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)

Experimental evidence has implicated oxidative stress in the development of Parkinson's disease, amyotrophic lateral sclerosis, and other degenerative neuronal disorders. Recently, peroxynitrite, which is formed by the nearly diffusion-limited reaction of nitric oxide with superoxide, has been suggested to be a mediator of oxidant-induced cellular injury. The potential role of peroxynitrite in the pathology associated with Parkinson's disease was evaluated by examining its effect on DOPA synthesis in PC12 pheochromocytoma cells. Peroxynitrite was generated from the compound 3-morpholinosydnonimine (SIN-1), which releases superoxide and nitric oxide simultaneously. Exposure of PC12 cells to peroxynitrite for 60 min greatly diminished their ability to synthesize DOPA without apparent cell death. The inhibition was due neither to the formation of free nitrotyrosine nor the oxidation of DOPA by peroxynitrite. The inhibition in DOPA synthesis by SIN-1 was abolished when superoxide was scavenged by the addition of superoxide dismutase. These data indicated that neither nitric oxide nor hydrogen peroxide generated by the dismutation of superoxide is responsible for the SIN-1-mediated inhibition of DOPA production. The inhibition of DOPA synthesis at high concentration of SIN-1 persisted even after removal of SIN-1. The inactivation of the tyrosine hydroxylase may be responsible for the significant decline in DOPA formation by peroxynitrite. Inactivation of tyrosine hydroxylase may be part of the initial insult in oxidative damage that eventually leads to cell death.
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PMID:Peroxynitrite-mediated inhibition of DOPA synthesis in PC12 cells. 759 27

A dramatic loss of glutamate transport has been observed in sporadic amyotrophic lateral sclerosis and has been postulated to contribute to the disease. Experimentally, this hypothesis was corroborated by mimicking the chronic loss of glutamate transport in postnatal rat spinal cord organotypic cultures through the use of glutamate transport inhibitors. This system is characterized by a relatively selective slow loss of ventral horn motor neurons resulting from glutamate transport inhibition. In this study, spinal cord organotypic cultures were used to test various drugs to evaluate their neuroprotective properties against this slow glutamate-mediated neurotoxicity The most potent neuroprotectants were drugs that altered glutamate neurotransmission, including non-NMDA receptor antagonists (GYKI-52466, PD144216, and PD13997) and drugs that could block presynaptic release or synthesis (riluzole and gabapentin). In addition, some antioxidants (U83836E and N-t-butyl-alpha-phenylnitrone) and inhibitors of nitric oxide synthesis (NG-monomethyl-L-arginine acetate) were modestly neuroprotective. The calcium endonuclease inhibitor aurintricarboxylic acid and the calcium release inhibitor dantrolene also provided partial motor neuron protection. However, several antioxidants and calcium channel antagonists had no excitotoxic neuroprotectant activity. This system provides a preclinical screening method for the burgeoning number of drugs postulated for clinical trials in motor neuron disease and a model to evaluate the mechanisms of chronic glutamate toxicity.
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PMID:Neuroprotective strategies in a model of chronic glutamate-mediated motor neuron toxicity. 761 20

N-methyl-D-aspartate receptors, found throughout the mammalian brain, are a component of the major excitatory transmitter system. Strong evidence exists that N-methyl-D-aspartate receptors, by promoting excessive entry of Ca2+ into neurons, play a role in neuronal damage that follows head injury, strokes, and epileptic seizures, and is associated with degenerative diseases such as Alzheimer's disease. Huntington's disease, Parkinson's disease, and amyotrophic lateral sclerosis. We have investigated whether N-methyl-D-aspartate receptors exist in peripheral neurons, and, if so, whether their activation may result in tissue injury. We report that N-methyl-D-aspartate receptors exist in the lung, that their activation triggers acute injury, and that, as in toxicity to central neurons, this injury is associated with stimulation of nitric oxide synthesis, and can be attenuated by inhibition of this synthesis. Finally, vasoactive intestinal peptide, which protects the lung and heart against oxidant injury and promotes neuronal survival and differentiation also prevented N-methyl-D-aspartate lung injury, apparently by inhibiting a key neurotoxic action of nitric oxide, but not its production. The findings suggest that N-methyl-D-aspartate receptors exist in the peripheral nervous system and that activation of these receptors, resulting in damage to peripheral neurons, may be a novel mechanism of lung and other organ injury.
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PMID:N-methyl-D-aspartate receptors outside the central nervous system: activation causes acute lung injury that is mediated by nitric oxide synthesis and prevented by vasoactive intestinal peptide. 761 71

