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)

Two regioisomers with C3 or D3 symmetry of water-soluble carboxylic acid C60 derivatives, containing three malonic acid groups per molecule, were synthesized and found to be equipotent free radical scavengers in solution as assessed by EPR analysis. Both compounds also inhibited the excitotoxic death of cultured cortical neurons induced by exposure to N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), or oxygen-glucose deprivation, but the C3 regioisomer was more effective than the D3 regioisomer, possibly reflecting its polar nature and attendant greater ability to enter lipid membranes. At 100 microM, the C3 derivative fully blocked even rapidly triggered, NMDA receptor-mediated toxicity, a form of toxicity with limited sensitivity to all other classes of free radical scavengers we have tested. The C3 derivative also reduced apoptotic neuronal death induced by either serum deprivation or exposure to Abeta1-42 protein. Furthermore, continuous infusion of the C3 derivative in a transgenic mouse carrying the human mutant (G93A) superoxide dismutase gene responsible for a form of familial amyotrophic lateral sclerosis, delayed both death and functional deterioration. These data suggest that polar carboxylic acid C60 derivatives may have attractive therapeutic properties in several acute or chronic neurodegenerative diseases.
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PMID:Carboxyfullerenes as neuroprotective agents. 925

Although growth hormone (GH) replacement therapy is increasingly utilized in the management of adult hypopituitary patients, optimum dosing schedules are poorly defined. The use of weight-based or surface area-based dosing may result in overtreatment, and individual variation in susceptibility on the basis of gender and other factors is now being recognized. To optimize GH replacement and to explore further gender differences in susceptibility, we used a dose titration regimen, starting at the initiation of GH replacement therapy, in 50 consecutive adult-onset hypopituitary patients, and compared the results with those in 21 patients previously treated using a weight-based regimen. Titrated patients commenced GH 0.8 IU/day subcutaneously (0.4 IU/day if hypertensive or glucose tolerance impaired). Serum insulin-like growth factor I (IGF-I) was measured at 0, 2, 4, 6, 8, 10, and 12 weeks in all patients. Serum IGF binding protein 3 and acid labile subunit were measured at the same time points in 17 patients (8 male, 9 female). Patients were reviewed every 4 weeks and the dose of GH increased, if necessary, to achieve a serum IGF-I level between the median and the upper end of the age-related reference range. There was no significant difference between mean serum IGF-I at 2 and 4 weeks, or between 6 and 8 weeks, indicating that the full effects of a change in dose are evident within 2 weeks of that change. Maintenance doses were significantly higher in females than males [1.2 (0.8-2.0) vs. 0.8 (0.4-1.6) IU/day; median (range); P < 0.0001], and the median time to achieve maintenance dose was significantly shorter in males [4 (2-12) vs. 9 (2-26) weeks; P < 0.0001]. Median maintenance dose was lower overall than in a group of 21 patients initially commenced on GH using a weight-based dosing schedule, with subsequent adjustment of dose during clinical follow-up [1.5 (0.4-3.2) IU/day; P = 0.02]. Reduction in waist measurement and waist to hip ratio at 6 and 12 months was similar in females (P < 0.001) and males (P < 0.01). Well-being improved significantly after 3 months of GH therapy (14.2 +/- 5.9 vs. 7.4 +/- 4.5 SD; P < 0.0001), and there were no gender differences. Adult Growth Hormone Deficiency Assessment (AGHDA) scores at 6 months were similar to maintenance scores in patients commenced on weight-based regimens. Measurements of ALS and IGFBP-3 added no useful extra information to IGF-I in managing the dose titration. The practical scheme outlined for dose titration of GH replacement resulted in rapid achievement of lower maintenance doses than those achieved using conventional weight-based regimens without loss of efficacy. It was particularly important in female patients who demonstrated decreased overall sensitivity to GH and required higher doses to achieve the same effects as males. This constitutes the first report of a uniform titration regimen based on a defined target range of serum IGF-I in a large patient cohort.
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PMID:Optimizing growth hormone replacement therapy by dose titration in hypopituitary adults. 981 68

