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)

Beta-N-methylamino-L-alanine (BMAA) is a nonprotein amino acid that may be involved in neurodegenerative diseases. It is produced by a large variety of cyanobacteria and is found at high levels in the brains of Alzheimer's disease and amyotrophic lateral sclerosis patients. Although BMAA is clearly a neurotoxin, previous studies using cortical cultures indicated that millimolar concentrations were required to cause toxicity. We tested the toxicity of BMAA in septal cultures containing cholinergic neurons and mesencephalic cultures containing dopaminergic neurons. We found that cholinergic, but not dopaminergic, neurons were selectively vulnerable to BMAA toxicity, with toxicity occurring at 30 microM. The toxicity of BMAA to total septal neurons involved activation of N-methyl D-aspartate receptors, whereas the death of cholinergic neurons was mediated by AMPA/kainate receptors.
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PMID:Selective death of cholinergic neurons induced by beta-methylamino-L-alanine. 1993 80

Our objective was to determine if chronic treatment with the non-competitive AMPA antagonist talampanel is efficacious and safe in subjects with ALS. A double-blind, placebo-controlled, multicenter, randomized clinical trial of nine months treatment duration was conducted in 59 subjects with ALS, with 40 subjects receiving talampanel 50 mg p.o. t.i.d, and 19 subjects receiving placebo. Primary outcome measure was rate of decline in isometric arm strength (as measured by change in arm strength megaslope of the Tufts Quantitative Neuromuscular Exam (TQNE)). Other efficacy endpoints included rate of decline in respiratory function, isometric leg strength, bulbar function, fine motor function, the ALS Functional Rating Scale (ALSFRS), and survival. Secondary safety outcome measures were frequency of adverse events, neurological status, plasma concentration of talampanel, vital signs, routine laboratory tests, and electrocardiograms. Decline in muscle strength was 15% less in talampanel treated subjects, and decline in ALSFRS was 30% slower in talampanel treated subjects. Talampanel was safe in subjects with ALS. Mortality rates (8% talampanel, 5% placebo) and drug discontinuation rates (25% talampanel, 16% placebo) were similar in active treatment and placebo groups. Dizziness and somnolence occurred significantly more often in talampanel treated subjects. Although no efficacy measure reached statistical significance, there was a repeated trend toward slower decline in ALSFRS and isometric muscle strength in talampanel treated subjects. Talampanel was well tolerated in subjects with ALS. Although certain adverse events occurred more frequently in the active treatment group, the rate of subject drop-out after nine months did not exceed that seen in other trials. These findings provide strong support for a phase III trial to determine the efficacy of talampanel in subjects with ALS.
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PMID:A phase II trial of talampanel in subjects with amyotrophic lateral sclerosis. 1996 Dec 64

The progressive degeneration of motor neurons in amyotrophic lateral sclerosis (ALS) is a complex and multifactorial process. Both excitotoxicity (excessive stimulation of glutamate receptors) and a shortage of the vascular endothelial growth factor (VEGF) have been implicated in the disease pathogenesis. In this study, both disease mechanisms were further characterized and their therapeutic potential was evaluated. Motor neurons were found to be particularly vulnerable to AMPA receptor stimulation (one subtype of glutamate receptors) and the toxicity was initiated by the influx of calcium ions through the AMPA receptors. Only AMPA receptors that lack a certain subunit (GluR2) are permeable to calcium ions, and compared to other neurons motor neurons had low GluR2 levels. Reducing GluR2 levels aggravated motor neuron death in culture and accelerated the process of motor neuron degeneration in vivo. The regulation of GluR2 expression was investigated further. Astrocytes were found to influence neuronal GluR2 expression and thus their vulnerability to excitotoxicity. In addition, the growth factor VEGF, which could slow down motor neuron degeneration in rats, stimulated GluR2 expression in motor neurons and protected against excessive AMPA receptor stimulation, providing a link between two important disease mechanisms in ALS. Clinical trials with AMPA receptor antagonists and VEGF will hopefully lead to a better treatment of patients with ALS.
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PMID:The role of AMPA receptors and VEGF in ALS. 2008 35

In the fatal neurodegenerative disease amyotrophic lateral sclerosis (ALS), motor neurons degenerate with signs of organelle fragmentation, free radical damage, mitochondrial Ca2+ overload, impaired axonal transport and accumulation of proteins in intracellular inclusion bodies. Subgroups of motor neurons of the brainstem and the spinal cord expressing low amounts of Ca2+ buffering proteins are particularly vulnerable. In ALS, chronic excitotoxicity mediated by Ca2+-permeable AMPA type glutamate receptors seems to initiate a self-perpetuating process of intracellular Ca2+ dysregulation with consecutive endoplasmic reticulum Ca2+ depletion and mitochondrial Ca2+ overload. The only known effective treatment, riluzole, seems to reduce glutamatergic input. This review introduces the hypothesis of a "toxic shift of Ca2+" within the endoplasmic reticulum-mitochondria Ca2+ cycle (ERMCC) as a key mechanism in motor neuron degeneration, and discusses molecular targets which may be of interest for future ERMCC modulating neuroprotective therapies.
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PMID:Calcium dysregulation in amyotrophic lateral sclerosis. 2011 97

The alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptor (AMPAR) subunit GluR2, which regulates excitotoxicity and the inflammatory cytokine tumour necrosis factor alpha (TNFalpha) have both been implicated in motor neurone vulnerability in amyotrophic lateral sclerosis/motor neurone disease. TNFalpha has been reported to increase cell surface expression of AMPAR subunits to increase synaptic strength and enhance excitotoxicity, but whether this mechanism occurs in motor neurones is unknown. We used primary cultures of mouse motor neurones and cortical neurones to examine the interaction between TNFalpha receptor activation, GluR2 availability, AMPAR-mediated calcium entry and susceptibility to excitotoxicity. Short exposure to a physiologically relevant concentration of TNFalpha (10 ng/mL, 15 min) caused a marked redistribution of both GluR1 and GluR2 to the cell surface as determined by cell surface biotinylation and immunofluorescence. Using fura-2-acetoxymethyl ester microfluorimetry, we showed that exposure to TNFalpha caused a rapid reduction in the peak amplitude of AMPA-mediated calcium entry in a PI3-kinase and p38 kinase-dependent manner, consistent with increased insertion of GluR2-containing AMPAR into the plasma membrane. This resulted in a protection of motor neurones against kainate-induced cell death. Our data therefore, suggest that TNFalpha acts primarily as a physiological regulator of synaptic activity in motor neurones rather than a pathological drive in amyotrophic lateral sclerosis.
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PMID:Tumour necrosis factor alpha induces rapid reduction in AMPA receptor-mediated calcium entry in motor neurones by increasing cell surface expression of the GluR2 subunit: relevance to neurodegeneration. 2013 65

Amyotrophic lateral sclerosis-Parkinson dementia complex (ALS-PDC) is a neurodegenerative disease with ALS, parkinsonism, and Alzheimer's symptoms that is prevalent in the Guam population. beta-N-Methylamino alanine (BMAA) has been proposed as the toxic agent damaging several neuronal types in ALS-PDC, including substantia nigra pars compacta dopaminergic (SNpc DAergic) neurons. BMAA is a mixed glutamate receptor agonist, but the specific pathways activated in DAergic neurons are not yet known. We combined electrophysiology, microfluorometry, and confocal microscopy analysis to monitor membrane potential/current, cytosolic calcium concentration ([Ca(2+)](i)) changes, cytochrome-c (cyt-c) immunoreactivity, and reactive oxygen species (ROS) production induced by BMAA. Rapid toxin applications caused reversible membrane depolarization/inward current and increase of firing rate and [Ca(2+)](i) in DAergic neurons. The inward current (I(BMAA)) was mainly mediated by activation of metabotropic glutamate receptor 1 (mGluR1), coupled to transient receptor potential (TRP) channels, and to a lesser extent, AMPA receptors. Indeed, mGluR1 (CPCCOEt) and TRP channels (SKF 96365; Ruthenium Red) antagonists reduced I(BMAA), and a small component of I(BMAA) was reduced by the AMPA receptor antagonist CNQX. Calcium accumulation was mediated by mGluR1 but not by AMPA receptors. Application of a low concentration of NMDA potentiated the BMAA-mediated calcium increase. Prolonged exposure to BMAA caused significant modifications of membrane properties, calcium overload, cell shrinkage, massive cyt-c release into the cytosol and ROS production. In SNpc GABAergic neurons, BMAA activated only AMPA receptors. Our study identifies the mGluR1-activated mechanism induced by BMAA that may cause the neuronal degeneration and parkinsonian symptoms seen in ALS-PDC. Moreover, environmental exposure to BMAA might possibly also contribute to idiopathic PD.
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PMID:Metabotropic glutamate receptor 1 mediates the electrophysiological and toxic actions of the cycad derivative beta-N-Methylamino-L-alanine on substantia nigra pars compacta DAergic neurons. 2039 40

