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)

1. Free radicals may play an important role in several pathological conditions of the central nervous system (CNS) where they directly injure tissue and where their formation may also be a consequence of tissue injury. 2. Free radicals produce tissue damage through multiple mechanisms, including excito-toxicity, metabolic dysfunction, and disturbance of intracellular homeostasis of calcium. 3. Oxidative stress can significantly worsen acute insults, such as ischemia, as well as chronic neurodegenerative disorders including amyotrophic lateral sclerosis (ALS) and Parkinson's disease. 4. For instance, recent findings suggest a causal role for chronic oxidative stress in familial ALS, as this disease is linked to missence mutations of the copper/zinc superoxide dismutase (SOD). 5. Thus, therapeutic approaches which limit oxidative stress may be potentially beneficial in several neurological diseases.
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PMID:Free radicals as mediators of neuronal injury. 987 73

In the CNS, reactive oxygen species (ROS) have been implicated in a wide range of degenerative processes including amyotrophic lateral sclerosis, ischemia-reperfusion injury, Alzheimer disease, Parkinson disease and aging. However, the exact mechanism is unknown, and there is little information on possible roles of ROS in cell injury and the process on recovery of astrocytes, the most abundant glial cells in the brain. We examined hydrogen peroxide (H2O2)-induced DNA fragmentation and thymidine incorporation into cultured astrocytes as an indicator of the process of recovery from astrocytic DNA injury. Astrocytes were isolated from cerebral cortices of 0-day-old rats and treated with 1 mM dibutyryl cyclic AMP for 4 days. H2O2 of 100 microM stimulated thymidine incorporation into astrocytes. Caffeine, ryanodine, cyclic ADP-ribose (endogenous ryanodine receptor agonist) and beta-NAD+ (precursor of cyclic ADP-ribose) suppressed partially the stimulatory effect of H2O2. Ruthenium red (ryanodine receptor antagonist) facilitated further the stimulatory effect of H2O2. The facilitated effect of ruthenium red on H2O2-induced thymidine incorporation was suppressed by caffeine, ryanodine, cyclic ADP-ribose and beta-NAD+. H2O2-induced DNA fragmentation and astrocytic death were suppressed by ruthenium red. These findings suggest that the process of recovery from astrocytic DNA injury by H2O2 may be regulated by Ca2+ efflux from ryanodine-sensitive intracellular Ca2+ stores.
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PMID:[Role of ryanodine receptors in hydrogen peroxide-induced DNA fragmentation and thymidine incorporation in cultured rat astrocytes]. 1019 Jan 45

As the most predominant excitatory neurotransmitter, glutamate has the potential to influence the function of most neuronal circuits in the central nervous system. To limit receptor activation during signaling and prevent the overstimulation of glutamate receptors that can trigger excitotoxic mechanisms and cell death, extracellular concentrations of excitatory amino acids are tightly controlled by transport systems on both neurons and glial cells. L-Glutamate is a potent neurotoxin, and the inadequate clearance of excitatory amino acids may contribute to the neurodegeneration seen in a variety of conditions, including epilepsy, ischemia, and amyotrophic lateral sclerosis. To establish the contributions of carrier systems to the etiology of neurological disorders, and to consider their potential utility as therapeutic targets, a detailed understanding of transporter function and pharmacology is required. This review summarizes current knowledge of the structural and functional diversity of excitatory amino acid transporters and explores how they might serve as targets for drug design.
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PMID:Excitatory amino acid transporters: a family in flux. 1033 Oct 91

Glutamate excitotoxicity, oxidative stress, and mitochondrial dysfunctions are common features leading to neuronal death in cerebral ischemia, traumatic brain injury, Parkinson's disease, Huntington's disease, Alzheimer's disease and amyotrophic lateral sclerosis. Nitric oxide (NO) alone or in cooperation with superoxide anion and peroxynitrite is emerging as a predominant effector of neurodegeneration The use of NO synthase (NOS) inhibitors and mutant mice lacking each NOS isoform have provided evidence for the injurious effects of NO derived from neuronal or inducible isoforms. New neuroprotective strategies have been proposed with selective NOS inhibitors for the neuronal (ARL17477) or the inducible (1400 W) isoforms or with compounds combining in one molecule selective nNOS inhibition and antioxidant properties (BN 80933), in experimental ischemia-induced acute neuronal damage. The efficacy of these new strategies is well established in acute neuronal injury but remains to be determined in more chronic neurological diseases.
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PMID:Nitric oxide synthases: targets for therapeutic strategies in neurological diseases. 1044 86

