating (e.g., multiple sclerosis) disorders. Consequently, there has been interest in identification of pharmacological agents with potent ability to interrupt oxygen radical formation or cell membrane lipid peroxidative mechanisms. Our laboratories have developed a novel series of potent lipid peroxidation inhibitors known as the 21-aminosteroids or "lazaroids." One of these compounds, U-74006F or tirilazad mesylate, has shown efficacy in animal models of brain injury and focal cerebral ischemia. In addition, the compound has been found to attenuate the increased lipid peroxidation observed in Alzheimer's brain tissue, to retard anterograde degeneration of motor nerve fibers, and to be effective in decreasing the clinical disease severity and blood-brain barrier disruption observed in the multiple sclerosis model of experimental allergic encephalomyelitis. Another series of antioxidants, the 2-methylaminochromans typified by the compound U-78517F, have been discovered that are even more potent and effective inhibitors of lipid peroxidation than the 21-aminosteroids.
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PMID:Novel inhibitors of iron-dependent lipid peroxidation for neurodegenerative disorders. 151 Mar 73

Regional cerebral oxygen utilisation (rCMRO2), oxygen extraction (rOER), blood flow (rCBF), and blood volume (rCBV) have been determined for fifteen patients with multiple sclerosis in remission using positron emission tomography (PET). Cerebral oxygen utilisation and blood flow were significantly reduced in both white matter and peripheral cortical grey matter in the multiple sclerosis patients compared to a group of normal controls. No evidence of regional cerebral ischaemia in the multiple sclerosis group was found. Lowest levels of cerebral oxygen utilisation were found in patients with cerebral atrophy, and in patients in whom a significant fall in present full-scale IQ from estimated pre-morbid levels had occurred. No correlation was found between rCMRO2 values and severity of locomotor dysfunction or clinical disease duration.
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PMID:Studies on regional cerebral oxygen utilisation and cognitive function in multiple sclerosis. 633 32

In muscles with sustained voluntary contraction, EMG activity is transiently inhibited after transcranial magnetic stimulation. We recorded this postexcitatory silent period (SP) at 1.5 times individual stimulus threshold level from the first dorsal interosseus muscle in 65 neurologic patients aged 11 to 80 years. When compared with 20 healthy volunteers and a subgroup of patients with peripheral neurologic conditions not affecting the tested pathways, the SP was significantly longer on the paretic side in cerebral ischemia (p < 0.001) and chronic inflammatory CNS diseases, such as multiple sclerosis or neurosarcoidosis (p < 0.01). There was a similar tendency in pyramidal tract lesions due to CNS tumors and spinal cord trauma. In lesser degrees of paresis, SP duration is more sensitive than central motor conduction time (CMCT), but its specificity awaits further evaluation. SP is dependent on the integration of motor excitatory and inhibitory pathways and, possibly, sensorimotor reflex systems. In contrast to SP duration, which proved to be an independent variable giving supplementary information over the usual CMCT measurement, SP onset latency correlates well with CMCT and peripheral nerve conduction slowing, as in polyradiculoneuritis.
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PMID:Latency and duration of the muscle silent period following transcranial magnetic stimulation in multiple sclerosis, cerebral ischemia, and other upper motoneuron lesions. 819 Mar

Multiple sclerosis (MS) and stroke pathology are characterized blood-brain barrier breakdown, leucocyte emigration, and tissue destruction. Each process is thought to involve the matrix metalloproteinases (MMP), but little is known of their expression. We undertook to investigate whether MMP expression is dependent on the nature of the CNS lesion and whether expression would coincide with the histopathology. MS or cerebral-infarct tissue was examined for the presence of gelatinase-A, gelatinase-B, matrilysin and stromelysin-1. Gelatinases A and B and matrilysin expression was found to be up-regulated in microglia/macrophages within acute MS lesions. In active-chronic MS lesions, matrilysin and gelatinase-A expression was pronounced in the active borders. In chronic MS lesions, the expression of matrilysin was confined to macrophages within perivascular cuffs. The pattern of MMP expression in infarct lesions differed considerably. Gelatinase-B was strongly expressed by neutrophils in tissue from patients up to 1 week after an infarct, whereas gelatinase-A and matrilysin staining was much less marked. From 1 week to 5 years, neutrophils were absent and the large number of macrophages present were expressing matrilysin and gelatinase A. Only a low level of gelatinase-A and matrilysin expression was observed in normal brain controls. Thus, MMPs are expressed in inflammatory lesions in the CNS, but their individual expression is dependent on the nature and chronicity of the lesion. However, the general pattern of expression, in perivascular cuffs and in active lesions, supports a role for these enzymes as mediators of blood-brain barrier breakdown and tissue destruction, both in MS and in cerebral ischaemia.
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PMID:Differential matrix metalloproteinase expression in cases of multiple sclerosis and stroke. 936 66

