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)

We analysed free amino acid contents in anterior horn, posterior horn, lateral column and posterior column of the spinal cord transections from autopsied cases of amyotrophic lateral sclerosis (ALS), and compared the results with those from non-ALS cases. Content of free glutamate (Glu), and aspartate (Asp) was reduced significantly not only in the lateral portion where pyramidal tracts run through but also in other portions of cervical cords of ALS cases. Contents of glycine, gamma-aminobutyric acid and taurine were not different between ALS and non-ALS cervical cords. The results suggest that some metabolic disorders of these excitatory amino acid transmitter candidates may exist in ALS spinal cord.
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PMID:[Free amino acid contents in the spinal cord of amyotrophic lateral sclerosis]. 790 68

Glutamate excitotoxicity is implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). We report the results of a double blind, placebo controlled, trial using 100 mg of oral daily lamotrigine (3,5-diamino-6-(2,3 dichlorophenyl)-1,2,4-triazine) which inhibits glutamate release. 67 patients were entered and at trial termination of 1.5 years 15 had withdrawn (9 active and 6 placebo) and 12 had died (6 active and 6 placebo). Mean age at entry was 57.5 years for the active and 58.6 years for the placebo groups. Patients were seen at 3 monthly intervals and scored according to neurological deficit based upon age of onset, bulbar and respiratory involvement, ambulation and functional disability. The mean change in clinical scores for the active versus placebo groups over the trial period was 7.1 +/- 3.3 and 9.0 +/- 3.3 respectively (0.05 < p < 0.10). Changes in cortical threshold and MEP/CMAP ratios to magnetic stimulation also did not differ significantly between the two groups. We conclude that lamotrigine in the doses administered does not alter the course of ALS.
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PMID:Anti-glutamate therapy in amyotrophic lateral sclerosis: a trial using lamotrigine. 790 90

Mutations in the gene for Cu/Zn superoxide dismutase (SOD1) have been detected in some families with an autosomal dominant form of amyotrophic lateral sclerosis; these mutations appear to reduce the activity of this enzyme. To determine whether decreased SOD activity could contribute to motor neuron loss, SOD1 was inhibited chronically with either antisense oligodeoxynucleotides or diethyldithiocarbamate in spinal cord organotypic cultures. Chronic inhibition of SOD resulted in the apoptotic degeneration of spinal neurons, including motor neurons, over several weeks. Motor neuron loss was markedly potentiated by the inhibition of glutamate transport. In this paradigm, motor neuron toxicity could be entirely prevented by the antioxidant N-acetylcysteine and, to a lesser extent, by the non-N-methyl-D-aspartate glutamate receptor antagonist 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine hydrochloride. These data support the hypothesis that the loss of motor neurons in familial amyotrophic lateral sclerosis could be due to a reduction in SOD1 activity, possibly potentiated by inefficient glutamate transport.
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PMID:Chronic inhibition of superoxide dismutase produces apoptotic death of spinal neurons. 791 Apr 2

Motor neurone disease, or amyotrophic lateral sclerosis, is a serious progressive neurological disorder, characterized by loss of UMN and LMN. Pathological features include characteristic intracytoplasmic MN inclusion bodies and appearances on ubiquitin staining. The aetiopathogenesis of the disease remains unknown and there is, to date, no effective treatment. Several abnormalities have been demonstrated in neurotransmitter, neuropeptide and gene expression studies. Abnormalities in glutamate metabolism have led to the excitotoxin hypothesis of MN destruction. Other theories include deficits in MN trophic factors, trans-synaptic degeneration, impaired ability to detoxify putative toxic agents and impaired DNA/RNA metabolism. The existence of familial forms, some of which show linkage to markers in chromosome 21, allows a genetic approach to the mechanisms of disease. Recent studies suggest that mutations in the Cu/Zn SOD gene may be important in some of the familial forms. The atypical forms seen in the Western Pacific have stimulated a search for environmental agents. Agents undergoing therapeutic trials at present include CNTF, IGF1 glutamate antagonists, branched-chain amino acids and TRH analogue.
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PMID:Motor neurone disease. 792 18

Therapeutic trials for amyotrophic lateral sclerosis have attracted much attention, but no drug tested has been effective yet. Three major theories of pathogenesis form the basis for these trials: autoimmunity, chronic excitotoxic stimulation due to accumulation of glutamate, and, in the familial form, peroxidation due to subnormal activity of superoxide dismutase. In striking contrast to the negative results of all of the other drug trials, riluzole (a glutamate antagonist) was said to benefit patients with bulbar onset but not those with spinal onset. Problems with the original trial may be clarified by other studies now in progress. The most optimistic news is the response to therapy of multifocal motor neuropathy, a disorder that clinically resembles motor neuron disease. This year, three groups reported benefit from intravenous immunoglobulin therapy.
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PMID:Amyotrophic lateral sclerosis. 795 38

The reduction of glutamate content has been observed in the spinal cord of the wobbler mouse, a purported model of amyotrophic lateral sclerosis (ALS). To elucidate glutamate receptors in the wobbler spinal cord, we measured densities of N-methyl-D-aspartate (NMDA), kainate, alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA) and metabotropic glutamate (mGlu) binding sites using in vitro autoradiography. In wobbler mice, NMDA, kainate, and AMPA binding sites were increased in the dorsal horn and kainate binding sites were also increased in the intermediate zone. However, mGlu binding was unchanged. These results disagree with those observed in ALS spinal cords, in which NMDA and kinate binding sites are decreased. The wobbler mouse may have the glutamate dysfunction, but in a different way from ALS.
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PMID:Quantitative autoradiographic distribution of glutamate receptors in the cervical segment of the spinal cord of the wobbler mouse. 795 5

