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Query: UMLS:C0002736 (amyotrophic lateral sclerosis)
 19,048 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This work shows that the neurotoxic excitatory amino acids beta-N-methylamino alanine, BMAA, and kainate, modulate neurite outgrowth; this was assessed by measuring the levels of two separate neurofilament proteins (68 kD and 160 kD), in a mouse neuroblastoma cell line, (NB41A3). BMAA has been proposed to be the exogenous excitotoxin in Guam disease or amyotrophic lateral sclerosis (ALS/parkinsonian/dementia; Guam ALS-PD). Kainate is a glutamate analogue which causes excitotoxic damage associated with excessive entry of calcium into neurons. The results show that at low doses (10(-9) to 10(-7) M) both BMAA and kainate decrease the concentration of the two neurofilament proteins. However at high doses (10(-6) to 10(-5) M) they cause an apparent accumulation of the neurofilament proteins; the effect is more marked with BMAA. These results support the continued development of an in vitro test for neurotoxicity based on neurite outgrowth.
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PMID:Use of neurite outgrowth as an in vitro method of assessing neurotoxicity. 851 88

Glutamate transport is critical for synaptic inactivation of glutamate and prevention of excitotoxicity. The following four glutamate transporters have been identified in human brain: EAAT1, EAAT2, EAAT3, and EAAT4. Deficient glutamate transport has been identified in the motor cortex and the spinal cord of tissue from amyotrophic lateral sclerosis (ALS) patients. The defect appears to be due to a selective loss of the astroglial specific glutamate transporter protein EAAT2. In these studies we sought to extend our understanding of glutamate transporters in ALS by examining the mRNA for each transporter subtype in ALS motor cortex. All tissue was matched for age and postmortem delay. There was no quantitative change in mRNA for EAAT1, EAAT2, or EAAT3 in ALS motor cortex, even in patients with a large loss of EAAT2 protein (95% decrease compared with control) and decreased tissue glutamate transport (73% decrease compared with control). These studies suggest that the dramatic abnormalities in EAAT2 may be due to translational or post-translational processes.
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PMID:Glutamate transporter gene expression in amyotrophic lateral sclerosis motor cortex. 861 55

Peristimulus time histograms (PSTHs) of discharging single motor units, recorded from the extensor digitorum communis (EDC) during randomly applied cortical magnetic stimulation, were obtained in 42 normal subjects aged 24 to 83 years and 42 patients with amyotrophic lateral sclerosis (ALS) aged 37 to 84 years. Normal subjects had an early period of increased firing probability occurring at about 20 msec poststimulus, reflecting an underlying compound excitatory postsynaptic potential (EPSP) induced by fast-conducting, descending volleys of the corticomotoneuronal core facilitating the single spinal motoneuron. There was an age-dependent, linear decline in the amplitude of the EPSP (r = 0.673). We estimated that by age 50 years about 35% of corticomotoneurons are lost or nonfunctioning in normal controls. Compared with age-matched controls, the EPSP in most patients with ALS was reduced, and it was unmeasurable in six. We postulate this reflects a loss of corticomotoneurons. Seven (16.7%) patients phenotypically the same as the others had EPSPs that were larger than age-predicted values. This may reflect glutamate-induced excitotoxicity in a subset of ALS. In a single patient with chronic spinal muscular atrophy the EPSP was normal.
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PMID:Cortical projections to spinal motoneurons: changes with aging and amyotrophic lateral sclerosis. 862 89

Several aspects of amyotrophic lateral sclerosis are reviewed, with special emphasis on arguments based on etiological and pathogenic theories currently in vogue: free radicals, glutamate-induced toxic excitation, trophic factors, autoimmunity and axon transport. Each of these theories has inspired therapeutic trials, some of which are already completed and others are still in progress. More than one neurodegenerative mechanism may be involved in amyotrophic lateral sclerosis, meaning that it might be necessary to combine several drugs in future trials.
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PMID:[Amyotrophic lateral sclerosis]. 869 48

Amyotrophic lateral sclerosis (ALS) is a fatal, enigmatic disorder characterised by relentless progression of muscle wasting and weakness until death ensues due to respiratory muscle failure. Intellectual functions are usually spared. ALS, known also as motor neuron disease (MND) in the UK, maladie de Charcot in France and Lou Gehrig's disease in the US, is usually sporadic, but between 5 and 10% of all cases are hereditary, usually inherited as autosomal dominant. Previously thought to be untreatable, as well as incurable, just in the last 3 years ALS has been the greatest clinical application of recent exciting break-throughs in preclinical neurobiology research. Although definitive information regarding the cause(s) and pathogenesis of ALS still escapes us, meaningful demonstration of intercession in the downhill course with specific therapy has been suggested, giving reason to be hopeful, if cautiously and critically optimistic. This review focuses on the recent work from the fields of growth/trophic factors, glutamate/neurotoxicity, neuroprotection and proteases and inhibitors, as well as the approaches to measuring specific effects in patients with the illness. It ends with a eye to the horizon, and the future, and where ALS treatment strategies may be heading after the millennium.
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PMID:Amyotrophic lateral sclerosis: current and future treatment strategies. 874 Dec 31

