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)

It has been suggested that the degeneration of motor neurons in amyotrophic lateral sclerosis is a consequence of excitotoxicity resulting from a loss of synaptosomal glutamate uptake. The role of synaptosomal glutamate uptake in the pathogenesis of motor neuron disease was studied in the Mnd mouse. Glutamate uptake in spinal-cord synaptosomes declined in parallel with the onset of behavioral deficits in Mnd mice but lagged considerably behind the appearance of pathology in motor neurons. Glutamate uptake did not decline significantly in corpus striatum, and GABA uptake did not change significantly in either spinal cord or striatum. The presence of pronounced histopathological changes before the loss of glutamate uptake suggests that the decline of glutamate uptake is a consequence rather than the primary cause of motor neuron disease in the Mnd mouse.
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PMID:Synaptosomal glutamate uptake declines progressively in the spinal cord of a mutant mouse with motor neuron disease. 809 77

Motor evoked potentials (MEPs) were recorded from selected non-wasted, non-denervated hand muscles in 40 patients with Amyotrophic Lateral Sclerosis (ALS) with both upper and lower motor neuron signs. In most the compound muscle action potential (CMAP) of the target muscle was normal. Compared to the control group, cortical threshold in ALS varied considerably and there was a significant (r2 = 0.702) inverse, exponential, correlation between cortical threshold and MEP/CMAP ratio. There was a linear correlation between threshold and disease duration (r2 = 0.66) so that early in the disease threshold was normal and later the motor cortex could not be stimulated. It is suggested that early in ALS normal threshold reflects glutamate-induced hyper-excitability of the corticomotoneuron. The findings lend support to the hypothesis that ALS is primarily a disease of the corticomotoneuron.
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PMID:Cortical excitability in amyotrophic lateral sclerosis: a clue to pathogenesis. 809 92

Hereditary canine spinal muscular atrophy (HCSMA) is a lower motor neuron disease found in Brittany Spaniels that shares clinical and pathological features with human amyotrophic lateral sclerosis (ALS). Since acidic excitatory amino acids and the neuropeptide N-acetyl-aspartyl-glutamate (NAAG) are reduced in spinal cord and cerebral cortex in ALS, the levels of these substances were measured in nervous tissue in Brittany Spaniels heterozygous and homozygous for HCSMA. Significant reductions in the levels of endogenous aspartate, glutamate, N-acetylaspartate (NAA), and NAAG were found in the spinal cord in homozygous but not heterozygous HCSMA. In contrast, the activity of N-acetylated-alpha-linked-amino dipeptidase (NAALADase), an enzyme that cleaves NAAG into NAA and Glu, was significantly increased. None of these parameters was affected in the motor cortex or occipital cortex. Since NAA and NAAG are highly concentrated in motoneurons, they may play a role in the pathogenesis of motor neuron disease.
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PMID:Abnormal acidic amino acids and N-acetylaspartylglutamate in hereditary canine motoneuron disease. 811 34

The cortical silent period (C-SP) was elicited by transcranial magnetic stimulation in 25 normal subjects and 19 patients with amyotrophic lateral sclerosis (ALS). The inhibitory (S-X) period was highly stimulus intensity (SI)-dependent (mean r2 = 0.89 for both normals and patients with ALS). The range of the C-SP (difference between maximum and minimum S-X intervals) was age-dependent for normals (r2 = 0.701, P < 0.001) but not patients with ALS. Means, maximums and ranges for the C-SP were not significantly different between normal and ALS groups and thresholds to cortical stimulation were also comparable. There was a significant, linear, relation between the maximum C-SP and disease duration of ALS (P = 0.002). The maximum C-SP was shorter early in the disease. It is hypothesized that the reduced inhibition early in the course of ALS might reflect glutamate-induced corticomotoneuronal excitotoxicity.
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PMID:The cortical silent period and amyotrophic lateral sclerosis. 811 92

Data from the literature about plasma and CSF amino acid (AA) levels in amyotrophic lateral sclerosis (ALS) remain controversial. To refine such analyses we used HPLC, and report a study of plasma and CSF AA concentrations in patients with ALS, the type of the disease (spinal and bulbar onset) being precisely determined. In ALS, there is a decrease in the plasma levels of the large neutral amino acids (LNAA) alanine, isoleucine, leucine, methionine and tyrosine which was particularly striking in the bulbar type (p < 0.05). Plasma glutamate levels do not differ between ALS and controls, but are significantly increased in ALS with spinal onset and decreased in the bulbar type (p < 0.05 vs controls, p < 0.001 bulbar vs spinal). In CSF, the analysis of the whole ALS group shows no difference from controls. However, there is an increase of CSF serine, glutamine and alanine in ALS with spinal onset (p < 0.05). Our results do not support an abnormal profile of excitatory AA concentrations in ALS. The heterogeneous changes we observed, mainly concerning LNAAs, may be explained by a blood-CSF barrier disturbance in the disease. As AA levels clearly differ between ALS types, with low concentrations in bulbar ALS, this dual profile probably explains some of the discrepancies between previous studies.
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PMID:Fasting plasma and CSF amino acid levels in amyotrophic lateral sclerosis: a subtype analysis. 808 43

