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)

The elevation of taurine level in the central nervous system of patients with amyotrophic lateral sclerosis (ALS) indicates the presence of derangement in sulfur amino acid metabolism in this disease. In the metabolic pathway from methionine to taurine and in its branch pathways, excitatory sulfur amino acids are formed. These are cysteine (Cys), cysteine sulfinic acid (CSA), cysteic acid (CA), homocysteine sulfinic acid (HCSA), homocysteic acid (HCA) and S-sulfo cysteine (SC). This study was undertaken to investigate whether these excitatory sulfur amino acids have any cytotoxicity, since excitotoxicity has recently been implicated in the pathogenesis of ALS. Primary cultures of cerebral neurons were prepared from fetal rats, using an established method. Neuronal cell injury was assessed by examination of cultures with phase-contrast microscopy and with bright-field examination of trypan blue staining, a dye staining non-viable cells. The morphological estimate of cell injury was confirmed by the measurement of the activity of lactate dehydrogenase, released from damaged or destroyed cells, in the extracellular fluid. This convenient and quantitative index invariably correlated with the morphological estimates. Among the 6 sulfur amino acids, CSA and HCSA showed cytotoxicity, while Cys, CA, HCA and SC did not. K0.5 of CSA was 80 microM, and that of HCSA was 300 microM. The cytotoxicity of CSA was stronger than that of glutamate, K0.5 of which was 100 microM. Relevance of these excitotoxic sulfur amino acids, especially CSA to the pathogenesis of ALS has not been studied. This possibility will be a subject for future study.
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PMID:[Cytotoxicity of excitatory sulfur amino acids in primary cultured rat cerebral neurons]. 882 91

Excitatory sulfur amino acids (SAAs) seem to be important, because derangement of SAA metabolism has been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). Since the concentration of excitatory SAAs in the neural tissue is extremely low, their presence or absence has not been conclusive in the literature. I determined cysteine sulfinic acid (CSA), cysteic acid (CA), homocysteine sulfinic acid (HCSA) and homocysteic acid (HCA) in rat brain by high-performance liquid chromatography using a Shimazu HPLC system LC10. Among the 4 excitatory SAAs mentioned above, the peaks of CA, HCSA and HCA did not appear at the chromatographic retention time corresponding to that of the authentic compounds. Only the peak of CSA was identified by matching retention time with the external standard as well as consistent co-elution with the added authentic compound. Thus the existence of CSA was confirmed and its concentration was 9.18 +/- 3.54 pmol/mg wet weight. Although the other 3 excitatory SAAs were not detected in rat brain, their presence in human brain cannot presently be excluded, because the size of the amino acid pool in rat brain is not the same as that in human brain. I examined in rat brain whether the concentration of CSA would possibly change when taurine, the final product of the metabolic pathway of SAAs, is experimentally increased. The inhalation of nitrous oxide (N2O) and the thyroidectomy have both been known to give rise to the elevation of taurine in the central nervous system, the mechanism of which is reportedly due to the impairment of the folate cycle. The metabolic flow of the SAA pathway is increased as a result of slowing down of the folate cycle, the damage of which has been shown in the brain of N2O-inhaled rats and thyroidectomized rats as well as of patients with ALS. The concentration of CSA was significantly increased in the cerebrum and the brainstem of the N2O-inhaled rats and the thyroidectomized rats, and in the cerebellum of the latter. CSA, recently demonstrated as a neurotransmitter, has been reported to have neurotoxicity stronger than that of gultamate in cultured rat cerebral neurons. The measurement of excitatory SAAs, especially CSA in nervous tissue of ALS will be required, although relevance of excitatory SAAs to the pathogenesis of ALS is not certain at present.
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PMID:[Changes in cysteine sulfinic acid in rat brain under the experimental elevation of taurine content]. 890 83

Transport of glutamate, the disturbance of which has been implicated in amyotrophic lateral sclerosis (ALS), may be influenced by various substances. Excitatory sulfur amino acids (SAAs) could be increased in ALS, because the elevation of taurine, the final product of the metabolic pathway of SAAs, has been reported in this intractable disease. I examined effects of excitatory SAAs on the transport of glutamate in synaptosomes. Synaptosome fractions were prepared by discontinuous density-gradient centrifugation from the rat cerebral cortex, and were incubated at 35 degrees C with varying concentrations of L-[3H] glutamate in the absence or presence of excitatory SAAs; cysteine sulfinic acid (CSA), cysteic acid (CA), homocysteine sulfinic acid (HCSA), homocysteic acid (HCA) and S-sulfocysteine (SC). Kinetic characterization of uptake confirmed the high-affinity nature of the transport system, the Michaelis constant (Km) for glutamate uptake being 10 microM. The nature of inhibition was competitive. Potent inhibition of transport was exhibited by CSA and CA, whereas substantially weaker inhibitory effects were exhibited by HCSA, and almost no effects by HCA or SC. Inhibition by excitatory SAAs, especially CSA and CA of the high-affinity glutamate transporter may be involved in the pathogenesis of ALS.
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PMID:[Effects of excitatory sulfur amino acids on glutamate transport in synaptosomes isolated from the rat cerebral cortex]. 1034 42