Glutamate-induced excitotoxicity is responsible for neuronal death in acute neurological conditions as well as in chronic neurodegeneration. In this review, we give an overview of the contribution of excitotoxicity in the pathogenesis of amyotrophic lateral sclerosis (ALS). The selective motor neuron death that is the hallmark of this neurodegenerative disease seems to be related to a number of intrinsic characteristics of these neurons. Most of these characteristics relate to calcium entry and calcium handling in the motor neurons as intracellular free calcium concentrations increase quickly due to a high glutamate-induced calcium influx in combination with a low calcium buffering capacity. The high calcium influx is because of the presence of GluR2 lacking, calcium-permeable AMPA receptors while a low expression of calcium binding proteins explains the low calcium buffering capacity. In the absence of these proteins, mitochondria play an important role to remove calcium from the cytoplasm. While all of these characteristics make at least a subpopulation of motor neurons intrinsically very prone to AMPA receptor mediated excitotoxicity, this vulnerability is further increased by the disease process. Mutated genes as well as unknown factors do not only influence the intrinsic characteristics of the motor neurons, but also the properties of the surrounding astrocytes. In conclusion, excitotoxicity remains an intriguing pathological pathway that could not only explain the selectivity of the motor neuron death but also the role of surrounding non-neuronal cells in ALS. In addition, excitotoxicity is also an interesting drug-able target as indicated by the only FDA-approved drug, riluzole, as well as by a number of ongoing clinical trials.
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PMID:Amyotrophic lateral sclerosis and excitotoxicity: from pathological mechanism to therapeutic target. 2040 81

GluR2 is a subunit of the AMPA receptor, and the adenosine for the Q/R site of its pre-mRNA is converted to inosine (A-to-I conversion) by the enzyme called adenosine deaminase acting on RNA 2 (ADAR2). Failure of A-to-I conversion at this site affects multiple AMPA receptor properties, including the Ca(2+) permeability of the receptor-coupled ion channel, thereby inducing fatal epilepsy in mice (Brusa et al., 1995; Feldmeyer et al., 1999). In addition, inefficient GluR2 Q/R site editing is a disease-specific molecular dysfunction found in the motor neurons of sporadic amyotrophic lateral sclerosis (ALS) patients (Kawahara et al., 2004). Here, we generated genetically modified mice (designated as AR2) in which the ADAR2 gene was conditionally targeted in motor neurons using the Cre/loxP system. These AR2 mice showed a decline in motor function commensurate with the slow death of ADAR2-deficient motor neurons in the spinal cord and cranial motor nerve nuclei. Notably, neurons in nuclei of oculomotor nerves, which often escape degeneration in ALS, were not decreased in number despite a significant decrease in GluR2 Q/R site editing. All cellular and phenotypic changes in AR2 mice were prevented when the mice carried endogenous GluR2 alleles engineered to express edited GluR2 without ADAR2 activity (Higuchi et al., 2000). Thus, loss of ADAR2 activity causes AMPA receptor-mediated death of motor neurons.
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PMID:Induced loss of ADAR2 engenders slow death of motor neurons from Q/R site-unedited GluR2. 2222 19

The causes of amyotrophic lateral sclerosis (ALS) are mostly undefined; however, excitotoxic injury and astrogliosis may contribute to motor neuron (MN) degeneration. Group I metabotropic glutamate (mGlu) receptors are over-expressed in reactive astrocytes in ALS, but the functional significance of this over-expression is presently unknown. We examined the role of group I mGlu receptors on excitotoxic death of spinal cord MNs grown in cultures enriched of astrocytes bearing a reactive phenotype. A prolonged exposure to the selective non-competitive mGlu5 receptor antagonist MPEP reduced AMPA-mediated toxicity and cobalt uptake in MNs. Expression levels of the GluR1 (but not GluR2) AMPA receptor subunit and levels of brain-derived neurotrophic factor (BDNF) were reduced in mixed spinal cord cultures pretreated with MPEP. In addition, neuroprotection by MPEP was less than additive with that produced by a neutralizing anti-BDNF antibody and a treatment with exogenous BDNF masked the protective effect of MPEP, suggesting that mGlu5 receptors and BDNF converge in facilitating excitotoxic MN death. The protective effect of MPEP was absent in cultures with a reduced number of astrocytes. We suggest that blocking astrocytic mGlu5 receptors is a potential therapeutic strategy in ALS.
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PMID:A prolonged pharmacological blockade of type-5 metabotropic glutamate receptors protects cultured spinal cord motor neurons against excitotoxic death. 2123 1

Glutamate is the major excitatory neurotransmitter in the mammalian nervous system. The properties of their ionotropic glutamate receptors largely determine how different neurons respond to glutamate. RNA editing in pre-mRNAs encoding subunits of glutamate receptors, particularly the GluR 2 subunit of AMPA receptors, controls calcium permeability, response time, and total ion flow in individual receptors as well as the density of AMPA receptors at synapses through effects on ER assembly, sorting, and plasma membrane insertion. When RNA editing fails in a neuron, calcium influx through AMPA receptors may cause neuron death by glutamate excitotoxicity, as in the case of vulnerable hippocampal CA1 pyramidal neurons that die after transient forebrain ischemia. Elevated cerebrospinal glutamate is common in ALS and loss of GluR 2 Q/R site RNA editing has been reported to occur selectively in lower motor neurons in a majority of Japanese sporadic ALS patients. We describe our methods for laser microdissection followed by RT-PCR analysis to study RNA editing in single motor neurons.
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PMID:Laser microdissection and pressure catapulting of single human motor neurons for RNA editing analysis. 2137 42


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