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

It is widely held that a glutamate-like toxin that resembles N-methyl-D-aspartate may be responsible for the death of nerve cells seen after severe neurological insults including stroke, seizures, and degenerative disorders, such as Huntington disease, Alzheimer disease, and the amyotrophic lateral sclerosis-parkinsonism-dementia complex found on Guam. One puzzling fact about these maladies is the differential vulnerability of specific groups of neurons peculiar to each condition. We report here that an identified population of central neurons, rat retinal ganglion cells, are resistant to the neurotoxic effects of millimolar concentrations of glutamate under otherwise normal culture conditions. Patch-clamp experiments show that this resistance is associated with a very small ionic current response to N-methyl-D-aspartate. Varying the ionic milieu by increasing the extracellular Ca2+ concentration, however, results in a striking increase in glutamate-induced cell death in this population. Under these conditions, Mg2+ or the amino acid antagonist MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo-(alpha,gamma)-cyclohepten-5 ,10-imine maleate], blockers of N-methyl-D-aspartate receptor-coupled ion channels, completely abrogate the lethal effects of glutamate. These findings strongly suggest that Ca2+ entry through N-methyl-D-aspartate-activated channels is responsible for this type of neuronal death and suggest strategies that may be clinically useful in the treatment of various neurological disorders.
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PMID:Central mammalian neurons normally resistant to glutamate toxicity are made sensitive by elevated extracellular Ca2+: toxicity is blocked by the N-methyl-D-aspartate antagonist MK-801. 290 Nov 1

Because recent studies showed a systemic defect in glutamate metabolism in amyotrophic lateral sclerosis (ALS), we measured the levels of free amino acids in frontal and cerebellar cortex and two areas of spinal cord obtained at autopsy from 22 patients who died of this disease. Glutamate levels were significantly decreased (by 21 to 40% of control values) in all areas investigated; cervical and lumbar spinal cord showed the greatest change. Aspartate levels were also significantly reduced (by 32 to 35%) in the spinal cord only. A positive correlation was shown between the changes of glutamate and aspartate as well as a significant alteration in the glutamate to glutamine ratio in the spinal cord of patients with ALS. Although we cannot exclude the possibility that these abnormalities may partly result from neuronal cell loss, the data suggest the presence of a generalized defect that may affect the neurotransmitter and metabolic pool of glutamate. The defect may be expressed more severely in the spinal cord than in other central nervous system areas. These results, taken together with the previously shown systemic abnormality, raise the possibility that distribution of glutamate between the intracellular and extracellular pool may be altered in ALS and may mediate the neurodegeneration.
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PMID:The neuroexcitotoxic amino acids glutamate and aspartate are altered in the spinal cord and brain in amyotrophic lateral sclerosis. 290 29

beta-N-Oxalylamino-L-alanine (BOAA) and beta-N-methylamino-L-alanine (BMAA) are chemically related excitant amino acids isolated from the seed of Lathyrus sativus (BOAA) and Cycas circinalis (BMAA), consumption of which has been linked to lathyrism (an upper motor neuron disorder) and Guam amyotrophic lateral sclerosis (ALS), respectively. Both diseases are associated with degeneration of motor neurons. Experimentally, single doses of BOAA or BMAA induce seizures in neonatal mice and postsynaptic neuronal oedema and degeneration in explants of mouse spinal cord and frontal cortex. Preliminary studies show that these behavioural and pathological effects are differentially blocked by glutamate-receptor antagonists. In macaques, several weeks of daily oral doses of BOAA produce clinical and electrophysiological signs of corticospinal dysfunction identical to those seen in comparably well-nourished animals receiving a fortified diet based on seed of Lathyrus sativus. By contrast, comparable oral dosing with BMAA precipitates tremor and weakness, bradykinesia and behavioural changes, with conduction deficits in the principal motor pathway. BOAA and BMAA (or a metabolite thereof) are the first members of the excitotoxin family to have been shown to possess chronic motor-system toxic potential. These observations provide a rational basis for searching for comparable endogenous neurotoxins in sporadic and inherited forms of human motor neuron disease.
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PMID:Discovery and partial characterization of primate motor-system toxins. 310 39

