Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002736 (amyotrophic lateral sclerosis)
 19,048 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Derangements in glutamate neurotransmission have been implicated in several neurodegenerative disorders including, stroke, epilepsy, Huntington's disease, Alzheimer's disease, and amyotrophic lateral sclerosis (ALS). Activation of the N-methyl-D-aspartate (NMDA) receptor subtype of glutamate receptors results in the influx of calcium which binds calmodulin and activates neuronal nitric oxide synthase (nNOS), to convent L-arginine to citrulline and nitric oxide (NO). NO has many roles in the central nervous system as a messenger molecule, however, when generated in excess NO can be neurotoxic. Excess NO is in part responsible for glutamate neurotoxicity in primary neuronal cell culture and in animal models of stroke. It is likely that most of the neurotoxic actions of NO are mediated by peroxynitrite (ONOO-), the reaction product from NO and superoxide anion. In pathologic conditions, peroxynitrite and oxygen free radicals can be generated in excess of a cell antioxidant capacity resulting in severe damage to cellular constituents including proteins, DNA and lipids. The inherent biochemical and physiological characteristics of the brain, including high lipid concentrations and energy requirements, make it particularly susceptible to free radical and oxidant mediated insult. Increasing evidence indicates that many neurologic disorders may have components of free radical and oxidative stress induced injury.
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PMID:Nitric oxide neurotoxicity. 881 21

The elevation of taurine level in the central nervous system of patients with amyotrophic lateral sclerosis (ALS) indicates the presence of derangement in sulfur amino acid metabolism in this disease. In the metabolic pathway from methionine to taurine and in its branch pathways, excitatory sulfur amino acids are formed. These are cysteine (Cys), cysteine sulfinic acid (CSA), cysteic acid (CA), homocysteine sulfinic acid (HCSA), homocysteic acid (HCA) and S-sulfo cysteine (SC). This study was undertaken to investigate whether these excitatory sulfur amino acids have any cytotoxicity, since excitotoxicity has recently been implicated in the pathogenesis of ALS. Primary cultures of cerebral neurons were prepared from fetal rats, using an established method. Neuronal cell injury was assessed by examination of cultures with phase-contrast microscopy and with bright-field examination of trypan blue staining, a dye staining non-viable cells. The morphological estimate of cell injury was confirmed by the measurement of the activity of lactate dehydrogenase, released from damaged or destroyed cells, in the extracellular fluid. This convenient and quantitative index invariably correlated with the morphological estimates. Among the 6 sulfur amino acids, CSA and HCSA showed cytotoxicity, while Cys, CA, HCA and SC did not. K0.5 of CSA was 80 microM, and that of HCSA was 300 microM. The cytotoxicity of CSA was stronger than that of glutamate, K0.5 of which was 100 microM. Relevance of these excitotoxic sulfur amino acids, especially CSA to the pathogenesis of ALS has not been studied. This possibility will be a subject for future study.
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PMID:[Cytotoxicity of excitatory sulfur amino acids in primary cultured rat cerebral neurons]. 882 91

The distribution of the different glutamate receptor subunits in human spinal cord has yet to be fully elucidated. The aim of this study was to examine the distribution of the N-methyl-D-aspartate (NMDA) glutamate receptor modulatory subunit NR2A, in control human spinal cord and to examine in parallel the expression of the mRNA in amyotrophic lateral sclerosis (ALS). The aetiology of ALS is poorly understood, although abnormalities in glutamate and glycine transport have been reported as well as alterations in NMDA receptors including the NR1 subunit; suggesting a role for glutamate in the disease process. We have used the technique of in situ hybridisation to localise this receptor subunit to the laminae of human spinal cord and have found that it shows a widespread distribution similar to that previously reported for the universal NMDA receptor subunit NR1. Quantitation of mRNA expression in control and ALS cases showed a significant widespread loss of NR2A from both dorsal and ventral horns with losses of 55% and 78%, respectively, in ALS as compared to control. These results were substantiated by analysis of spinal cord homogenates, which showed a significant total decrease of 50% in ALS spinal cord as compared to control.
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PMID:Distribution of the N-methyl-D-aspartate glutamate receptor subunit NR2A in control and amyotrophic lateral sclerosis spinal cord. 884 5