Much interest has focused on the role of glutamate-mediated excitotoxicity in the etiopathogenesis of amyotrophic lateral sclerosis (ALS). We therefore conducted a phase I study of high-dose dextromethorphan (DM) in ALS. DM is a selective, noncompetitive antagonist of the N-methyl-D-aspartate subtype of the glutamate receptor. Thirteen patients were given DM in an escalating dose fashion, to a target of 10 mg/kg/day or the maximum tolerable dose, and then maintained on this dose for up to 6 months. Total daily doses ranged from 4.8 to 10 mg/kg (median, 7 mg/kg). Side effects were dose limiting in most patients. The most common side effects were light-headedness, slurred speech, and fatigue. Detailed pharmacokinetic and neuropsychology studies were performed. This study demonstrates the feasibility of long-term administration of high-dose DM in ALS, as well as in other conditions associated with glutamate excitotoxicity.
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PMID:High-dose dextromethorphan in amyotrophic lateral sclerosis: phase I safety and pharmacokinetic studies. 799 81

Perhaps as many as 25-50% of adult patients and children with acquired immunodeficiency syndrome (AIDS) eventually suffer from neurological manifestations, including dysfunction of cognition, movement, and sensation. How can human immunodeficiency virus type 1 (HIV-1) result in neuronal damage if neurons themselves are for all intents and purposes not infected by the virus? This article reviews a series of experiments leading to a hypothesis that accounts at least in part for the neurotoxicity observed in the brains of AIDS patients. There is growing support for the existence of HIV- or immune-related toxins that lead indirectly to the injury or demise of neurons via a potentially complex web of interactions among macrophages (or microglia), astrocytes, and neurons. HIV-infected monocytoid cells (macrophages, microglia, or monocytes), after interacting with astrocytes, secrete eicosanoids, i.e., arachidonic acid and its metabolites, including platelet-activating factor. Macrophages activated by HIV-1 envelope protein gp120 also appear to release arachidonic acid and its metabolites. In addition, interferon-gamma (IFN-gamma) stimulation of macrophages induces release of the glutamate-like agonist, quinolinate. Furthermore, HIV-infected macrophage production of cytokines, including TNF-alpha and IL1-beta, contributes to astrogliosis. A final common pathway for neuronal susceptibility appears to be operative, similar to that observed in stroke, trauma, epilepsy, neuropathic pain, and several neurodegenerative diseases, possibly including Huntington's disease, Parkinson's disease, and amyotrophic lateral sclerosis. This mechanism involves the activation of voltage-dependent Ca2+ channels and N-methyl-D-aspartate (NMDA) receptor-operated channels, and, therefore, offers hope for future pharmacological intervention. This article focuses on clinically tolerated calcium channel antagonists and NMDA antagonists with the potential for trials in humans with AIDS dementia in the near future.
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PMID:HIV-related neuronal injury. Potential therapeutic intervention with calcium channel antagonists and NMDA antagonists. 799 15

Amyotrophic lateral sclerosis (ALS) is a neurological disorder neuropathologically characterized by a progressive degeneration of upper and lower motoneurons. The origin of the neuronal death is presently unknown but recent findings suggest that neurodegeneration could be related to an excitotoxic disorder. We have recently shown that the cerebrospinal fluid (CSF) of ALS patients contains for neurones in cultures cytotoxic factors whose toxic properties are mediated by AMPA/kainate receptors, a subgroup of glutamate post-synaptic receptors. This study reports that riluzole partially prevents in vitro the neuronal degeneration produced by ALS CSF (neuronal survival 60.6 +/- 13.1%). Riluzole (5 x 10(-7) M) which reduces excitatory amino acid release, could represent a new pharmacological agent susceptible to be proposed to patients affected by this dramatic neurological disease.
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PMID:Neuroprotective effects of riluzole in ALS CSF toxicity. 806 Dec 81

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder affecting motor neurons. Glutamate, a potent central-nervous-system toxin, has been proposed as one possible factor in this motoneuron disease. Serum from patients with ALS is known to be toxic when added to neurons in culture. We report on the toxicity to rat neurons in culture of cerebrospinal fluid (CSF) from patients with ALS. CSF were obtained from 10 ALS patients, 10 neurological controls, and 10 other controls. ALS CSF was added at dilutions of 50%, 20%, or 10% and neuron survival was assessed after 24 h. The neuroprotective effects of antagonists to two glutamate receptors were also assessed. ALS CSF was significantly neurotoxic, with a neuronal survival rate of only 47% compared with 80% or so for control CSF. This neurotoxicity was blocked by CNQX, an antagonist to the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)/kainate receptor but not by two N-methyl-D-aspartate (NMDA) antagonists. ALS CSF contains a specific neurotoxic factor which is AMPA/kainate-like which could have a role in the neuronal degeneration of this disease.
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PMID:Cell culture evidence for neuronal degeneration in amyotrophic lateral sclerosis being linked to glutamate AMPA/kainate receptors. 809 16


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