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)

Amyotrophic lateral sclerosis (ALS) is a paralytic disorder characterized by degeneration of large motor neurons of the brain and spinal cord. A subset of ALS is inherited (familial ALS, FALS) and is associated with more than 70 different mutations in the SOD1 gene. Here we report that lymphoblast cell lines derived from FALS patients with 16 different mutations in SOD1 gene exhibit significant increase of intracellular reactive oxygen species (ROS) compared with sporadic ALS (SALS) and normal controls (spouses of ALS patients). The ROS generation did not correlate with SOD1 activity. Further, cells incubated with vitamin C, catalase or the flavinoid quercetin significantly reduced ROS in all groups. The catalase inhibitor 3-amino-1,2,4-triazole resulted in a ten-fold increase of ROS in all groups. Neither L-nitroarginine, a nitric oxide synthase inhibitor or vitamin E altered the ROS levels. Thus, these studies suggest that hydrogen peroxide (H(2)O(2)) is a major ROS elevated in FALS lymphoblasts and it may contribute to the degeneration of susceptible cells. Further, we postulate a mechanism by which increased H(2)O(2) could be generated by mutant SOD1.
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PMID:Increased reactive oxygen species in familial amyotrophic lateral sclerosis with mutations in SOD1. 1093 May 89

Enhanced production of nitrotyrosine and subsequent protein nitration has been proposed as the mechanism by which mutant SOD1 causes death of motor neurons in a familial form of amyotrophic lateral sclerosis (FALS-1). We have tested this hypothesis in a primary culture model in which mutant human SOD1 was expressed in motor neurons of dissociated spinal cord cultures. Preventing formation of nitrotyrosine by inhibiting nitric oxide synthase rescued cultured motor neurons from excitotoxic death induced by adding glutamate to the culture medium, but failed to significantly delay death of motor neurons expressing the G93A mutant SOD1. The results do not support generation of nitrotyrosine being the predominant lethal gain of function conferred by mutations in SOD1.
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PMID:Nitrotyrosination contributes minimally to toxicity of mutant SOD1 associated with ALS. 1133 99

1. The Wobbler mouse suffers an autosomal recessive mutation producing severe motoneuron degeneration and astrogliosis in the spinal cord. It has been considered a suitable model of human motoneuron disease, including the sporadic form of amyotrophic lateral sclerosis (ALS). 2. Evidences exist demonstrating increased oxidative stress in the spinal cord of Wobbler mice, whereas antioxidant therapy delayed neurodegeneration and improved muscle trophism. 21-Aminosteroids are glucocorticoid-derived hydrophobic compounds with antioxidant potency 3 times higher than vitamin E and 100 times higher than methylprednisolone. They do not bind to intracellular receptors, and prevent lipid peroxidation by insertion into membrane lipid bilayers. 3. In common with the spinal cord of ALS patients, Wobbler mice present astrocytosis with hyperexpression of glial fibrillary acidic protein (GFAP), and increased expression of nitric oxide synthase (NOS) and growth-associated protein (GAP-43) in motoneurons. Here, we review our studies on the effects of a 21-aminosteroid on GFAP, NOS, and GAP-43. 4. First, we showed that 21-aminosteroid treatment further increased GFAP-expressing astrocytes in gray matter of the Wobbler spinal cord. This effect may provide neuroprotection if one considers a trophic and beneficial function of astrocytes during the course of degeneration. Other neuroprotectans used in Wobbler mice (T-588) also increased pre-existing astrocytosis. 5. Second, histochemical determination of NADPH-diaphorase, a parameter indicative of neuronal NOS activity, showed that the 21-aminosteroid down-regulated the high activity of this enzyme in ventral horn motoneurons. Therefore, suppression of nitric oxide by decreasing NADPH-diaphorase (NOS) activity may provide neuroprotection considering that excess NO is highly toxic to motoneurons. 6. Finally, 21-aminosteroid treatment significantly attenuated the aberrant expression of both GAP-43 protein and mRNA in Wobbler motoneurons. Hyperexpression of GAP-43 possibly indicated abnormal synaptogenesis, denervation, and muscle atrophy, parameters which may return to normal following antioxidant steroid treatment. 7. Besides 21-aminosteroids, other steroids also behave as neuroprotectans. In this regard, degenerative diseases may constitute potential targets of these hormones, based on the fact that the spinal cord expresses in a regional and cell-specific fashion, receptors for androgens. progesterone, adrenal steroids, and estrogens.
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PMID:Cellular basis of steroid neuroprotection in the wobbler mouse, a genetic model of motoneuron disease. 1156 36