Environmental toxins may be risk factors for some forms of diabetes mellitus and neurodegenerative diseases. The medicinal and food use of seed from the cycad plant (Cycas spp.), which contains the genotoxin cycasin, is a proposed etiological factor for amyotrophic lateral sclerosis/Parkinsonism-dementia complex (ALS/PDC), a prototypical neurodegenerative disease found in the western Pacific. Patients with ALS/PDC have a very high prevalence of glucose intolerance and diabetes mellitus (in the range of 50-80%). We investigated whether the cycad plant toxin cycasin (methylazoxymethanol (MAM) beta-D-glucoside) or the aglycone MAM are toxic in vitro to mouse or human pancreatic islets of Langerhans. Mouse pancreatic islets treated for 6 days with cycasin impaired the beta-cell insulin response to glucose, but this effect was reversible after a further 4 days in culture without the toxin. When mouse islets were exposed for 24 hr to MAM/MAM acetate (MAMOAc; 0.1-1.0 mM), there was a dose-dependent impairment in insulin release and glucose metabolism, and a significant decrease in islet insulin and DNA content. At higher MAM/MAMOAc concentrations (1.0 mM), widespread islet cell destruction was observed. Glucose-induced insulin release remained impaired even after removal of MAM and a further culturing for 4 days without the toxin. MAM damages islets by two possible mechanisms: (a) nitric oxide generation, as judged by increased medium nitrite accumulation; and (b) DNA alkylation, as judged by increased levels of O6-methyldeoxyguanosine in cellular DNA. Incubation of mouse islets with hemin (10 or 100 microM), a nitric oxide scavenger, or nicotinamide (5-20 mM) protected beta-cells from a decrease in glucose oxidation by MAM. In separate studies, a 24 hr treatment of human beta-islet cells with MAMOAc (1.0 mM) produced a significant decrease in both insulin content and release in response to glucose. In conclusion, the present data indicate that cycasin and its aglycone MAM impair both rodent and human beta-cell function which may lead to the death of pancreatic islet cells. These data suggest that a "slow toxin" may be a common aetiological factor for both diabetes mellitus and neurodegenerative disease.
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PMID:Cycad toxin-induced damage of rodent and human pancreatic beta-cells. 764 37

Nitric oxide has been proposed to mediate cytotoxic effects in inflammatory diseases. To investigate the possibility that overproduction of nitric oxide might play a role in the neuropathology of inflammatory and noninflammatory neurological diseases, we compared levels of the markers of nitric oxide, nitrite plus nitrate, in the CSF of controls with those in patients with various neurologic diseases, including Huntington's and Alzheimer's disease, amyotrophic lateral sclerosis, and HIV infection. We found that there were no significant increases in the CSF levels of these nitric oxide metabolites, even in patients infected with HIV or in monkeys infected with poliovirus, both of which have significantly elevated levels of the neurotoxin quinolinic acid and the marker of macrophage activation, neopterin. However, CSF quinolinic acid, neopterin, and nitrite/nitrate levels were significantly increased in a small group of patients with bacterial and viral meningitis.
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PMID:Cerebrospinal fluid nitrite/nitrate levels in neurologic diseases. 805 62

Cognitive impairment in the absence of lesions indicative of Alzheimer's disease and other dementing conditions has long been recognized in a subgroup of patients with motor neuron disease MND), including amyotrophic lateral sclerosis. However, the mechanisms underlying this cognitive deterioration and its relationship with the relatively selective involvement of motor neurons remains elusive. We used histo- and immunocytochemical labeling methods to study the nitrogen monoxide (NO; a.k.a. nitric oxide) synthase (NOS)-/NADPH diaphorase-containing neurons (NOSN) in three patients with MND and dementia (MND+D), two patients with MND without dementia, and 19 controls that included patients with Alzheimer and non-Alzheimer dementias. Patients with MND+D, but not those with MND without dementia, exhibit numerous dystrophic perikarya and neurites throughout all sensory, motor, association, and limbic neocortices examined. Interestingly, affected NOSN appear to correspond to some subtypes (smooth stellate and spiny neurons), while other neurons containing the same molecular phenotype (such as layer I local circuit neurons and layer II granule cells) are either spared or significantly less affected. These observations indicate that cognitive impairment and dementia in MND may be due, at least in part, to a pancortical involvement of certain types of NOSN. Consequently, the elucidation of the factors that make NOSN vulnerable in MND, and the prevention or pharmacological palliation of their loss, may eventually help to prevent or ameliorate cognitive impairment in MND and may also shed some light on the nature of the insult that targets motor neurons.
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PMID:Alterations in nitrogen monoxide-synthesizing cortical neurons in amyotrophic lateral sclerosis with dementia. 855 69