Glutamate is the major mediator of fast excitatory neurotransmission in the mammalian central nervous system. Disturbances of this neurotransmitter system have been implicated in chronic degenerative neurological disease. Recently, major advances in our knowledge and understanding of the molecular biology of the glutamatergic receptor system have been made. It is now known that functional glutamate receptors consist of various combinations of some 20 identified subunits. A growing body of circumstantial evidence suggests that the non-N-methyl-D-aspartate subtype of glutamate receptors may mediate, at least in part, the selective motor neuron death seen in the human neurodegenerative disease amyotrophic lateral sclerosis. We have used subunit specific immunocytochemistry to study the distribution and potential subunit composition of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) selective glutamate receptors, (a subgroup of non-N-methyl-D-aspartate selective glutamate receptors formed by combinations of GluR1-4 subunits), in the human motor system. Motor neurons in the spinal cord, brainstem, and motor cortex were relatively strongly immunoreactive with the GluR2/3 subunit antibody, moderately so with the GluR4 subunit antibody, and showed relatively low levels of immunoreactivity with the GluR1 subunit antibody. This is the first detailed study of AMPA receptor subunit expression in the human motor system. Motor neurons express a distinct subunit profile when compared with other groups of neurons in the human nervous system. There were no significant differences in the pattern of relative AMPA subunit expression (GluR2/3 > or = GluR4 > GluR1) between groups of motor neurons typically affected (in the spinal cord and hypoglossal nucleus), or spared (oculomotor and Onufs nucleus) by the amyotrophic lateral sclerosis disease process. However, oculomotor motor neurons had higher levels of expression of all AMPA subunit proteins which may indicate greater AMPA mediated glutamatergic input in the normal function of this neuronal population. This study does not support a role for differential subunit composition of AMPA receptors in determining the selective vulnerability of motor neurons in amyotrophic lateral sclerosis. However, the overall density of receptors may be of importance.
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PMID:An immunocytochemical study of the distribution of AMPA selective glutamate receptor subunits in the normal human motor system. 884 86

Abnormally high postabsorptive venous plasma glutamate levels have been reported for several diseases that are associated with a loss of body cell mass including cancer, human/simian immunodeficiency virus infection, and amyotrophic lateral sclerosis. Studies on exchange rates in well-nourished cancer patients now show that high venous plasma glutamate levels may serve as a bona fide indicator for a decreased uptake of glutamate by the peripheral muscle tissue in the postabsorptive period and may be indicative for a precachectic state. High glutamate levels are also moderately correlated with a decreased uptake of glucose and ketone bodies. Relatively high venous glutamate levels have also been found in non-insulin-dependent diabetes mellitus and to some extent also in the cubital vein of normal elderly subjects, i.e., in conditions commonly associated with a decreased glucose tolerance and progressive loss of body cell mass.
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PMID:Elevated venous glutamate levels in (pre)catabolic conditions result at least partly from a decreased glutamate transport activity. 886 15

Amyotrophic lateral sclerosis (ALS) is a severe neurological disorder clinically characterized by progressive muscle weakness, amyotrophy, fasciculations and signs of corticospinal tract deficits. The cause is unknown but several hypotheses are currently proposed. In familial forms of ALS, a mutation of the Cu-Zn superoxide dismutase gene was reported in some patients. Autoimmunity and neurofilament dysfunction were also observed. The last hypothesis is linked to excitotoxicity. This cellular phenomenon is associated with the overstimulation of glutamate post-synaptic receptors, leading to neuronal degeneration. Abnormal glutamate metabolism was also discovered in ALS patients. In these conditions, riluzole, a pharmacological agent that reduces glutamate release from nerve terminals, was administered to ALS patients. Riluzole is an anti-convulsant and a neuroprotective agent and specifically blocks sodium channels in their inactivated states. In a recent double blind placebo controlled study, riluzole was given to 77 patients (placebo 78 patients). After 1 year of treatment 58% of the placebo-treated patients were still alive compared to 74% of patients treated with riluzole. The prolonged survival was significant in the overall population and in the bulbar-onset group.
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PMID:Riluzole and ALS therapy. 887 31

To study the mechanisms by which glutamate-elicited acetylcholinesterase release (GEAR) might play a part in the pathogenesis of excitotoxically triggered motor neurone disease, and to investigate the interaction of GEAR with spinal glycinergic mechanisms, we measured acetylcholinesterase (AChE) and cholinergic markers, after stimulating ventral horn slices and synaptosomes from the mouse spinal cord, with both glutamate- and glycine-receptor agonists. Glutamate (GLU), kainate and AMPA, as well as glycine (GLY) evoked dose-related, calcium-dependent liberation of soluble forms of AChE from both slices and synaptosomes. GLY-evoked AChE release showed remarkable age-related postnatal changes. In the immature slice of the ventral horn. GLY potentiated the GEAR response in the presence of strychnine, suggesting N-methyl-D-aspartate (NMDA) receptor involvement, and was also able to evoke a strychnine-sensitive AChE release in the absence of exogenous GLU. After the 28th postnatal day, nearly all the AChE secreted was released either after the activation of non-NMDA glutamate receptors or by strychnine-sensitive GLY-evoked AChE release mechanisms. Both GEAR and GLY-evoked AChE release might impair the negative feedback loop which modulates the overactivation of motor neurones, and cause prolonged extracellular rises of soluble AChE. These effects might augment the vulnerability of motor neurones to excitotoxic stress, promote fiber outgrowth, and eventually accelerate the metabolic exhaustion of lower motor neurones. It is possible that the mechanisms described are operative at the spinal cord of ALS/MND patients.
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PMID:Glycine effects on glutamate-receptor elicited acetylcholinesterase release from slices and synaptosomes of the spinal ventral horn. 889 63