Heightened expression of both a proinflammatory cytokine, tumor necrosis factor alpha (TNF-alpha), and a survival peptide, insulin-like growth factor I (IGF-I), occurs in diverse diseases of the central nervous system, including Alzheimer's disease, multiple sclerosis, the AIDS-dementia complex, and cerebral ischemia. Conventional roles for these two proteins are neuroprotection by IGF-I and neurotoxicity by TNF-alpha. Although the mechanisms of action for IGF-I and TNF-alpha in the central nervous system originally were established as disparate and unrelated, we hypothesized that the signaling pathways of these two cytokines may interact during neurodegeneration. Here we show that concentrations of TNF-alpha as low as 10 pg/ml markedly reduce the capacity of IGF-I to promote survival of primary murine cerebellar granule neurons. TNF-alpha suppresses IGF-I-induced tyrosine phosphorylation of insulin receptor substrate 2 (IRS-2) and inhibits IRS-2-precipitable phosphatidylinositol 3'-kinase activity. These experiments indicate that TNF-alpha promotes IGF-I receptor resistance in neurons and inhibits the ability of the IGF-I receptor to tyrosine-phosphorylate the IRS-2 docking molecule and to subsequently activate the critical downstream enzyme phosphatidylinositol 3'-kinase. This intracellular crosstalk between discrete cytokine receptors reveals a novel pathway that leads to neuronal degeneration whereby a proinflammatory cytokine inhibits receptor signaling by a survival peptide.
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PMID:A new mechanism of neurodegeneration: a proinflammatory cytokine inhibits receptor signaling by a survival peptide. 1966 47

Neurological diseases during and following pregnancy represent a small subgroup of all neurological diseases. They can be divided into three groups. 1) Diseases which existed already before pregnancy or which appear just by chance during this phase like migraine, multiple sclerosis, myasthenia gravis, epilepsy, brain tumors or Guillain-Barre syndrome. 2) Diseases that can appear without pregnancy but which display a higher incidence in connection with pregnancy. Cerebral ischemia, intracerebral hemorrhage, subarachnoidal hemorrhage, intracranial venous thrombosis and compression neuropathies belong to this group. 3) Preeclampsia/eclampsia, HELLP syndrome, amniotic fluid embolism and pituitary apoplexy are diseases with neurological symptoms which occur only with pregnancy. The pregnancy itself can imply some restrictions or even a contraindication concerning diagnosis and therapy of these diseases. The decision in favour or against diagnostic or therapeutic approaches is determined by possible effects on the fetus and by potential danger resulting from not recognizing or not treating such a disease.
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PMID:[Neurologic diseases and pregnancy]. 1063 11

It has been hypothesized that increased expression of proinflammatory cytokines mediate a variety of central nervous system disorders such as multiple sclerosis, Alzheimer's disease, cerebral ischemia, spinal cord injury, HIV encephalopathy and chronic pain. In order to further examine the central role of TNF in neuropathic pain, transgenic mice were used in which expression of murine TNF was targeted to astrocytes using a glial fibrillary acidic protein (GFAP)-TNF fusion gene. Spinal nerve (L5) transection was performed in either the GFAP-TNF transgenic or wild type mice. Mechanical allodynia was significantly enhanced in the GFAP-TNF transgenic mice compared with the wild type mice. These data support a central role of glial expression of TNF in the generation of neuropathic pain.
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PMID:Transgenic expression of TNF by astrocytes increases mechanical allodynia in a mouse neuropathy model. 1071 21