Both oxidative stress and excitotoxicity are implicated in the pathogenesis of a number of neurodegenerative disorders, such as amyotrophic lateral sclerosis. We previously reported increased modification of proteins by 4-hydroxynonenal (HNE), a product of membrane lipid peroxidation, in the spinal cords of patients with amyotrophic lateral sclerosis relative to controls. In the current study, we examined the functional consequences of protein modification by HNE in a cell line with a motor neuron phenotype, NSC-19. Treatment of NSC-19 cells with FeSO4, which catalyzes lipid peroxidation, or HNE induced concentration-dependent decreases in glucose and glutamate transport. Vitamin E and propyl gallate blocked the impairment of glucose and glutamate transport caused by FeSO4 in these cells, but not that caused by HNE, whereas glutathione blocked the effects of FeSO4 as well as HNE. Both FeSO4 and HNE caused an increase in the number of apoptotic nuclei in NSC-19 cultures, but this occurred subsequent to the impairment of glucose and glutamate transport. Reductions in choline acetyltransferase activity were also observed in FeSO4- or HNE-treated NSC-19 cells before induction of apoptosis. Our results suggest that, prior to cell death, oxidative stress and HNE down-regulate cholinergic markers and impair glucose and glutamate transport in motor neurons, the latter of which may lead to excitotoxic degeneration of the cells.
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PMID:The lipid peroxidation product 4-hydroxynonenal impairs glutamate and glucose transport and choline acetyltransferase activity in NSC-19 motor neuron cells. 991 99

We determined the cerebrospinal fluid (CSF) levels of adenosine, a mediator of cerebral blood flow regulation, and neopterin, a macrophage-producing compound, in patients with neurological disorders. Compared to control subjects, the adenosine levels were significantly increased in the patients with acute-stage cerebral infarction (n=12, p<0.0001), acute meningitis (n=10, p<0.0001), or amyotrophic lateral sclerosis (ALS, n=12, p<0.05) (Mann-Whitney U-test). The neopterin levels were significantly increased in the 41 patients with human T-lymphotropic virus type I-associated myelopathy/tropical spastic paraparesis (HAM/TSP, p<0.0001), acute meningitis (p<0.0001), ALS (p<0.05) (Mann-Whitney U-test), or acute-stage cerebral infarction (p<0.005, Student's t-test). In the analysis of 41 HAM/TSP patients, the neopterin levels were significantly correlated with the cell number and glucose levels in the CSF, and were a sensitive marker of inflammation. Several of the HAM/TSP patients with increased adenosine levels were probably complicated with other diseases. The increased neopterin levels in the HAM/TSP group persisted, suggesting that the mononuclear cellular infiltration remained for a long time.
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PMID:Adenosine and neopterin levels in cerebrospinal fluid of patients with neurological disorders. 1022 68

ALS/Lt and ALR/Lt are inbred mouse strains selected for susceptibility and resistance to alloxan (AL)-induced diabetes. Within 24-h after AL administration in vivo, ALS/Lt islets were distinguished from ALR/Lt islets by more extensive necrotic changes. Within 7 days post-AL, ALS/Lt mice exhibited hyperglycemia and hypoinsulinemia, whereas ALR/Lt mice maintained normal plasma insulin and glucose levels. We have recently shown that resistance in ALR/Lt correlated with constitutively elevated systemic (and pancreatic) free radical defense status. In the present report, we examined whether ability to detoxify free radical stress extended to the level of ALR/Lt pancreatic islets. Cultured ALS/Lt islets exposed for 5 min to increasing (0-3 mmol/l) AL concentrations in vitro exhibited an 80% decline in numbers of intact islets after a subsequent 6-day culture period, as well as a 75% reduction in islet insulin content and a 94% decrease in glucose-stimulated insulin secretory capacity. In contrast, ALR/Lt islets remained viable and retained glucose-stimulated insulin secretory capacity as well as normal insulin content. This ALR/Lt islet resistance extended to hydrogen peroxide, a free radical generator whose entry into beta-cells is not dependent on glucose transporters. The elevated antioxidant defenses previously found in ALR/Lt pancreas were extended to isolated islets, which exhibited significantly higher glutathione and Cu-Zn superoxide dismutase 1 levels compared with ALS/Lt islets. A dominant genetic trait from ALR/Lt controlling this unusual AL resistance was indicated by the finding that reciprocal F1 mice of both sexes were resistant to AL administration in vivo. A backcross to ALS/Lt showed 1:1 segregation for susceptibility/resistance, indicative of a single gene controlling the phenotype. In conclusion, the ALR/Lt mouse may provide important insight into genetic mechanisms capable of rendering islets strongly resistant to free radical-mediated damage.
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PMID:Resistance of ALR/Lt islets to free radical-mediated diabetogenic stress is inherited as a dominant trait. 1053 53