Magnetic resonance spectroscopy (MRS) has provided a novel means of studying the brain biochemistry of motor neurone disease/amyotrophic lateral sclerosis (MND/ALS) patients in vivo in situ. Previous studies have demonstrated changes in the ratios of areas under specific spectral peaks in MND/ALS patients (Jones et al., 1995). However, the significance of such findings cannot be fully elucidated without first ascertaining the biochemical identity of each peak. Each peak in a MRS spectrum corresponds to the resonance of specific protons in a particular chemical environment. Many biochemicals contain similar protons in similar environments so it is possible that a single spectral peak could represent protons from more than one biochemical. In this study of major brain MRS peaks we have demonstrated that peaks are potentially composed of a number of protons from different chemicals. For example, the peak at chemical shift 2.01 ppm, conventionally recognised as the neurotransmitter N-acetyl aspartate, may actually be a result of the protons of the N-acetyl moiety (Frahm et al., 1991). We have consequently shown that other N-acetylated compounds such as N-acetyl glutamate are also capable of producing a peak here, whereas their non-acetylated derivatives are not. We have also shown GABA is capable of producing a peak at chemical shift 3.00 ppm, a peak which is generally assigned to creatine/phosphocreatine. These findings have important implications in the identification of spectral peaks in MRS studies and in the interpretation of spectral differences between MND patients and controls.
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PMID:Identification of brain metabolites by magnetic resonance spectroscopy in MND/ALS. 889 68

Previous studies have suggested that defective high-affinity glutamate uptake, due mainly to a major loss of the astroglial-specific GLT-1 glutamate transporter, underlies the selective motoneuron degeneration observed in sporadic ALS (24, 28). If a defect in glutamate transport underlies the pathogenesis of sporadic ALS, the glutamate transporter subtype found to be lost in sporadic ALS should be present in abundance in the affected motor nuclei under normal conditions. To investigate this, we used immunohistochemical methods to analyze the localization of two subtypes of high-affinity glutamate transporters in the cranial motor nuclei of normal monkey brain stem: GLT-1, localized to astroglia; and EAAC1, localized to neurons. Our results indicated that all motor cell groups of monkey brain stem are rich in the GLT-1 glutamate transporter, which is localized to astroglial cells and processes that surround and envelop motoneuron cell bodies and dendrites. Image analysis indicated that the abundance of GLT-1 immunoreactive astroglial elements in ALS-vulnerable motor cell groups (i.e., the trigeminal, facial, and hypoglossal motor cell groups) is higher than in ALS-resistant motor cell groups (i.e., the oculomotor, trochlear, and abducens motor cell groups), and statistical analysis showed that this difference is significant. Our results also indicated that both ALS-vulnerable and ALS-resistant motor cell groups of monkey brain stem are relatively poor in EAAC1 immunoreactivity. Therefore, in the case of a loss in the GLT-1 glutamate transporter in sporadic ALS, glutamate may increase in the vicinity of motoneurons in all brain-stem motor cell groups, but especially in the ALS-vulnerable motor cell groups, which are normally richer in GLT-1. Increased extracellular glutamate could lead to excess entry of Ca2+ into motoneurons via glutamate-gated or voltage-activated Ca2+ channels and produce degeneration of those motoneurons unable to resist the insult. Since motoneurons in the ALS-resistant motor cell groups of the brain stem are enriched in the Ca2+ buffering protein parvalbumin, they should be better able to resist the damage than the majority of motoneurons in the ALS-vulnerable motor cell groups, which lack parvalbumin (20).
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PMID:Differential abundance of glutamate transporter subtypes in amyotrophic lateral sclerosis (ALS)-vulnerable versus ALS-resistant brain stem motor cell groups. 893 60

The cause of ALS is not known but there are four main hypotheses about its etiology. First, an excess of extracellular glutamate in the CNS of patients with ALS resulting from a defect in glutamate reuptake may have excitotoxic effects on motor neurons. Clinical trials suggest the antiglutamate agent riluzole improves survival of patients with the disease. Second, ALS may be an autoimmune disease, but immunologically-based treatments have been unsuccessful. The third hypothesis is that ALS results from a lack of neurotrophic growth factors. Preliminary results from clinical trials indicate recombinant human insulin-like growth factor I offers therapeutic promise. Finally, familial ALS is sometimes linked to a gene encoding a Cu/Zn-binding superoxide dismutase; the mutations in ALS are thought to result in gain of function of dismutase activity. The involvement of superoxide dismutase in sporadic ALS is unclear.
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PMID:ALS. 895 92


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