Dexanabinol is a non-psychotropic cannabinoid NMDA receptor antagonist under development by Pharmos Corp for the potential treatment of cerebral ischemia, glaucoma, Alzheimer's disease, cardiac failure, head injury and multiple sclerosis (MS) [311522]; it is in phase III trials for traumatic brain injury (TBI) [388709]. Dexanabinol was licensed to Pharmos for development from its originator, the Hebrew University of Jerusalem [180441]. Pharmos is seeking to enter into a strategic agreement with another company to develop and commercialize dexanabinol [317369]. Unlike its enantiomer, HU-210 (Yissum Research Development Co), dexanabinol does not interact with cannabinoid receptors [223330]. It has also exhibited more effective antioxidant and anti-inflammatory properties than MK-801 (dizocilpine; Merck & Co Inc) [167980], [168212]. In addition, dexanabinol is generally well tolerated and appears toxicologically safe [170116]. Pharmos has been awarded a Small Business Innovation Research grant from the National Institutes of Health (NIH) National Institute of Neurological Disorders and Stroke, Division of Stroke and Trauma. The grant covers the development of new prodrugs and novel formulations of dexanabinol and will support additional study of dexanabinol compounds for various indications. The prodrugs being studied are part of the group of compounds that include dexanabinol [247958]. A Notice of Allowance was received in March 1999 on a patent covering the use of the drug in the treatment of MS [324163]. The use of dexanabinol and its derivatives to treat MS is described in US-05932610 [358503]. An oral formulation of dexanabinol is claimed in US-05891468. Dexanabinol analogs with special utility in acute and chronic pain are claimed in US-04876276, while dexanabinol analogs for neuroprotection are claimed in US-06096740. Pharmos estimates that the worldwide market for dexanabinol in the treatment of severe head trauma may reach $1 billion per year [319244].
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PMID:Dexanabinol Pharmos. 1124 4

Diffusion-weighted magnetic resonance imaging (DW-MRI) provides a unique form of MR contrast that enables the diffusional motion of water molecules to be quantitatively measured. As a consequence, DW-MRI provides information about the size, shape, integrity, and orientation of brain structures. Pathological processes able to alter tissue integrity by removing or modifying some of the structural barriers that normally restrict water molecular motion in biological tissues cause changes in water diffusion characteristics, which can be measured in-vivo using DW-MRI. Although DW-MRI has been shown to be of great clinical utility in the assessment of patients with cerebral ischemia, it is also increasingly being used to quantify in-vivo the extent and severity of multiple sclerosis (MS) pathology. The pathological elements of MS have the potential to alter the permeability or geometry of structural barriers to water molecular motion in the brain, optic nerve and spinal cord. The present review outlines the major contributions given by DW-MRI for the quantification of MS-related damage and for the understanding of MS pathophysiology.
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PMID:Overview of diffusion-weighted magnetic resonance studies in multiple sclerosis. 1133 88

Cannabinoid compounds are endowed with pharmacological properties that make them interesting candidates for therapeutic development. These properties have been known since antiquity. However, in the last decade extremely important advances in the understanding of the physiology, pharmacology, and molecular biology of the cannabinoid system have given this field of research fresh impetus and have renewed the interest in the possible clinical exploitation of these compounds. In the present review we summarize the effects elicited, at the cellular level, by cannabinoids acting through receptor-dependent and receptor-independent mechanisms. These data suggest different ways by which cannabinoids may act as neuroprotective agents (prevention of excitotoxicity by inhibition of glutamate release, antioxidant effects, anti-inflammatory actions, etc.). The experimental evidence supporting these hypotheses are presented and discussed with regard to both preclinical and clinical studies in disease states such as cerebral ischemia, brain trauma, and Multiple Sclerosis.
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PMID:Cannabinoids and neuroprotection. 1183 53


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