Defects in neurotransmitter glutamate transport may be an important component of chronic neurotoxicity in diseases such as amyotrophic lateral sclerosis. There are no reliable models of slow glutamate neurotoxicity. Most previous in vitro systems have studied the rapid neurotoxic effects of direct-acting glutamate agonists. Therefore, we developed a model of slow toxicity in cultured organotypic spinal cord slices. The model was based on selective inhibition of glutamate transport, which continuously raised the concentration of glutamate in the culture medium. This resulted in the slow degeneration of motor neurons over several weeks. Motor neuron toxicity was selectively prevented by non-N-methyl-D-aspartate glutamate receptor antagonists and glutamate synthesis or release inhibitors but not by N-methyl-D-aspartate receptor antagonists. Thus, selective inhibition of glutamate transport produces a model of clinically relevant slow neurotoxicity and appears to be mediated by the action of non-N-methyl-D-aspartate receptors. This data supports the hypothesis that the slow loss of motor neurons in amyotrophic lateral sclerosis could be due, in part, to defective glutamate transport.
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PMID:Chronic inhibition of glutamate uptake produces a model of slow neurotoxicity. 839 71

Genomic clones of the human non-N-methyl-D-aspartate (non-NMDA) glutamate receptor subunit GluR5 were isolated by high-stringency screening of a cosmid library using the rat cDNA as a probe. The chromosomal localization of the human GluR5 gene has been established. Southern hybridization of DNA isolated from mapping panels of Chinese hamster-human hybrid cell lines and high-resolution in situ suppression hybridization localize the GluR5 gene to chromosome 21q21.1-22.1. This coincides with the localization of a mutant gene causing familial amyotrophic lateral sclerosis (ALS), as Siddique et al. established by linkage analyses [Siddique, T., Figlewicz, D. A., Pericak-Vance, M. A., Haines, J. L., Rouleau, G., Jeffers, A. J., Sapp, P., Hung, W. Y., Bebout, J., McKenna-Yasek, D., Deng, G., Horvitz, H. R., Gusella, J. F., Brown, R. H. & Roses, A. D. (1991) N. Engl. J. Med. 324, 1381-1384]. Convergent evidence from other investigators suggests that chronic pathologic activation of motor neurons via non-NMDA glutamate receptors might induce excitotoxic injury of motor neurons, culminating in ALS. Together with the demonstration that GluR5 transcripts are expressed in the ventral horn of the spinal cord, the region in which susceptible motor neurons reside, the chromosomal localization suggests that a mutated GluR5 gene may be responsible for the familial form of ALS.
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PMID:The gene encoding the glutamate receptor subunit GluR5 is located on human chromosome 21q21.1-22.1 in the vicinity of the gene for familial amyotrophic lateral sclerosis. 841 20

Assuming the presence of glutamate-induced neurotoxicity in amyotrophic lateral sclerosis 14 patients were treated with dextromethorphan, an N-methyl-D-aspartate receptor antagonist. The patients were treated with 150 mg dextromethorphan or placebo daily for 12 weeks in a double-blind crossover trial, with a wash out period of 4 weeks between the two treatment periods. Thereafter the surviving patients were treated with 300 mg dextromethorphan daily for up to 6 months in an open trial. No positive effects on clinical or neurophysiological parameters (relative number of axons, and compound muscle action potentials in the abductor digiti minimi muscle) were observed either in the double-blind trial or in the open trial.
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PMID:A pilot trial of dextromethorphan in amyotrophic lateral sclerosis. 843 10

Since recent studies provided evidence for abnormal glutamate metabolism in amyotrophic lateral sclerosis, we measured amino acid levels in the fasting plasma of 52 ALS patients and an equal number of controls of a similar age. In addition, the content of amino acids, N-acetyl-aspartate (NAA) and N-acetyl-aspartyl-glutamate (NAAG) were measured in spinal cord and brain tissue obtained at autopsy from patients dying of ALS. Results showed significant elevations (by about 70%) in the plasma levels of glutamate in the ALS patients as compared to controls. In contrast, glutamate levels were significantly decreased in all CNS regions studied of ALS patients (by 21-40%), with the greatest changes occurring in the spinal cord. The ratio of glutamine to glutamate was altered significantly in the spinal cord ALS tissue. In addition, reductions in the levels of aspartate (by 32-35%), NAA, and NAAG (by 40-48%) were found in the spinal cord of ALS patients. These results are consistent with a generalized defect in the metabolism of neuroexcitotoxic amino acids. An altered distribution of these compounds may occur between their intracellular and extracellular pools with resultant abnormal potentiation of excitatory transmission mediated by glutamate receptors and selective degeneration of motor neurons.
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PMID:Altered metabolism of excitatory amino acids, N-acetyl-aspartate and N-acetyl-aspartyl-glutamate in amyotrophic lateral sclerosis. 845 87

Receptors for the major excitatory neurotransmitter glutamate may play key roles in neurodegeneration. The mouse Glur-5 gene maps to chromosome 16 between App and Sod-1. The homologous human GLUR5 gene maps to the corresponding region of human chromosome 21, which contains the locus for familial amyotrophic lateral sclerosis. This location, and other features, render GLUR5 a possible candidate gene for familial amyotrophic lateral sclerosis. In addition, dosage imbalance of GLUR5 may have a role in the trisomy 21 (Down syndrome). Further characterization of the murine glutamate receptor family includes mapping of Glur-1 to the same region as neurological mutants spasmodic, shaker-2, tipsy, and vibrator on chromosome 11; Glur-2 near spastic on chromosome 3; Glur-6 near waltzer and Jackson circler on chromosome 10; and Glur-7 near clasper on chromosome 4.
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PMID:Chromosomal localization of glutamate receptor genes: relationship to familial amyotrophic lateral sclerosis and other neurological disorders of mice and humans. 846 23


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