Neurological diseases, including global ischemia, Alzheimer's disease and amyotrophic lateral sclerosis, are characterized by selective patterns of neurodegeneration. Most studies of potential glutamate-receptor-mediated contributions to disease have focused on the highly Ca2+-permeable and widely distributed NMDA-receptor channel. However, an alternative hypothesis is that the presence of AMPA- or kainate-receptor channels that are directly permeable to Ca2+ ions (Ca-A/K-receptor channels) is of greater significance to the neuronal loss seen in these conditions. Besides a restricted distribution and high Ca2+ permeability, two other factors make Ca-A/K receptors appealing candidate contributors to selective injury: their high permeability to Zn2+ ions and the possibility that their numbers increase in disease-associated conditions. Further characterization of the functions of these channels should result in new approaches to treatment of these conditions.
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PMID:Ca2+-Zn2+ permeable AMPA or kainate receptors: possible key factors in selective neurodegeneration. 1090

The GLT-1 and GLAST astroglial transporters are the glutamate transporters mainly involved in maintaining physiological extracellular glutamate concentrations. Defects in neurotransmitter glutamate transport may represent an important component of glutamate-induced neurodegenerative disorders (such as amyotrophic lateral sclerosis) and CNS insults (ischemia and epilepsy). We characterized the protein expression of GLT-1 and GLAST in primary astrocyte-neuron cocultures derived from rat hippocampal tissues during neuron differentiation/maturation. GLT-1 and GLAST are expressed by morphologically distinct glial fibrillary acidic protein-positive astrocytes, and their expression correlates with the status of neuron differentiation/maturation and activity. Up-regulation of the transporters paralleled the content of the synaptophysin synaptic vesicle marker p38, and down-regulation was a consequence of glutamate-induced neuronal death or the reduction of synaptic activity. Finally, soluble factors in neuronal-conditioned media prevented the down-regulation of the GLT-1 and GLAST proteins. Although other mechanisms may participate in regulating GLT-1 and GLAST in the CNS, our data indicate that soluble factors dependent on neuronal activity play a major regulating role in hippocampal cocultures.
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PMID:The GLT-1 and GLAST glutamate transporters are expressed on morphologically distinct astrocytes and regulated by neuronal activity in primary hippocampal cocultures. 1093 89

Riluzole is a neuroprotective agent the efficacy of which was proven in amyotrophic lateral sclerosis in human and in animal models of cerebral ischemia. However, the dosage used in animal experiments was much higher than that in human. We investigated the efficacy of low dose riluzole, which was similar to the dose used in human trials, in animal model of global ischemia. Global ischemia was induced in male Mongolian gerbils for 5min under monitoring of rectal temperature. Riluzole (0.8 mg/kg) were injected intraperitoneally 30min before ischemia. Seven days after ischemia, animals were decapitated and surviving nerve cells in hippocampal CA1 area were quantified. The number of surviving cells was compared between in riluzole-treated and control groups and the former showed statistically significant better survivals than the latter (P<0.001).
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PMID:Neuroprotective effect of low dose riluzole in gerbil model of transient global ischemia. 1104 79

Creatine plays a role in cellular energy metabolism and potentially has a role in protein metabolism. Creatine monohydrate supplementation has been shown to result in an increase in skeletal muscle total and phosphocreatine concentration, increase fat-free mass, and enhance high-intensity exercise performance in young healthy men and women. Recent evidence has also demonstrated a neuroprotective effect of creatine monohydrate supplementation in animal models of Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, and after ischemia. A low total and phosphocreatine concentration has been reported in human skeletal muscle from aged individuals and those with neuromuscular disorders. A few studies of creatine monohydrate supplementation in the elderly have not shown convincing evidence of a beneficial effect with respect to muscle mass and/or function. Future studies will be required to address the potential for creatine monohydrate supplementation to attenuate age-related muscle atrophy and strength loss, as well as to protect against age-dependent neurodegenerative disorders such as Parkinson's disease and Alzheimer's disease.
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PMID:Potential benefits of creatine monohydrate supplementation in the elderly. 1108 37