A rapid and reproducible spinal motor neuron death occurs after sciatic nerve transection in neonatal rats. This neuronal death could be due to lack of retrogradely transported target derived neurotrophic factors, such as ciliary neurotrophic factor, brain-derived neurotrophic factor, leukemia inhibitory factor and glial cell line-derived neurotrophic factor. Another hypothesis suggests that glutamate and its receptors has been implicated as possible mechanism for motor neuron death. In order to investigate the effect of N-methyl-D-aspartate (NMDA) and non-NMDA receptor antagonists on axotomy-induced cell death in the spinal motor neurons of neonatal rats, we have studied neuroprotective effects of these receptor antagonists. Newborn rats were anesthetized with hypothermia. Sciatic nerve was transected near the obturator tendon in the left thigh. Animals were then treated daily with MK-801, APV, and CNQX for 14 days with intraperitoneal injections. Control animals received PBS in the same fashion. After the treatment, the number of spinal motor neurons in the L4-6 was counted. MK-801 and APV did not show any significant neuroprotective effect. By contrast, the number of surviving motor neurons was greater in animals that were treated with 1.0, 2.0 and 4.0 mg/kg of CNQX. This neuroprotective effect was not dose-related. We demonstrate that neuroprotective effect of CNQX on axotomized motor neurons, raises a possibility that such a agent may have therapeutic potential in motor neuronopathy and amyotrophic lateral sclerosis.
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PMID:CNQX prevents spinal motor neuron death following sciatic nerve transection in newborn rats. 874 38

Glutamate is one of the major excitatory neurotransmitter in the central nervous system. Glutamate acts on 4 different post synaptic receptors; NMDA (N-Methyl-D-aspartate) AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid), Kainate and metabotropic receptors. The three former receptors are linked to membrane ion channels whereas metabotropic receptors are coupled with a G protein. Glutamate is involved in the physiologic processes of learning, memory and motricity. Glutamate is also a potent neurotoxin responsible for toxic neuronal death of post synaptic neurons. This action has been denominated excitotoxicity and occurs as a consequence of a prolonged or a strong activation of glutamate post-synaptic receptors. The rise in intracellular calcium seems to play a major role in the pathological events following excitotoxicity. The pathophysiology of several acute or chronic neurological disorders has been linked to excitotoxicity. This excitotoxic process could be present in acute neuronal death observed in stroke, hypoglycemia and traumatisms of the central nervous system and in chronic neuronal degeneration observed in Amyotrophic Lateral Sclerosis (ALS), Alzheimer's disease, Parkinson's disease, Huntington's disease and neuro AIDS. A better knowledge of the cellular events induced by excitotoxicity will allow to consider new therapeutic approaches in various neurological disorders.
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PMID:[Role of glutamate and excitotoxicity in neurologic diseases]. 876 52

High affinity glutamate transporters regulate levels of extracellular glutamate in the central nervous system. Impaired glutamate transport has been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). The glutamate transporter subtypes GluT-1 and EAAC1 have previously been mapped to human chromosomes 5p13 and 9p24, respectively. In the present study, the GLT-1 subtype was mapped to human chromosome 11p11.2-p13 by fluorescence in situ hybridization. The possible clinical implications of this finding are discussed.
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PMID:Localization of the gene encoding the human L-glutamate transporter (GLT-1) to 11p11.2-p13 by fluorescence in situ hybridization. 878 89

A superoxide dismutase 1 (SOD-1)genetic defect has been identified in familial amyotrophic lateral sclerosis (ALS) and motor neuron degeneration has been described in SOD-1 transgenic mice. Because an excitotoxic mechanism has been implicated in ALS, we undertook studies to provide a description of excitotoxic degeneration of spinal motor neurons for comparison with the degenerative process observed in SOD-1 transgenic mice. Excitotoxin agonists selective for each of the three major types of inotropic glutamate receptors were applied directly onto the lumbar spinal cord of 21-day old rats following posterior laminectomy. N-methyl-D-aspartate (NMDA) preferentially affected dorsal horn neurons, whereas the non-NMDA agonist, kainic acid, preferentially affected motor neurons. Cytopathological changes in motor neurons closely resembled those described in SOD-1 mice. These changes consist of massively swollen dendritic processes in the presence of well-preserved presynaptic axon terminals; cell bodies of motor neurons filled with vacuoles that originate both from endoplasmic reticulum and mitochondria; pleomorphic changes in mitochondria; axons of motor neuron becoming swollen proximally with accumulation of vacuoles, organelles, filaments, and degeneration products in the swollen segment. The observed changes in motor axons resemble changes described in the spinal cord of ALS patients. These findings are consistent with the proposal that motor neuron degeneration in ALS may be mediated by an excitotoxic process involving hyperactivation with non-NMDA glutamate receptors.
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PMID:Motor neuron degeneration induced by excitotoxin agonists has features in common with those seen in the SOD-1 transgenic mouse model of amyotrophic lateral sclerosis. 878 80

A large number of studies have documented abnormalities of glutamate metabolism in ALS patients or in postmortem ALS tissue. These abnormalities include altered synthetic enzymes, tissue glutamate levels, transporter proteins, and postsynaptic receptors, as well as the presence of potentially toxic agonists. As yet, there is no hypothesis effectively linking all the observations to one central defect. Furthermore, it is not clear if the various abnormalities in glutamate systems represent a primary defect or a secondary response. For example, defects of glutamate transport subtypes could reflect the primary loss of the proteins or the secondary effect of another toxic insult. Nevertheless, experimental paradigms suggest that, even if secondary, glutamate could contribute to the death of motor neurons. Therefore, interventions to minimize the toxicity of glutamate (e.g., receptor antagonists, release inhibitors, or antioxidants) could partially ameliorate the degeneration of motor neurons. This has been observed experimentally in cultured motor neurons. More importantly, a small study with riluzole suggests that glutamate-acting drugs could alter the progression of the disease. Future studies with riluzole and other glutamate-acting agents will evaluate this possibility.
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PMID:Excitotoxic mechanisms in the pathogenesis of amyotrophic lateral sclerosis. 878 45


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