Beta-N-Methylamino-L-alanine (BMAA) and beta-N-oxalylamino-L-alanine (BOAA) are chemically related excitant amino acids present in the seeds of Cycas circinalis and Lathyrus sativus, respectively. Consumption of these seeds has been linked to Guam amyotrophic lateral sclerosis (BMAA) and lathyrism (BOAA) (a form of primary lateral sclerosis). We report that the acute neuronotoxic actions of these amino acids are blocked selectively by specific glutamate receptor antagonists. Administration of BOAA and BMAA to neonatal mouse cortex explants (EC100 = 28 microM and 1.6 mM, respectively) rapidly induces postsynaptic vacuolation (PSV) and neuronal degeneration characterized by dark/shrunken (D/S) cells. BOAA-mediated neuronotoxic effects are attenuated in a concentration-dependent manner by cis-2,3-piperidine dicarboxylic acid (PDA), an antagonist of quisqualate (QA)-preferring and kainate (KA)-preferring glutamate receptors. PDA maximally protected against BOAA-induced PSV by 84% at 1 mM and D/S cells by 80% at 0.5 mM. BMAA-induced cellular changes were antagonized selectively in a concentration-dependent manner by 2-amino-7-phosphono-heptanoic acid (AP7), an N-methyl-D-aspartate (NMDA) glutamate-receptor antagonist. AP7 maximally protected against BMAA-induced PSV and D/S by 88% at 1.0 and 0.5 mM, respectively. These protective actions were selective and specific since AP7 failed to attenuate BOAA-induced alterations, and PDA was ineffective in ameliorating BMAA-induced changes. Other glutamate receptor antagonists (glutamic diethyl ester and streptomycin) failed to protect the explants from the destructive action of either toxin. Taken collectively, our data indicate that the acute neuronotoxic actions of BOAA and BMAA (or a metabolite) operate through different glutamate receptor species.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Specific antagonism of excitotoxic action of 'uncommon' amino acids assayed in organotypic mouse cortical cultures. 312 8

Ingestion of the excitotoxic cycad seed amino acid beta-N-methylamino-L-alanine may be responsible for the neuronal degeneration associated with Guam amyotrophic lateral sclerosis-parkinsonism-dementia in man. However, the basis for the central neurotoxicity of beta-N-methylamino-L-alanine has been unclear, as it lacks the omega acidic (or equivalent electronegative) moiety characteristic of other excitatory amino acids. beta-N-methylamino-L-alanine produced neurotoxic and neuroexcitatory effects in murine cortical cell cultures only when physiological concentrations of bicarbonate were available in the extracellular bathing medium. Bicarbonate may interact noncovalently with beta-N-methylamino-L-alanine to produce, in combination, a molecular configuration that activates glutamate receptors.
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PMID:Beta-N-methylamino-L-alanine neurotoxicity: requirement for bicarbonate as a cofactor. 313 49

Beta-N-methylamino-L-alanine (BMAA) and beta-N-oxalylamino-L-alanine (BOAA) are chemically related amino acids present in the seeds of Cycas circinalis and Lathyrus sativus, respectively. Consumption of these seeds has been linked to Guam amyotrophic lateral sclerosis (BMAA) and lathyrism (BOAA; a form of primary lateral sclerosis). A single large dose of BOAA or BMAA causes seizures in newborn mice and postsynaptic neuronal edema and degeneration in CNS explants. We report that the acute neurotoxic actions of these amino acids are blocked selectively by specific glutamate-receptor antagonists (administered intracerebroventricularly) (i.c.v.) prior to the amino acid. Administration of BOAA i.c.v. to neonatal mice (ED100 = 50 micrograms) elicits a spectrum of time-dependent behavioral states including arm and leg rigidity, convulsions, and resting tremor. These are blocked in a dose-dependent manner by cis-2,3-piperidine dicarboxylic acid (PDA), an antagonist of quisqualate (QA)-preferring (A2) and kainate (KA)-preferring (A3) glutamate receptors (ED50s; 2.8 micrograms, rigidity; 1.4 micrograms, convulsions; 2.4 micrograms, resting tremor). BMAA induces a transitory hyperexcitable state followed by a long-lasting whole-body shake/wobble (ED100 = 1,000 micrograms, i.c.v.). These responses are antagonized selectively and dose-dependently by 2-amino-7-phosphonoheptanoic acid (AP7), an N-methyl-D-aspartate (NMDA) or A1 glutamate-receptor antagonist (ED50 = 0.45 microgram). Taken collectively, our data indicate that the acute neuronotoxic actions of BOAA and BMAA (or a metabolite) operate through different glutamate-receptor species. BMAA likely exerts most of its action indirectly via the A1 glutamate receptor, while BOAA acts principally at the A2 and/or A3 receptor.
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PMID:Specific antagonism of behavioral action of "uncommon" amino acids linked to motor-system diseases. 314 80

We investigated glutamate receptor-mediated neurotoxicity in vivo by means of infusing three specific agonists for non-NMDA receptors (acromelic acid A (ACRO), kainic acid and 1-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)) into the adult rat spinal subarachnoid space. ACRO induced long-lasting pure motor, rigid-spastic paraparesis in a dose-dependent manner (EC50: 220 pmol/h) that was accompanied by selective degeneration of spinal interneurons; leaving large anterior horn cells intact. Kainate and AMPA induced paraplegia but with relatively non-selective neuronal damage when given in doses more than 40-fold larger than those required for ACRO. When AMPA (> 100 nmol/h) was infused continuously using a mini-osmotic pump for more than 2 days, rats displayed progressive changes in motor behavior due to extensive damage in the caudal spinal cord where small neurons in the dorsal horns were the most vulnerable. Co-administration of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) specifically prevented neurotoxicity, suggesting a non-NMDA receptor-mediated mechanism. These results indicate that the non-NMDA receptor is heterogeneous, mediating neuronal damage with different selectivity. It is also suggested that chronic activation of glutamate receptors is capable of inducing slowly progressive neuronal death, which suggests relevance to the pathogenesis of ALS.
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PMID:Acute and late neurotoxicity in the rat spinal cord in vivo induced by glutamate receptor agonists. 759 34

