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)

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

A high-performance liquid chromatography (HPLC) method is described for determining subpicomole concentrations of beta-N-methylamino-L-alanine (BMAA) in plant and animal tissue. BMAA and other amino acids were reacted with 9-fluorenylmethyl chloroformate (FMOC) for 10 min under alkaline conditions to form highly fluorescent and stable derivatives. All amino acids, including BMAA, eluted from the column within 22 min. BMAA (tr = 18.02 +/- 0.07 min) was detected in Cycas circinalis L. seed and in serum, cerebrospinal fluid and brain tissue from BMAA-treated monkeys and rats. The primary amino acids glutamine, glutamic acid, aspartic acid, alanine, glycine and gamma-aminobutyric acid (GABA) could also be detected since they were well resolved from BMAA. These amino acids and BMAA were linear over the concentration range of 0.15-7.5 microM with a relative standard deviation ranging from 2.1-6.7%. This method should prove useful in studies to determine the role of BMAA in the Western Pacific amyotrophic lateral sclerosis/Parkinsonism-dementia complex for which cycad seed is the principal etiological candidate.
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PMID:Determination of beta-N-methylamino-L-alanine (BMAA) in plant (Cycas circinalis L.) and animal tissue by precolumn derivatization with 9-fluorenylmethyl chloroformate (FMOC) and reversed-phase high-performance liquid chromatography. 319 47

Patients with amyotrophic lateral sclerosis have increased levels of the neutrotransmitter norepinephrine in blood and cerebrospinal fluid and depressed levels of the inhibitory neurotransmitter gamma-aminobutyric acid in cerebrospinal fluid. These neurochemical alterations are most marked in patients bedridden with advanced disease, appear interrelated, and lead to cardiovascular alterations in patients with amyotrophic lateral sclerosis.
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PMID:Norepinephrine and gamma-aminobutyric acid in amyotrophic lateral sclerosis. 718 43

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

The chemical structure of gabapentin (Neurontin) is derived by addition of a cyclohexyl group to the backbone of gamma-aminobutyric acid (GABA). Gabapentin prevents seizures in a wide variety of models in animals, including generalized tonic-clonic and partial seizures. Gabapentin has no activity at GABAA or GABAB receptors of GABA uptake carriers of brain. Gabapentin interacts with a high-affinity binding site in brain membranes, which has recently been identified as an auxiliary subunit of voltage-sensitive Ca2+ channels. However, the functional correlate of gabapentin binding is unclear and remains under study. Gabapentin crosses several lipid membrane barriers via system L amino acid transporters. In vitro, gabapentin modulates the action of the GABA synthetic enzyme, glutamic acid decarboxylase (GAD) and the glutamate synthesizing enzyme, branched-chain amino acid transaminase. Results with human and rat brain NMR spectroscopy indicate that gabapentin increases GABA synthesis. Gabapentin increases non-synaptic GABA responses from neuronal tissues in vitro. In vitro, gabapentin reduces the release of several mono-amine neurotransmitters. Gabapentin prevents pain responses in several animal models of hyperalgesia and prevents neuronal death in vitro and in vivo with models of the neurodegenerative disease amyotrophic lateral sclerosis (ALS). Gabapentin is also active in models that detect anxiolytic activity. Although gabapentin may have several different pharmacological actions, it appears that modulation of GABA synthesis and glutamate synthesis may be important.
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PMID:Mechanisms of action of gabapentin. 968 47

The termination of chemical neurotransmission in the CNS involves the rapid removal of neurotransmitter from synapses by specific transport systems. Such mechanism operates for the three major amino acid neurotransmitters glutamate, gamma-aminobutyric acid (GABA) and glycine. To date, five different high-affinity Na(+)-dependent glutamate (Glu) transporters have been cloned: GLT1, GLAST, EAAC1, EAAT4 and EAAT5. The first two are expressed mainly by glial cells, and seem to be the predominant Glu transporters in the brain. A major function of Glu uptake in the nervous system is to prevent extracellular Glu concentrations from raising to neurotoxic levels in which glial transporters seem to play a critical role in protecting neurons from glutamate-induced excitotoxicity. Under particular conditions, glial GluTs have been shown to release Glu by reversal of activity, in a Ca(2+)--and energy-independent fashion. Furthermore, an activity of these transporters as ion channels or transducing units coupled to G-proteins has recently been reported. The localization, stoichiometry, and regulation of glial GluTs are outlined, as well as their possible contributions to nervous system diseases as ALS, AD and ischemic damage.
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PMID:Glial transporters for glutamate, glycine and GABA I. Glutamate transporters. 1124 80

