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)

Recent studies provided evidence for a generalized defect in glutamate metabolism in patients with amyotrophic lateral sclerosis, associated with widespread alterations in the central nervous system levels of this excitatory amino acid putative transmitter. Present data support the hypothesis that altered presynaptic glutamatergic mechanisms may be responsible for a neuroexcitotoxic cell loss in this disorder. High local concentrations of glycine, released from glycinergic terminals, may disrupt adaptive processes contributing to abnormal potentiation of excitatory transmission mediated by glutamate receptors and resultant selective degeneration of motor neurons. These considerations offer new therapeutic strategies for amyotrophic lateral sclerosis.
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PMID:Glutamate dysfunction and selective motor neuron degeneration in amyotrophic lateral sclerosis: a hypothesis. 237 40

Amino acids such as L-glutamate und L-aspartate are major excitatory neurotransmitters in the mammalian central nervous system (CNS) and potential neurotoxins (excitotoxins), which can destroy central neurons by excessive activation of respective receptors. In the last three decades evidence has accumulated that excitatory amino acids (EAA) are involved in many neurological diseases and that pharmacological intervention offers prospects of novel and more effective therapies. Three different receptor types for EAA have been identified, each being named by the selective agonist to which it is preferentially sensitive, i.e. N-methyl-D-aspartate- (NMDA), kainate- and quisqualate-receptors. In this review interest is focused primarily on the NMDA-receptor, whose structure has been subject of numerous electrophysiological and biochemical studies. Today, it is well established that the NMDA-receptor-ionophore complex has an agonist binding site for glutamate, NMDA and related EAAs which is coupled with an ion channel permeable to Na+, K+, Cl- and Ca2+. Four other binding sites for glycine, phencyclidine, Mg2+ and Zn2+ have been identified which can differentially modulate the function of the NMDA receptor. An additional polyamine binding site has recently been reported. Numerous studies on experimental animals demonstrate that modulators of NMDA-mediated neurotransmission may have antiepileptic, anxiolytic, muscle-relaxant and memory-enhancing effects. Particular interest has gained the possible neuroprotective efficacy of NMDA-receptor antagonists in neurological diseases such as hypoxia/ischemia, hypoglycemia, epilepsy and chronic neurodegenerative disorders (Huntington's, Alzheimer's and Parkinson's disease, amyotrophic lateral sclerosis, and AIDS encephalopathy).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[The N-methyl-D-aspartate receptor complex. Various sites of regulation and clinical consequences]. 197 26

Amino acid contents were measured in autopsied brains of five Guamanian patients with amyotrophic lateral sclerosis (ALS) or parkinsonism-dementia. Absence of the glutamate deficiency and taurine excess characteristic of sporadic ALS suggest that, despite clinical similarities, Guamanian ALS is a different disorder from sporadic ALS.
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PMID:Brain amino acid contents are dissimilar in sporadic and Guamanian amyotrophic lateral sclerosis. 225 Jan 69

Concentrations of glutamic acid have been reported to be elevated in fasting plasma and cerebrospinal fluid (CSF) of patients with amyotrophic lateral sclerosis (ALS); glycine concentrations have also been reported to be increased in the CSF of such patients. Autopsy studies have shown glutamate contents to be significantly decreased in brain and spinal cord in ALS. These observations suggested that a systemic abnormality of glutamate metabolism might underlie the pathogenesis of ALS. We report here the findings of our studies of amino acid concentrations in patients with the sporadic form of ALS. Glutamate concentrations were normal in the fasting plasma of a great majority of the patients with ALS. Concentrations of glutamate, aspartate, and glycine were normal in the CSF of all 17 patients examined. beta-N-Methylamino-L-alanine, a plant neurotoxin possibly responsible for causing the Guamanian form of ALS, was not detectable in the plasma or CSF of any of our patients. Our findings do not lend support to the hypothesis that the sporadic form of ALS results from overexcitation of motor neurons by excitatory amino acids.
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PMID:Amyotrophic lateral sclerosis: amino acid levels in plasma and cerebrospinal fluid. 237 40

Recently, the excitatory amino acid neurotransmitter glutamate was implicated in the pathogenesis of a variety of chronic degenerative neurological diseases in humans and animals. This report describes abnormalities in excitatory amino acids in the central nervous system of 18 patients with amyotrophic lateral sclerosis (ALS). The concentration of the excitatory amino acids glutamate and aspartate in the cerebrospinal fluid were increased significantly (p less than 0.01) by 100 to 200% in patients with ALS. Similarly, the concentrations of the excitatory neuropeptide N-acetyl-aspartyl glutamate and its metabolite, N-acetyl-aspartate, were elevated twofold to threefold in the cerebrospinal fluid from the patients. There was no relationship between amino acid concentrations and duration of disease, clinical impairment, or patient age. In the ventral horns of the cervical region of the spinal cord, the level of N-acetyl-aspartyl glutamate and N-acetyl-aspartate was decreased by 60% (p less than 0.05) and 40% (p less than 0.05), respectively, in 8 patients with ALS. Choline acetyltransferase activity was also diminished by 35% in the ventral horn consistent with motor neuron loss. We conclude that excitatory amino acid metabolism is altered in patients with ALS. Based on neurodegenerative disease models, these changes may play a role in motor neuron loss in ALS.
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PMID:Abnormal excitatory amino acid metabolism in amyotrophic lateral sclerosis. 237 40