Modern molecular biology has revealed vast numbers of large and complex proteins and genes that regulate body function. By contrast, discoveries over the past ten years indicate that crucial features of neuronal communication, blood vessel modulation and immune response are mediated by a remarkably simple chemical, nitric oxide (NO). Endogenous NO is generated from arginine by a family of three distinct calmodulin- dependent NO synthase (NOS) enzymes. NOS from endothelial cells (eNOS) and neurons (nNOS) are both constitutively expressed enzymes, whose activities are stimulated by increases in intracellular calcium. Immune functions for NO are mediated by a calcium-independent inducible NOS (iNOS). Expression of iNOS protein requires transcriptional activation, which is mediated by specific combinations of cytokines. All three NOS use NADPH as an electron donor and employ five enzyme cofactors to catalyze a five-electron oxidation of arginine to NO with stoichiometric formation of citrulline. The highest levels of NO throughout the body are found in neurons, where NO functions as a unique messenger molecule. In the autonomic nervous system NO functions NO functions as a major non-adrenergic non-cholinergic (NANC) neurotransmitter. This NANC pathway plays a particularly important role in producing relaxation of smooth muscle in the cerebral circulation and the gastrointestinal, urogenital and respiratory tracts. Dysregulation of NOS activity in autonomic nerves plays a major role in diverse pathophysiological conditions including migraine headache, hypertrophic pyloric stenosis and male impotence. In the brain, NO functions as a neuromodulator and appears to mediate aspects of learning and memory. Although endogenous NO was originally appreciated as a mediator of smooth muscle relaxation, NO also plays a major role in skeletal muscle. Physiologically muscle-derived NO regulates skeletal muscle contractility and exercise-induced glucose uptake. nNOS occurs at the plasma membrane of skeletal muscle which facilitates diffusion of NO to the vasculature to regulate muscle perfusion. nNOS protein occurs in the dystrophin complex in skeletal muscle and NO may therefore participate in the pathophysiology of muscular dystrophy. NO signalling in excitable tissues requires rapid and controlled delivery of NO to specific cellular targets. This tight control of NO signalling is largely regulated at the level of NO biosynthesis. Acute control of nNOS activity is mediated by allosteric enzyme regulation, by posttranslational modification and by subcellular targeting of the enzyme. nNOS protein levels are also dynamically regulated by changes in gene transcription, and this affords long-lasting changes in tissue NO levels. While NO normally functions as a physiological neuronal mediator, excess production of NO mediates brain injury. Overactivation of glutamate receptors associated with cerebral ischemia and other excitotoxic processes results in massive release of NO. As a free radical, NO is inherently reactive and mediates cellular toxicity by damaging critical metabolic enzymes and by reacting with superoxide to form an even more potent oxidant, peroxynitrite. Through these mechanisms, NO appears to play a major role in the pathophysiology of stroke, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis.
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PMID:Endogenous nitric oxide synthesis: biological functions and pathophysiology. 1063 Jun 82