Riluzole is used as therapeutic agent in amyotrophic lateral sclerosis. We investigated the interaction of riluzole with recombinant GABA (gamma-aminobutyric acid)(A) receptor channels (alpha(1)beta(2)gamma(2)-subunits) and glycine receptor channels (alpha(1)beta-subunits) transiently expressed in HEK293 cells. For electrophysiological experiments, the patch-clamp technique in combination with tools for ultrafast solution exchange was used. Saturating concentrations of GABA or glycine were applied with different concentrations of riluzole to outside-out patches containing alpha(1)beta(2)gamma(2) GABA(A) receptor channels or alpha(1)beta-glycine receptor channels on their surface, respectively. The current declined after application of GABA or glycine with three time constants of desensitization to a steady-state current amplitude. Application of riluzole resulted in a shift to fast desensitized states at both receptors. The proportion of the time constants of fast desensitization increased and the time constants of slow desensitization and the steady-state current decreased whereas the maximal current amplitudes were not affected by riluzole. The data of the study demonstrate for the first time interaction of GABAergic and glycinergic currents with riluzole under physiological conditions.
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PMID:Interaction of the neuroprotective drug riluzole with GABA(A) and glycine receptor channels. 1127 91

Small-conductance, calcium-activated K+ channels (SK channels) are voltage-insensitive channels that have been identified molecularly within the last few years. As SK channels play a fundamental role in most excitable cells and participate in afterhyperpolarization (AHP) and spike-frequency adaptation, pharmacological modulation of SK channels may be of significant clinical importance. Here we report the functional expression of SK3 in HEK293 and demonstrate a broad pharmacological profile for these channels. Brain slice studies commonly employ 4-aminopyridine (4-AP) to block voltage-dependent K+ channels or a methyl derivative of bicuculline, a blocker of gamma-aminobutyric acid (GABA)-gated Cl- channels, in order to investigate the role of various synapses in specialized neural networks. However, in this study both 4-AP and bicuculline are shown to inhibit SK3 channels (IC50 values of 512 microM and 6 microM, respectively) at concentrations lower than those used for brain slice recordings. Riluzole, a potent neuroprotective drug with anti-ischemic, anticonvulsant and sedative effects currently used in the treatment of amyotrophic lateral sclerosis, activates SK3 channels at concentrations of 3 microM and above. Amitriptyline, a tricyclic antidepressive widely used clinically, inhibits SK3 channels with an IC50 of 39.1 +/- 10 microM (n=6).
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PMID:Pharmacological modulation of SK3 channels. 1137 58

Unlike traditional, tracer-based methods of molecular imaging, magnetic resonance spectroscopy (MRS) is based on the behavior of specific nuclei within a magnetic field and the general principle that the resonant frequency depends on the nucleus' immediate chemical environment. Most clinical MRS research has concentrated on the metabolites visible with proton spectroscopy and measured in specified tissue volumes in the brain. This methodology has been applied in various neurodegenerative disorders, most frequently utilizing measures of N-acetylaspartate as a neuronal marker. At short echo times, additional compounds can be quantified, including myo-inositol, a putative marker for neuroglia, the excitatory neurotransmitter glutamate and its metabolic counterpart glutamine, and the inhibitory neurotransmitter gamma-aminobutyric acid. 31P-MRS can be used to study high-energy phosphate metabolites, providing an in vivo assessment of tissue bioenergetic status. This review discusses the application of these techniques to patients with neurodegenerative disorders, including Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis.
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PMID:MR spectroscopy in neurodegenerative disease. 1727 31

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by a progressive loss of motor neurons. Visualizing corresponding metabolic changes in the brain of patients with ALS with proton magnetic resonance spectroscopy ((1)H-MRS) may provide surrogate markers for an early disease detection, for monitoring the progression and for evaluating a treatment response. The primary objective of our study was to evaluate whether modifications in MR metabolite levels occur before clinical disease onset, and whether these changes are directly linked to a distinct spatial progression pattern in the CNS. Therefore, age-dependent alterations in the cerebral and spinal metabolic profile in the mouse model of ALS overexpressing the mutated human G93A-superoxide dismutase 1 (G93A-SOD1) were determined by high-resolution MRS of tissue extracts at 14.1 Tesla. Both non-transgenic mice (control mice) and transgenic mice overexpressing the non-mutated human SOD1 (tg-SOD1) served as controls. In the spinal cord of G93A-SOD1 mice significantly decreased levels of N-acetyl aspartate were already detected 34 days postpartum, i.e. about 60 days before the average disease onset caused by motor neuron decline. In addition, glutamine and gamma-aminobutyric acid concentrations were significantly diminished at Day 75, which is still in the presymptomatic phase of the disease. These metabolic changes were further progressive in the course of the disease and started to involve the brainstem at Day 75. Overall, high-resolution (1)H-MRS allows a sensitive spatial and temporal metabolite profiling in the presymptomatic phase of ALS even before significant neuronal cell loss occurs.
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PMID:Metabolic progression markers of neurodegeneration in the transgenic G93A-SOD1 mouse model of amyotrophic lateral sclerosis. 1743 58


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