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

Continuous subcutaneous administration of polyamine-modified catalase that has increased permeability at the blood-brain barrier showed both a highly significant delay in onset and an increase in survival in a transgenic mouse model of familial amyotrophic lateral sclerosis having a point mutation in the gene encoding copper/zinc superoxide dismutase. These results suggest that hydrogen peroxide-mediated oxidative stress with subsequent free radical damage involving nitric oxide and possibly hydroxyl radicals in motor neurons may be the culprit in familial amyotrophic lateral sclerosis.
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PMID:Therapeutic benefit of polyamine-modified catalase as a scavenger of hydrogen peroxide and nitric oxide in familial amyotrophic lateral sclerosis transgenics. 1111 54

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder that causes motoneuron degeneration, paralysis and death. Mutations in Cu, Zn superoxide dismutase (SOD1) are one cause of this disease. It is widely suspected that increased reactive oxidative species (ROS) is involved in motoneuron degeneration but whether such an involvement plays a role in ALS progression in vivo is uncertain. We treated mice expressing human mutant SOD1 G93A with EUK-8 and EUK-134, two synthetic SOD/catalase mimetics that have shown efficacy in several animal models of human diseases. These treatments reduced levels of oxidative stress and prolonged survival. The results suggest that oxidative stress plays an active role in ALS and illustrate the potential for treatment strategies aimed specifically against ROS.
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PMID:Synthetic superoxide dismutase/catalase mimetics reduce oxidative stress and prolong survival in a mouse amyotrophic lateral sclerosis model. 1134 26

Evidence of oxidative stress is apparent in both acute and chronic neurodegenerative diseases, such as stroke, Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). Increased generation of reactive oxygen species simply overwhelm endogenous antioxidant defences, leading to subsequent oxidative damage and cell death. Tissue culture and animal models have been developed to mimic some of the biochemical changes and neuropathology found in these diseases. In doing so, it has been experimentally demonstrated that oxidative stress plays a critical role in neuronal cell death. Antioxidant enzymes, such as superoxide dismutase (SOD), catalase and glutathione peroxidase (GPx) have demonstrated therapeutic efficacy in models of neurodegeneration. However, delivery and stability issues have reduced the enthusiasm to clinically develop these proteins. Most recently, SOD mimetics, small molecules which mimic the activity of endogenous superoxide dismutase, have come to the forefront of antioxidant therapeutics. This review will examine the experimental evidence supporting the use of scavengers of superoxide anions in treating some neurodegenerative diseases, such as stroke, PD and ALS, but also the pitfalls that have met antioxidant molecules in clinical trials.
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PMID:Oxidative stress in neurodegenerative diseases: therapeutic implications for superoxide dismutase mimetics. 1271 37

Glutamate excitotoxicity is implicated in the aetiology of amyotrophic lateral sclerosis (ALS) with impairment of glutamate transport into astrocytes a possible cause of glutamate-induced injury to motor neurons. It is possible that mutations of Cu/Zn superoxide dismutase (SOD1), responsible for about 20% of familial ALS, down-regulates glutamate transporters via oxidative stress. We transfected primary mouse astrocytes to investigate the effect of the FALS-linked mutant hSOD1(G93A) and wild-type SOD1 (hSOD1wt) on the glutamate uptake system. Using western blotting, immunocytochemistry and RT-PCR it was shown that expression of either hSOD1(G93A) or hSOD1wt in astrocytes produced down-regulation of the levels of a glutamate transporter GLT-1, without alterations in its mRNA level. hSOD1(G93A) or hSOD1wt expression caused a decrease of the monomeric form of GLT-1 without increasing oxidative multimers of GLT-1. The effects were selective to GLT-1, since another glutamate transporter GLAST protein and mRNA levels were not altered. Reflecting the decrease in GLT-1 protein, [3H]d-aspartate uptake was reduced in cultures expressing hSOD1(G93A) or hSOD1wt. The hSOD1-induced decline in GLT-1 protein and [3H]d-aspartate uptake was not blocked by the antioxidant Trolox nor potentiated by antioxidant depletion using catalase and glutathione peroxidase inhibitors. Measurement of 2',7'-dichlorofluorescein (DCF)-induced fluorescence revealed that expression of hSOD1(G93A) or hSOD1wt in astrocytes does not lead to detectable increase of intracellular reactive oxygen species. This study suggests that levels of GLT-1 protein in astrocytes are reduced rapidly by overexpression of hSOD1, and is due to a property shared between the wild-type and G93A mutant form, but does not involve the production of intracellular oxidative stress.
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PMID:Expression of SOD1 G93A or wild-type SOD1 in primary cultures of astrocytes down-regulates the glutamate transporter GLT-1: lack of involvement of oxidative stress. 1469 May 36

The brain is deficient in oxidative defense mechanisms and hence is at greater risk of damage mediated by reactive oxygen species (ROS) resulting in molecular and cellular dysfunction. Emerging evidence suggesting the activation of glutamate gated cation channels, may be another source of oxidative stress, leading to neuronal degeneration. Oxidative stress has been implicated in the development of neurodegenerative diseases like Parkinsonism, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, epileptic seizures, and stroke. Melatonin, the pineal hormone, acts as a direct free radical scavenger and indirect antioxidant. It is suggested that the increase in neurodegenerative diseases is attributable to a decrease in the levels of melatonin with age. Melatonin has been shown to either stimulate gene expression for the antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase) or to increase their activity. Additionally, it neutralizes hydoxyl radical, superoxide radical, peroxyl radical, peroxynitrite anion, singlet oxygen, hydrogen peroxide, nitric oxide, and hypochlorous acid. Unlike other antioxidants, melatonin can easily cross all morphophysiological barriers, e.g., the blood brain barrier, and enters cells and subcellular compartments. Though evidence are accumulating to suggest the potential of melatonin in neurodegenerative conditions, much information needs to be generated before the drug can find place in neurology clinics.
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PMID:Neuroprotective role of melatonin in oxidative stress vulnerable brain. 1526 48