Although degeneration of lower motor neurons is the most striking abnormality in amyotrophic lateral sclerosis (ALS), more subtle alterations may occur in the brain. Mutations in copper/zinc superoxide dismutase (Cu/Zn-SOD) are responsible for some cases of inherited ALS, and expression of mutant Cu/Zn-SOD in transgenic mice results in progressive motor neuron loss and a clinical phenotype similar to that of ALS patients. It is now reported that Cu/Zn-SOD mutant mice exhibit increased vulnerability to focal ischemic brain injury after transient occlusion of the middle cerebral artery. Levels of glucose and glutamate transport in cerebral cortex synaptic terminals were markedly decreased, and levels of membrane lipid peroxidation were increased in Cu/Zn-SOD mutant mice compared to nontransgenic mice. These findings demonstrate that mutant Cu/Zn-SOD may endanger brain neurons by a mechanism involving impairment of glucose and glutamate transporters. Moreover, our data demonstrate a direct adverse effect of the mutant enzyme on synaptic function.
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PMID:ALS-linked Cu/Zn-SOD mutation impairs cerebral synaptic glucose and glutamate transport and exacerbates ischemic brain injury. 1072 10

Prompted by our recent observations that GLUT-1 is expressed in fetal muscles, but not in adult muscle fibers, we decided to investigate whether GLUT-1 expression could be reactivated. We studied different stimuli concerning their ability to induce GLUT-1 expression in mature human skeletal muscle fibers. Metabolic stress (obesity, non-insulin-dependent diabetes mellitus), contractile activity (training), and conditions of de- and reinnervation (amyotrophic lateral sclerosis) could not induce GLUT-1 expression in human muscle fibers. However, regenerating muscle fibers in polymyositis expressed GLUT-1. In contrast to GLUT-1, GLUT-4 was expressed in all investigated muscle fibers. Although the significance of GLUT-1 in adult human muscle fibers appears limited, GLUT-1 may be of importance for the glucose supplies in immature and regenerating muscle.
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PMID:Induction of GLUT-1 protein in adult human skeletal muscle fibers. 1105 76

A 10-year-old, non-pregnant Dutch Warmblood mare was referred to the Department of Equine Science because of chronic weight loss, despite good appetite, and dullness. Clinical examination revealed muscle atrophy, trembling of the limb muscles, an abnormal stance in which all four limbs were placed under the body, and an abnormal low head carriage. The plasma vitamin E concentration was markedly decreased (0.2 mumol/l), the electromyographic (EMG) examination was consistent with denervation, and the oral glucose absorption test was below the reference value (40% increase over the resting glucose level). Because of the clinical diagnosis of equine motor neuron disease (EMND), the horse was euthanazed and post-mortem examination confirmed this diagnosis. Based on the similarity in pathological findings, EMND can be compared to amyotrophic lateral sclerosis (ALS) in humans. However, in horses, only the lower motor neurons and occasionally some nuclei of the cranial nerves are affected. Because of the low plasma vitamin E concentration found in horses with EMND, an absolute or a relative antioxidant deficiency can be involved in the pathogenesis. In general, it is a progressive disease process and stabilization of the situation is the best feasible result. There is no specific therapy other than vitamin E supplementation and the prognosis is poor.
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PMID:[Equine motor neuron disease: a review based on a case report]. 1141 73

Positron emission tomography (PET) has enabled us to study the human brain with unrivalled sensitivity, and has already established its place in the research of neurological conditions such as Parkinson's disease and epilepsy. PET has been used as a tool in the study of patients with motor neuron disease (MND) for well over ten years now, but its potential in diagnosis and to identify surrogate markers of disease expression (phenotype) and progression has yet to be fully realized. The early studies using 2-18fluoro-2-deoxy-D-glucose to measure regional changes in cerebral metabolic rate for glucose gave the first clues to the more widespread involvement of the brain in MND. Later studies exploited the development of activation studies using 15O-containing tracers, which allowed correlation with neuropsychological measures, and the refinement of mapping techniques to delineate the extra-motor areas involved in the disease process. More recently, studies involving ligands such as 11C-flumazenil have allowed the exploration of functional reorganisation in MND, and inhibitory interneuronal pathways which may be crucial in modulation of disease expression. In the future new ligands will be applied in combination with other modalities of investigation (multimodal magnetic resonance imaging; neurophysiological studies) in order to understand the pathophysiology of this heterogeneous condition. Although the potential of PET has not yet been realized in ALS, it is likely to play a part in defining new diagnostic and surrogate markers of disease extent and severity.
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PMID:Positron emission tomography (PET)--its potential to provide surrogate markers in ALS. 1146 36


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