Several studies have suggested that excessive generation of nitric oxide (NO) may contribute to the pathogenesis of amyotrophic lateral sclerosis (ALS). Recently, a selective induction of the neuronal isoform of nitric oxide synthase (nNOS) in glial cells has been reported in an animal model of familial ALS. We therefore examined in postmortem tissue the expression of nNOS in patients with sporadic ALS and patients without any history of neurological disease. Using immunohistochemistry, we found an up-regulation of nNOS in glial cells of the spinal cord and subcortical white matter in ALS patients compared to controls. The enhanced glial nNOS expression seen in ALS patients could conceivably contribute to motoneuronal degeneration through NO-mediated cytotoxic effects.
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PMID:Glial cells of the spinal cord and subcortical white matter up-regulate neuronal nitric oxide synthase in sporadic amyotrophic lateral sclerosis. 1157 93

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by selective motor neuronal death. The cause of ALS is unclear, but accumulating evidence, such as the insufficient clearance of glutamate through the glutamate transporter, and the specific distribution of Ca2+-permeable AMPA receptors in spinal motor neurons, indicates that glutamate-induced neurotoxicity is involved in its pathogenesis. Interestingly, nitric oxide (NO), which has been identified as an endothelium-derived relaxing factor (EDRF), was found to be a pivotal inducer of glutamate-induced neuronal death. NO is generated by nitric oxide synthase (NOS), of which there are three subtypes: neuronal NOS expressed mainly in neurons, inducible NOS in astroglia, and endothelial NOS in vessels. NO-related toxicity is caused by peroxynitrite, formed by the reaction of NO with superoxide anions, resulting in the nitration of tyrosine residues in neurofilaments, irreversible inhibition of the mitochondrial respiratory chain, and inhibition of the glutamate transporter. Clinically, the axonal spheroids of motor neurons are reported to be immunoreactive to anti-nitrotyrosine antibody, and there are elevated levels of the metabolites of NO in the cerebrospinal fluid of ALS patients. Since physiologically normal motor neurons express limited amounts of neuronal NOS, the source of NO is considered to be non-motor neurons expressing neuronal NOS, astroglia expressing inducible NOS, or motor neurons themselves inducing neuronal NOS. Conversely, neurons containing neuronal NOS are known to be resistant to toxic stimuli, which raises the possibility that such neurons are protected by NO. Several mechanisms have been reported to mediate the NO-related neuroprotection, including cyclic guanosine 3',5'-monophosphate (cyclic GMP), a downstream product of NO generation. This review summarizes previous studies on NO, focusing on its dual functions of neurotoxicity or neuroprotection, and discusses the putative roles of NO in relation to the pathogenesis of ALS.
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PMID:The role of nitric oxide in amyotrophic lateral sclerosis. 1167 75

Oxidative stress mediated by nitric oxide (NO) and its toxic metabolite peroxynitrite has previously been associated with motor neuron degeneration in amyotrophic lateral sclerosis (ALS). Degenerating spinal motor neurons in familial and sporadic ALS are typically surrounded by reactive astrocytes expressing the inducible form of NO synthase (iNOS), suggesting that astroglia may have a pathogenic role in ALS. We report here that a brief exposure of spinal cord astrocyte monolayers to peroxynitrite (0.25-1 mM) provoked long-lasting reactive morphological changes characterized by process-bearing cells displaying intense glial fibrillary acidic protein and iNOS immunoreactivity. Furthermore, peroxynitrite caused astrocytes to promote apoptosis of embryonic motor neurons subsequently plated on the monolayers. Neuronal death occurred within 24 hr after plating, as evidenced by the presence of degenerating motor neurons positively stained for activated caspase-3 and nitrotyrosine. Motor neuron death was largely prevented by NOS inhibitors and peroxynitrite scavengers but not by trophic factors that otherwise will support motor neuron survival in the absence of astrocytes. The bacterial lipopolysaccharide, a well-known inflammatory stimulus that induces iNOS expression in astrocytes, provoked the same effects on astrocytes as peroxynitrite. Thus, spinal cord astrocytes respond to extracellular peroxynitrite by adopting a phenotype that is cytotoxic to motor neurons through peroxynitrite-dependent mechanisms.
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PMID:Peroxynitrite triggers a phenotypic transformation in spinal cord astrocytes that induces motor neuron apoptosis. 1175 77

The authors investigated for a correlation between the expression of nitric oxide synthases (NOSs) with the severity of motor neuronal loss in the anterior horns of patients with amyotrophic lateral sclerosis (ALS). Spinal cords from six patients with ALS and from three normal controls were examined. The sections of cervical, lumbar, and sacral cord including Onuf's nucleus, which are seldom degenerated until the late stage, were stained with three antibodies against NOSs (anti-n-NOS, anti-e-NOS, and anti-i-NOS) using ABC methods. Perikarya of motor neurons in ALS, but not in controls, were immunoreactive against anti-n-NOS and e-NOS. Anti-i-NOS did not recognize the motor neurons of ALS or of controls. The immunoreactivity for n- and e-NOSs was approximately the same in the sections of cervical, lumbar, and sacral cord in ALS. No significant differences in immunoreactivity were observed among the patients with ALS. These results suggest that the expression of NOSs does not immediately affect neuronal loss in ALS.
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PMID:Expression of nitric oxide synthases in the anterior horn cells of amyotrophic lateral sclerosis. 1185 8