beta-N-methylamino-L-alanine (BMAA) is a neurotoxic glutamate agonist possibly responsible for the neuronal degeneration found in the Guam amyotrophic lateral sclerosis-Parkinsonism-dementia complex. The basis for glutamate receptor activation by BMAA has been unclear, as BMAA lacks the omega electronegative moiety characteristic of other excitatory amino acids. We recently reported that the neuroexcitatory and neurotoxic effects of BMAA depend strongly on the presence of bicarbonate ions and proposed that an interaction between bicarbonate and the beta amino group of BMAA produces a molecular configuration appropriate for activating glutamate receptors. We now report that bicarbonate potentiates the ability of BMAA to open NMDA receptor-activated channels in isolated membrane patches. Furthermore, the neurotoxic and neuroexcitatory effects of two structural analogs of BMAA, DL-2,4-diaminobutyrate and DL-2,3-diaminopropionate, were also potentiated by bicarbonate. These findings support the bicarbonate cofactor hypothesis for BMAA action and provide direct evidence that it may be generalizable to certain other compounds.
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PMID:Bicarbonate dependence of glutamate receptor activation by beta-N-methylamino-L-alanine: channel recording and study with related compounds. 256 69

Repeated dietary consumption of the neurotoxic amino acid beta-N-methylamino-L-alanine (BMAA), found in the seeds of Cycas circinalis, has been postulated as causing both amyotrophic lateral sclerosis (ALS) and the parkinsonism-dementia syndrome (PD) that were formerly very prevalent among the indigenous people of the Marianas Islands. Cynomolgus monkeys fed BMAA have been reported to develop behavioral and neuropathological changes like those found in human ALS. We gave large amounts of BMAA, totaling 15.5 g/kg of the L-isomer, by gavage to mice over 11 weeks without observing any behavioral abnormalities. When killed, these animals showed none of the neurochemical or neuropathological changes that would be expected in ALS or Parkinson's disease. Their striatal dopamine contents were normal, and there were no reductions in the contents of glutamate and aspartate in cerebral cortex like those encountered in sporadic human ALS. The results of this experiment do not support chronic ingestion of BMAA as the causative factor for Guamanian ALS or PD.
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PMID:Beta-N-methylamino-L-alanine. Chronic oral administration is not neurotoxic to mice. 261 65

Thirty-two patients affected by amyotrophic lateral sclerosis (ALS) were included in a controlled, open therapeutic trial with branched chain amino acids (BCAA). Patients with bulbar muscle involvement were evaluated separately. No statistically significant differences were found in the clinical outcome between the patients treated and the control groups. Blood L-glutamate levels measured in eight patients were normal. The failure of BCAA in the treatment of the patients could be due to different disorders with unpredictable outcome included under the diagnosis of ALS.
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PMID:Branched-chain amino acids in the treatment of amyotrophic lateral sclerosis. 261 87

Amino acid contents were measured in autopsied brains of eight patients with the sporadic form of amyotrophic lateral sclerosis (ALS) and in brains of control subjects dying without neurologic or psychiatric disease. Glutamic acid content was reduced in most brain regions and in the cervical cord in the ALS patients, while glutamine contents were normal. Taurine contents were increased, and gamma-aminobutyric acid contents were decreased in some brain regions in the ALS patients. The brain glutamate deficiency in ALS is unexplained, but insufficient production or release of this excitatory neurotransmitter might have important secondary effects on motor neurons.
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PMID:Brain glutamate deficiency in amyotrophic lateral sclerosis. 289 Oct 83

Glutamate levels were determined in the fasting plasma of 22 patients with early-stage primary amyotrophic lateral sclerosis (ALS) and compared to those of healthy and diseased controls. There was a significant increase (by approximately 100%, p less than 0.0005) in the plasma glutamate of the ALS patients as compared with the controls. Oral glutamate loading (60 mg of monosodium glutamate per kilogram of body weight, taken orally after overnight fasting) resulted in significantly greater elevations in the plasma glutamate and aspartate levels in the ALS patients than in the controls. Glutamate, a potentially neuroexcitotoxic compound, is thought to be the transmitter of the corticospinal tracts and certain spinal cord interneurons. A systemic defect in the metabolism of this amino acid may underlie primary ALS.
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PMID:Abnormal glutamate metabolism in amyotrophic lateral sclerosis. 289 63


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