(-)-Deprenyl, used for the treatment of Parkinson's disease, was reported to possess neurorescuing/antiapoptotic effects independent of its MAO-B inhibiting properties. It is metabolized to (-)-desmethyldeprenyl, which seems to be the active principle, and further to (-)-amphetamine and (-)-methamphetamine, which antagonize its rescuing effects. These complications may explain the limited neurorescuing potential of (-)-deprenyl observed clinically. CGP 3466 (dibenzo[b,f]oxepin-10-ylmethyl-methyl-prop-2-ynyl-amine), structurally related to (-)-deprenyl, exhibits virtually no MAO-B nor MAO-A inhibiting properties and is not metabolized to amphetamines. It was shown to bind to glyceraldehyde-3-phosphate dehydrogenase, a glycolytic enzyme with multiple other functions including an involvement in apoptosis, and shows neurorescuing properties qualitatively similar to, but about 100-fold more potent than those of (-)-deprenyl in several in vitro and in vivo paradigms. In concentrations ranging from 10(-13)-10(-5) M, it rescues partially differentiated PC12 cells from apoptosis induced by trophic withdrawal, cerebellar granule cells from apoptosis induced by cytosine arabinoside, rat embryonic mesencephalic dopaminergic cells from death caused by MPP+, and PAJU human neuroblastoma cells from death caused by rotenone. However, it did not affect apoptosis elicited by a variety of agents in rapidly proliferating cells from thymus or skin or in liver or kidney cells. In vivo, it rescued facial motor neuron cell bodies in rat pups after axotomy, rat hippocampal CA1 neurons after transient ischemia/hypoxia, and mouse nigral dopaminergic cell bodies from death induced by MPTP, in doses ranging between 0.0003 and 0.1 mg/kg p.o. or s.c., depending on the model. It also partially prevented the loss of tyrosine hydroxylase immunoreactivity in the substantia nigra of 6-OHDA-lesioned rats and improved motor function in these animals. Moreover, it prolonged the life-span of progressive motor neuronopathy (pmn) mice (a model for ALS), preserved their body weight and improved their motor performance. This was accompanied by a decreased loss of motor neurons and motor neuron fibers, and protection of mitochondria. The active concentration- or dose-ranges in the different in vitro and in vivo paradigms were remarkably similar. In several paradigms, bell-shaped dose-response curves were observed, the rescuing effect being lost above about 1 mg/kg, a fact that must be considered in clinical investigations.
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PMID:Neurorescuing effects of the GAPDH ligand CGP 3466B. 1120 40

Until about a decade ago, few researchers in clinical or evolutionary biology paid much attention to mitochondria. But over the years, as technological advances in molecular biology made nuclear functions more accessible to them, interest in mitochondria began to revive. First, geneticists started tracing certain rare inherited disorders to mutations in the mitochondria's circular genome. More recently, other researchers have speculated that mitochondria might contribute to aging, either by releasing tissue-damaging reactive oxygen molecules or by impairing and depriving the cell of the energy it needs to function. One the most important recent developments has been the recognition that mitochondria play a central role in the regulation of programmed cell death, or apoptosis. Now, we know that mitochondria play a decisive role in life-death decisions for the cell and may choose between the apoptotic and necrotic pathways. Mitochondria can trigger cell death in a number of ways: by disrupting electron transport and energy metabolism, by activating the mitochondrial permeability transition, by releasing and/or activating proteins that mediate apoptosis. Any or all of these mechanisms may help to explain how mitochondrial defects contribute to the pathogenesis of neuronal death or dysfunction in ischemia/reperfusion injury as well as in human degenerative diseases including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and Huntington's disease. This has opened up new avenues for understanding the pathogenesis of neurodegeneration and may lead to new and more effective therapeutic approaches to these diseases.
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PMID:[Mitochondria: recent pathophysiological discoveries and new therapeutic perspectives]. 1122 75


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