The pathogenesis of sporadic amyotrophic lateral sclerosis (ALS) is unknown, but defects in synaptosomal high-affinity glutamate transport have been observed. In experimental models, chronic loss of glutamate transport can produce a loss of motor neurons and, therefore, could contribute to the disease. With the recent cloning of three glutamate transporters, i.e., EAAC1, GLT-1, and GLAST, it has become possible to determine if the loss of glutamate transport in ALS is subtype specific. We developed C-terminal, antioligopeptide antibodies that were specific for each glutamate transporter. EAAC1 is selective for neurons, while GLT-1 and GLAST are selective for astroglia. Tissue from various brain regions of ALS patients and controls were examined by immunoblot or immunocytochemical methods for each transporter subtype. All tissue was matched for age and postmortem delay. GLT-1 immunoreactive protein was severely decreased in ALS, both in motor cortex (71% decrease compared with control) and in spinal cord. In approximately a quarter of the ALS motor cortex specimens, the loss of GLT-1 protein (90% decrease from control) was dramatic. By contrast, there was only a modest loss (20% decrease from control) of immunoreactive protein EAAC1 in ALS motor cortex, and there was no appreciable change in GLAST. The minor loss of EAAC1 could be secondary to loss of cortical motor neurons. As a comparison, glial fibrillary acidic protein, which is selectively localized to astroglia, was not changed in ALS motor cortex. Because there is no loss of astroglia in ALS, the dramatic abnormalities in GLT-1 could reflect a primary defect in GLT-1 protein, a secondary loss due to down regulation, or other toxic processes.
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PMID:Selective loss of glial glutamate transporter GLT-1 in amyotrophic lateral sclerosis. 761 29

The neurotoxicity of glutamate has recently been postulated to participate in the pathogenesis of amyotrophic lateral sclerosis (ALS), and branched-chain amino acids have been proposed as possible therapeutic compounds for this disease. This study was undertaken to investigate whether branched-chain amino acids have any protective effect on cultured neurons exposed to glutamate. Primary cultures of cerebral neurons were prepared from fetal rats, using an established technique. For the assessment of glutamate toxicity, photomicrographs were taken before and after glutamate exposure both with phase-contrast and with bright field following incubation in trypan blue, a dye normally excluded by healthy cells. The activity of lactate dehydrogenase released from damaged cells was also measured. Exposure to glutamate in various concentrations was carried out, and leucine, isoleucine and varine, each separately, were added in advance to culture dishes. Glutamate neurotoxicity was confirmed, but no protective effect of branched-chain amino acids was observed. Although possible clinical benefit of branched-chain amino acids in ALS may not be denied, they do not prevent glutamate neurotoxicity in cultured cerebral neurons.
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PMID:[Effect of branched-chain amino acids on glutamate neurotoxicity in primary cultured rat cerebral neurons]. 761 70

A dramatic loss of glutamate transport has been observed in sporadic amyotrophic lateral sclerosis and has been postulated to contribute to the disease. Experimentally, this hypothesis was corroborated by mimicking the chronic loss of glutamate transport in postnatal rat spinal cord organotypic cultures through the use of glutamate transport inhibitors. This system is characterized by a relatively selective slow loss of ventral horn motor neurons resulting from glutamate transport inhibition. In this study, spinal cord organotypic cultures were used to test various drugs to evaluate their neuroprotective properties against this slow glutamate-mediated neurotoxicity The most potent neuroprotectants were drugs that altered glutamate neurotransmission, including non-NMDA receptor antagonists (GYKI-52466, PD144216, and PD13997) and drugs that could block presynaptic release or synthesis (riluzole and gabapentin). In addition, some antioxidants (U83836E and N-t-butyl-alpha-phenylnitrone) and inhibitors of nitric oxide synthesis (NG-monomethyl-L-arginine acetate) were modestly neuroprotective. The calcium endonuclease inhibitor aurintricarboxylic acid and the calcium release inhibitor dantrolene also provided partial motor neuron protection. However, several antioxidants and calcium channel antagonists had no excitotoxic neuroprotectant activity. This system provides a preclinical screening method for the burgeoning number of drugs postulated for clinical trials in motor neuron disease and a model to evaluate the mechanisms of chronic glutamate toxicity.
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PMID:Neuroprotective strategies in a model of chronic glutamate-mediated motor neuron toxicity. 761 20


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