In the neural tissue of patients with amyotrophic lateral sclerosis (ALS), the elevation of taurine, the final product of the metabolic pathway of sulfur amino acids (SAAs), has been reported, suggesting that excitatory SAAs, the intermediates of this pathway, could also be increased. This study was undertaken to evaluate whether excitatory SAAs have the ability to inhibit cystine uptake. Since immature neurons have not yet expressed the receptor channels, they are not susceptible to excitotoxicity. Inhibition of cystine transport leads to a depletion of glutathione, and results in cell death due to oxidative stress. Cell cultures were obtained from the cerebral cortex of fetal Wistar rats. Cytotoxicity studies were performed 48 hours after plating by addition of the culture medium containing SAAs; cysteine sulfinic acid, cysteic acid, homocysteine sulfinic acid (HCSA), homocysteic acid (HCA) and S-sulfocysteine. Cell death was quantified by the release of the cytosolic enzyme lactate dehydrogenase, and single cell assessment of apoptosis was carried out by staining cells with acridine orange, DNA isolation and agarose gel electrophoresis were also performed. Protection of cycloheximide, a protein synthesis inhibitor, against non-receptor mediated excitatory SAA cytotoxicity was also assessed. HCA and HCSA showed cytotoxicity, the morphology and biochemistry of which were compatible to apoptosis. It will be a subject for future study to examine whether this mechanism of cell death is primarily present in ALS.
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PMID:[Apoptosis induced by excitatory sulfur amino acids in primary cultured rat immature cerebral neurons]. 1034 43

Mutations in human Cu,Zn-superoxide dismutase (SOD1) cause approximately 20% of familial amyotrophic lateral sclerosis (FALS) cases. The mechanism of late-onset disease manifestation despite the innate mutation has no clear explanation. The relationship between homocysteine (HC) and amyotrophic lateral sclerosis (ALS) has not been investigated, in spite of the similarity in their pathogenesis. We investigated the effect of HC on the motor neuronal cell-line transfected with SOD1 of either wild-type or one of two mutant forms (G93A and A4V). In the MTT assay, HC induced significant cytotoxicity in A4V, but not in G93A, as compared with wild-type, even at the physiological concentration of 10 microM. This HC-induced cytotoxicity was inhibited by the antioxidant trolox and the Cu (I) chelator bathocuproinedisulfonate. Here we show that the vulnerability of the A4 V mutant involves the cytotoxic copper-mediated pathway, and that HC may be a lifelong precipitating factor in some forms of FALS, suggesting the possible treatment modality with vitamin supplements.
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PMID:Homocysteine induces oxidative cytotoxicity in Cu,Zn-superoxide dismutase mutant motor neuronal cell. 1193 Jan 44

Major achievements made over the last several years have highlighted the important roles of creatine and the creatine kinase reaction in health and disease. Inborn errors of metabolism have been identified in the three main steps involved in creatine metabolism: arginine:glycine amidinotransferase (AGAT), S-adenosyl-L-methionine:N-guanidinoacetate methyltransferase (GAMT), and the creatine transporter. All these diseases are characterized by a lack of creatine and phosphorylcreatine in the brain, and by (severe) mental retardation. Similarly, knockout mice lacking the brain cytosolic and mitochondrial isoenzymes of creatine kinase displayed a slightly increased creatine concentration, but no phosphorylcreatine in the brain. These mice revealed decreased weight gain and reduced life expectancy, disturbed fat metabolism, behavioral abnormalities and impaired learning capacity. Oral creatine supplementation improved the clinical symptoms in both AGAT and GAMT deficiency, but not in creatine transporter deficiency. In addition, creatine supplementation displayed neuroprotective effects in several animal models of neurological disease, such as Huntington's disease, Parkinson's disease, or amyotrophic lateral sclerosis. All these findings pinpoint to a close correlation between the functional capacity of the creatine kinase/phosphorylcreatine/creatine system and proper brain function. They also offer a starting-point for novel means of delaying neurodegenerative disease, and/or for strengthening memory function and intellectual capabilities.Finally, creatine biosynthesis has been postulated as a major effector of homocysteine concentration in the plasma, which has been identified as an independent graded risk factor for atherosclerotic disease. By decreasing homocysteine production, oral creatine supplementation may, thus, also lower the risk for developing, e.g., coronary heart disease or cerebrovascular disease. Although compelling, these results require further confirmation in clinical studies in humans, together with a thorough evaluation of the safety of oral creatine supplementation.
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PMID:Health implications of creatine: can oral creatine supplementation protect against neurological and atherosclerotic disease? 1204 43