Oxidative stress has been proposed as a pathogenetic mechanism in Alzheimer's disease. One mechanism of oxidative damage is the nitration of tyrosine residues in proteins, mediated by peroxynitrite breakdown. Peroxynitrite, a reaction product of nitric oxide and superoxide radicals, has been implicated in N-methyl-D-aspartate receptor-mediated excitotoxic damage. Reported evidence of oxidative stress in Alzheimer's disease includes increased iron, alterations in protective enzymes, and markers of oxidative damage to proteins and lipids. In this report, we demonstrate the presence of nitrotyrosine in neurofibrillary tangles of Alzheimer's disease. Nitrotyrosine was not detected in controls lacking neurofibrillary tangles. Immunolabeling was demonstrated to be specific nitrotyrosine in a series of control experiments. These observations link oxidative stress with a key pathological lesion of Alzheimer's disease, the neurofibrillary tangle, and demonstrate a pathogenetic mechanism in common with the other major neurodegenerative diseases of aging, Parkinson's disease and amyotrophic lateral sclerosis. These findings further implicate nitric oxide expression and excitotoxicity in the pathogenesis of cell death in Alzheimer's disease.
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PMID:Evidence of neuronal oxidative damage in Alzheimer's disease. 868 45

Oxidative stress refers to the cytopathologic consequences of a mismatch between the production of free radicals and the ability of the cell to defend against them. Growing data from experimental models and human brain studies suggest oxidative stress may play an important role in neuronal degeneration in diseases such as Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis. Mitochondrial oxidative metabolism, nitric oxide, phospholipid metabolism, and proteolytic pathways are potential sources of intracellular free radicals. Alterations in free radical defense systems may also contribute to oxidative stress. A net increase in reactive oxygen species can produce damage to lipids, proteins, and DNA and induce necrosis or apoptosis. Elucidating the pathways important in the production of and defense from free radicals may be important in devising new pharmacologic strategies to slow or halt neuronal degeneration.
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PMID:Oxidative stress in neurodegenerative diseases. 872 83

To investigate whether nitric oxide (NO) plays a role in degenerative neurologic disease (DND), we measured nitrite, nitrate and cyclic GMP in cerebrospinal fluid (CSF) samples from patients with Parkinson's disease (PD), spinocerebellar ataxia (SCA) and amyotrophic lateral sclerosis (ALS). We found no significant change in CSF nitrite, nitrate or cyclic GMP in patients with any DND compared with control values. These results suggest that NO production is preserved in PD, SCA and ALS.
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PMID:Nitrite, nitrate and cGMP in the cerebrospinal fluid in degenerative neurologic diseases. 874 72

Peroxynitrite, formed from nitric oxide and superoxide, may affect neurofilament assembly and cause neurofilament accumulation in motoneurons. This hypothesis may reconcile the mutations of two genes: superoxide dismutase-1 in some patients with familial amyotrophic lateral sclerosis, and the gene for the heavy neurofilament in some patients with sporadic amyotrophic lateral sclerosis previously reported. We found colocalization of superoxide dismutase-1 and nitric oxide synthase in the foci of neurofilament accumulation as 'conglomerates' in upper motor neurons and 'axonal spheroids' in lower motor neurons. In addition, all the specific molecules related to the reactions, including calmodulin, 3', 5'-cyclic guanosine-monophosphate, citrulline, and nitrotyrosine were found strongly immunopositive in the site of neurofilament accumulation. Our data support the view that the neurofilament aggregates are tightly linked with superoxide dismutase-1 and nitric oxide synthase activities. Both enzymes may focally contribute to peroxynitrite formation at light neurofilament, which is rich in both tyrosine and arginine residues and hence considered as the vulnerable site for nitrotyrosine formation. Nitrotyrosine is known to inhibit phosphorylation and if it impairs phosphorylation of neurofilament subunits, either light or heavy, may alter the slow axonal transport culminating in proximo-distal accumulation of NF and slowly progressive motoneuron death.
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PMID:Colocalization of NOS and SOD1 in neurofilament accumulation within motor neurons of amyotrophic lateral sclerosis: an immunohistochemical study. 881 14


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