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by selective motor neuron death. The exact mechanism responsible for this selectivity is not clear, although it is known that motor neurons are very sensitive to excitotoxicity. This high sensitivity is due to a high density of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors on their surface and to a limited Ca(2+) buffering capacity. Ca(2+) can enter the cell upon stimulation through voltage-operated Ca(2+) channels and through the Ca(2+)-permeable portion of AMPA receptors. How this Ca(2+) kills motor neurons is incompletely understood. In the present study, we report that kainate (KA)-induced motor neuron death is purely mediated through Ca(2+) entering motor neurons through Ca(2+)-permeable AMPA receptors and that voltage-operated Ca(2+) channels play no significant role. In contrast to what has been observed in other neuronal models or after N-methyl-D-aspartate stimulation, NO synthase inhibition and a number of antioxidants did not protect motor neurons from KA-induced death. Only PD150606, derived from alpha-mercaptoacrylic acid and considered as a selective calpain antagonist, inhibited dose-dependently the KA-induced motor neuron death. However, other calmodulin and calpain inhibitors were not effective. At least part of the inhibitory effect of PD150606 is due to an irreversible inhibition of the Ca(2+) influx through the Ca(2+)-permeable AMPA receptor. These results demonstrate the interesting property of PD150606 to interfere with excitotoxicity-dependent motor neuron death and show that PD150606 is not an exclusive calpain/calmodulin antagonist.
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PMID:An alpha-mercaptoacrylic acid derivative (PD150606) inhibits selective motor neuron death via inhibition of kainate-induced Ca2+ influx and not via calpain inhibition. 1198 29

Increasing evidence has suggested that inflammation in the brain is closely associated with the pathogenesis of several degenerative neurologic disorders, including Parkinson's disease, Alzheimer's diseases, multiple sclerosis, amyotrophic lateral sclerosis, and AIDS dementia. The hallmark of brain inflammation is the activation of glial cells, especially that of microglia that produce a variety of proinflammatory and neurotoxic factors, including cytokines, fatty acid metabolites, free radicals--such as nitric oxide (NO) and superoxide. Excessive production of NO, as a consequence of nitric oxide synthase induction in activated glia, has been attributed to participate in neurodegeneration. Using primary mixed neuron-glia cultures and glia-enriched cultures prepared from embryonic rodent brain tissues, we have systemically studied the relationship between the production of NO and neurodegeneration in response to stimulation by the inflammagen lipopolysaccharide. This review summarizes our recent findings on the kinetics of NO generation, the relative contribution of microglia and astrocytes to NO accumulation, the relationship between NO production and neurodegeneration, and points of intervention along the pathways associated with NO generation to achieve neuroprotection. We also describe our results relating to the effect of several opioid-related agents on microglial activation and neuroprotection. Among these agents, the opioid receptor antagonist naloxone, especially its non-opioid enantiomer (+)-naloxone, promises to be of potential therapeutic value for the treatment of inflammation-related diseases.
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PMID:Role of nitric oxide in inflammation-mediated neurodegeneration. 1207 84

Missense mutations in the human Cu/Zn superoxide dismutase gene (SOD-1) cause many cases of autosomal dominant familial amyotrophic lateral sclerosis (FALS). The accumulation of intracellular calcium is one of the primary mechanisms of motor neuronal degeneration associated with mutations in SOD-1. In order to investigate the effect of various calcium modulators and the SOD-1 mutation on neuronal death, we tested motoneuron-neuroblastoma hybrid (VSC 4.1) cells constitutively expressing human SOD-1 gene with mutations (A4V, G93A) or wild-type. These cells were treated with endogenous calcium releaser (ryanodine, thapsigargin, cyclic ADP-ribose) or calcium mobilizer through cell membrane (4-bromo-calcium ionophore A23187). In particular, calcium ionophore reduced survival in the cells expressing mutant SOD-1. Cell death was associated with increased nitric oxide (NO) generation. This toxicity was attenuated when a nitric oxide synthase (NOS) inhibitor was added. Exogenous NOadministration (S-nitrosoglutathione) also induced cell death. The NO-dependent guanylyl cyclase-cGMP cascade inhibitor protected the mutant cells from the toxic effects of calcium ionophore. Our data suggests that motoneuron degeneration with the SOD-1 mutation may be mediated by calcium dysregulation, particularly by the exogenous calcium influx. This process induces oxidative stress generation that results in motor neuronal death through the guanylyl cyclase-cGMP dependent cascade.
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PMID:Alteration in intracellular calcium homeostasis reduces motor neuronal viability expressing mutated Cu/Zn superoxide dismutase through a nitric oxide/guanylyl cyclase cGMP cascade. 1215 55


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