In the present study, we used the transgenic mice expressing a human Cu/Zn SOD mutation (SOD1(G93A)) as an in vivo model of ALS and performed immunohistochemical studies to investigate the changes of homocysteine in the central nervous system of symptomatic transgenic mice. In control and presymptomatic transgenic mice, homocysteine-immunoreactive astrocytes were not detected in any region. In symptomatic transgenic mice, homocysteine-immunoreactive astrocytes were distributed in the spinal cord, brainstem and cerebellar nuclei of transgenic mice. In the hippocampal formation of transgenic mice, pyramidal cells in the CA1-3 regions and granule cells in the dentate gyrus showed homocysteine immunoreactivity. The present study provides the first in vivo evidence that homocysteine immunoreactive astrocytes were found in the central nervous system of symptomatic SOD(G93A) transgenic mice, suggesting that reactive astrocytes may play an important role in the pathogenesis and progress of ALS. This study also suggests that increased expression of homocysteine in the hippocampal neurons might reflect a role of homocysteine in an abnormality of hippocampal function of ALS.
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PMID:Immunohistochemical study on the distribution of homocysteine in the central nervous system of transgenic mice expressing a human Cu/Zn SOD mutation. 1265 Sep 83

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease caused by selective degeneration of motor neurons. Mutations in copper/zinc superoxide dismutase (SOD1) account for 20% cases of familial ALS (fALS), but the underlying pathogenetic mechanisms are largely unknown. Using SOD1(G93A) mice model of ALS, we demonstrated that mutation in SOD1 caused a significant increase in the level of plasma homocysteine (Hcy). To investigate whether Hcy-lowering therapy is beneficial to this disease, we applied folic acid (FA) and vitamin B12 which are important factors involved in the Hcy metabolism to assess the neuroprotective effect of FA and B12 in the SOD1(G93A) mice. Our results showed FA or FA+B12 treatment significantly delayed the disease onset and prolonged the lifespan, accompanied by the significant reduction of motor neuron loss. Furthermore, we found that FA or FA+B12 treatment significantly attenuated the plasma Hcy level, suppressed the activation of microglia and astrocytes, and inhibited the expression of inducible nitric oxide synthase (iNOS) and tumor necrosis factor-alpha (TNF-alpha) in spinal cord. Moreover, FA or FA+B12 treatment decreased the levels of cleaved caspase-3 and poly(ADP-ribose)polymerase (PARP) but up-regulated the level of anti-apoptotic protein Bcl-2. However, B12 treatment alone did not show any significant benefit to this disease. These results provide evidence to demonstrate that elevated Hcy is involved in the pathogenesis of fALS and FA therapy may have therapeutic potential for the treatment of the disease.
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PMID:Folic acid protects motor neurons against the increased homocysteine, inflammation and apoptosis in SOD1 G93A transgenic mice. 1843 68

Homocysteine (Hcy) exerts multiple neurotoxic mechanisms that have also been shown to be relevant in the pathogenesis of amyotrophic lateral sclerosis (ALS). We reviewed the published evidence to assess possible correlations between Hcy and ALS. A Medline literature search was performed to identify all studies on Hcy and ALS or motor neurons published from 1 January 1966 through 28 February 2009. Twelve studies (one in vitro, eight in vivo, and three studies on human subjects) were reviewed. The in vitro and in vivo animal studies showed that Hcy can damage motor neurons by inducing oxidative stress and stimulating excitotoxic receptors. In preliminary studies on human subjects, ALS subjects had higher median Hcy levels compared to age- and sex-matched controls. Higher Hcy levels were also correlated with a possible marker of disease progression. Finally, a short-term treatment with a high dose of methylcobalamin, which reduces Hcy levels, was effective in improving compound motor action potentials in patients with ALS. In conclusion, several types of evidence show that accumulation of Hcy may increase the risk and progression of motoneuronal degeneration. If this is confirmed, early interventions to decrease Hcy levels may be useful to modify ALS progression and possibly onset.
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PMID:Homocysteine levels and amyotrophic lateral sclerosis: A possible link. 1955 35

This review focuses on the putative role of hyper-homocysteinemia in the pathogenesis of different diseases affecting the nervous system, including stroke, Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis and amyotrophic lateral sclerosis. However, a firm pathogenic role of homocysteine in these diseases has never been established. Lowering plasma homocysteine levels trough vitamin therapy failed to prevent vascular diseases. Conversely, normalization of hyper-homocysteinemia caused improvement in patients with cognitive impairment. B vitamin deficiency is the main determinant of homocysteine levels. However, it has been hypothesized that homocysteine might be a mere marker of vitamin deficiency or an indicator of disease rather than a risk factor. A more consistent use of thresholds to define deficiency is needed to recommend routine screening, monitoring and supplementation of B vitamins to ameliorate the prognosis of the above mentioned disorders. To date, data are insufficient to firmly establish which one of the hypotheses made is correct and the question concerning the real meaning of hyper-homocysteinemia in the pathology of the nervous system still remains an intriguing medical dilemma.
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PMID:Homocysteine, vitamin determinants and neurological diseases. 2003 53


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