Recent studies suggest that motor neuron (MN) death may be non-cell autonomous, with cell injury mediated by interactions involving non-neuronal cells, such as microglia and astrocytes. To help define these interactions, we used primary MN cultures to investigate the effects of microglia activated by lipopolysaccharide or IgG immune complexes from patients with amyotrophic lateral sclerosis. Following activation, microglia induced MN injury, which was prevented by a microglial iNOS inhibitor as well as by catalase or glutathione. Glutamate was also required since inhibition of the MN AMPA/kainate receptor by CNQX prevented the toxic effects of activated microglia. Peroxynitrite and glutamate were synergistic in producing MN injury. Their toxic effects were also blocked by CNQX and prevented by calcium removal from the media. The addition of astrocytes to cocultures of MN and activated microglia prevented MN injury by removing glutamate from the media. The protective effects could be reversed by inhibiting astrocytic glutamate transport with dihydrokainic acid or pretreating astrocytes with H2O2. Astrocytic glutamate uptake was also decreased by activated microglia or by added peroxynitrite. These data suggest that free radicals released from activated microglia may initiate MN injury by increasing the susceptibility of the MN AMPA/kainate receptor to the toxic effects of glutamate.
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PMID:Activated microglia initiate motor neuron injury by a nitric oxide and glutamate-mediated mechanism. 1545 95

A critical role of mitochondrial dysfunction and oxidative damage has been hypothesized in both aging and neurodegenerative diseases. Much of the evidence has been correlative, but recent evidence has shown that the accumulation of mitochondrial DNA mutations accelerates normal aging, leads to oxidative damage to nuclear DNA, and impairs gene transcription. Furthermore, overexpression of the antioxidant enzyme catalase in mitochondria increases murine life span. There is strong evidence from genetics and transgenic mouse models that mitochondrial dysfunction results in neurodegeneration and may contribute to the pathogenesis of Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, hereditary spastic paraplegia, and cerebellar degenerations. Therapeutic approaches targeting mitochondrial dysfunction and oxidative damage in these diseases therefore have great promise.
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PMID:Mitochondria take center stage in aging and neurodegeneration. 1617 23

Markers of oxidative stress have been found in spinal cord, cortex, cerebrospinal fluid, and plasma of SALS patients. Mitochondrial and calcium metabolism dysfunction were also found in peripheral lymphocytes from SALS patients. In this study, we demonstrate that lymphocytes from SALS patients are more prone to undergo alteration of cell membrane integrity both in basal conditions and following oxidative stress induced by H2O2 treatment. The expression of the antioxidant proteins, Bcl-2, SOD1 and catalase in basal conditions, was significantly lower in lymphocytes from SALS patients than in lymphocytes from age and sex matched controls. Exposure to H2O2 induced a time-dependent decrease of Bcl-2 and SOD1 in control lymphocytes. Conversely, the levels of these proteins remained unchanged in SALS lymphocytes even after 18 h stress. Catalase expression was not significantly modified by oxidative stress. Our results demonstrate that two factors involved in the genesis and/or progression of the familial form of the disease with SOD1 mutation are altered also in the sporadic form of ALS and suggest that the oxidative stress protection pathway is deregulated in lymphocytes from ALS patients.
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PMID:Modified expression of Bcl-2 and SOD1 proteins in lymphocytes from sporadic ALS patients. 1649 3

Amyotrophic lateral sclerosis (ALS) is caused by motor neuron loss in the spinal cord, but the mechanisms responsible are not known. Ubiquitous transgenic overexpression of copper/zinc superoxide dismutase (SOD1) mutations causing familial ALS (SOD1mut) leads to an ALS phenotype in mice; however, restricted expression of SOD1mut in neurons alone is not sufficient to cause this phenotype, suggesting that non-neuronal SOD1mut expression is also required for disease manifestation. Recently, several investigators have suggested that SOD1mut -mediated oxidative stress in skeletal muscle may contribute to ALS pathogenesis. The purpose of this study was to examine oxidative stress and antioxidant enzyme adaptation in 95-day-old SOD1-G93A skeletal muscle. We observed significant elevations in both malondialdehyde (22% and 31% in red and white gastrocnemius, respectively) and protein carbonyls (53% in red gastrocnemius) in SOD1-G93A mice. Copper/zinc SOD activity was higher in red and white SOD1-G93A gastrocnemius (7- and 10-fold, respectively), as was manganese SOD (4- and 5-fold, respectively) and catalase (2- and 2.5-fold, respectively). Taken together, our data demonstrate oxidative stress and compensatory antioxidant enzyme upregulation in SOD1-G93A skeletal muscle.
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PMID:Oxidative stress and antioxidant enzyme upregulation in SOD1-G93A mouse skeletal muscle. 1658 67


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