Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004134 (ataxia)
 15,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The intent of this paper is to review the recent literature on exercise-induced hyperammonemia (EIH) and to compare the current interpretations of ammonia accumulation during exercise with the recognized clinical symptoms of progressive ammonia toxicity. In doing so, we will speculate on possible exercise-induced symptoms of CNS dysfunction which could result from elevated ammonia during intense short-duration or prolonged exercise. Ammonia is a ubiquitous metabolic product producing multiple effects on physiological and biochemical systems. Its concentration in several body compartments is elevated during exercise, predominantly by increased activity of the purine nucleotide cycle (PNC) in skeletal muscle. Depending on the intensity and duration of exercise, muscle ammonia may be elevated to the extent that it leaks (diffuses) from muscle to blood, and thereby can be carried to other organs. The direction of movement of ammonia or the ammonium ion is dependent on concentration and pH gradients between tissues. In this manner, ammonia can also cross the blood-brain barrier (BBB), although the rate of diffusion of ammonia from blood to brain during exercise is unknown. It seems reasonable to assume that exhaustive exercise may induce a state of acute ammonia toxicity which, although transient and reversible relative to disease states, may be severe enough in critical regions of the CNS to affect continuing coordinated activity. Regional differences in brain ammonia content, detoxification capacity, and specific sensitivity may account for the variability of precipitating factors and latency of response in CNS-mediated dysfunction arising from an exercise stimulus, e. g., motor incoordination, ataxia, stupor. There have been numerous suggestions that elevated ammonia is associated with, or perhaps is responsible for, exercise fatigue, although evidence for this relies extensively on temporal relationships. Fatigue may become manifest both as a peripheral organ or central nervous system phenomenon, or combination of both. Thus, we must examine the sequential or concomitant changes in ammonia concentration occurring in the periphery, the central nervous system (CNS), and the cerebrospinal fluid (CSF) induced by any effector, not only exercise, to interpret and rationalize the diverse physical, physiological, biochemical, and clinical symptoms produced by hyperammonemic states. Since more is known about elevated brain ammonia during other diverse conditions such as disease states, chemically induced convulsion, and hyperbaric hyperoxia, some of these relevant data are discussed.
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PMID:Exercise-induced hyperammonemia: peripheral and central effects. 219 91

Friedreich's ataxia (FRDA), the most common inherited ataxia, is a neurodegenerative disease caused by a reduction in the levels of the mitochondrial protein frataxin, the function of which remains a controversial matter. Several therapeutic approaches are being developed to increase frataxin expression and reduce the intramitochondrial iron aggregates and oxidative damage found in this disease. In this study, we tested separately the response of a Drosophila RNAi model of FRDA (Llorens et al., 2007) to treatment with the iron chelator deferiprone (DFP) and the antioxidant idebenone (IDE), which are both in clinical trials. The FRDA flies have a shortened life span and impaired motor coordination, and these phenotypes are more pronounced in oxidative stress conditions. In addition, under hyperoxia, the activity of the mitochondrial enzyme aconitase is strongly reduced in the FRDA flies. This study reports that DFP and IDE improve the life span and motor ability of frataxin-depleted flies. We show that DFP eliminates the excess of labile iron in the mitochondria and thus prevents the toxicity induced by iron accumulation. IDE treatment rescues aconitase activity in hyperoxic conditions. These results validate the use of our Drosophila model of FRDA to screen for therapeutic molecules to treat this disease.
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PMID:Deferiprone and idebenone rescue frataxin depletion phenotypes in a Drosophila model of Friedreich's ataxia. 2354 74

Friedreich's ataxia (FRDA), the most common inherited ataxia in the Caucasian population, is a multisystemic disease caused by a significant decrease in the frataxin level. To identify genes capable of modifying the severity of the symptoms of frataxin depletion, we performed a candidate genetic screen in a Drosophila RNAi-based model of FRDA. We found that genetic reduction in TOR Complex 1 (TORC1) signalling improves the impaired motor performance phenotype of FRDA model flies. Pharmacologic inhibition of TORC1 signalling by rapamycin also restored this phenotype and increased the lifespan and ATP levels. Furthermore, rapamycin reduced the altered levels of malondialdehyde + 4-hydroxyalkenals and total glutathione of the model flies. The rapamycin-mediated protection against oxidative stress is due in part to an increase in the transcription of antioxidant genes mediated by cap-n-collar (Drosophila ortholog of Nrf2). Our results suggest that autophagy is indeed necessary for the protective effect of rapamycin in hyperoxia. Rapamycin increased the survival and aconitase activity of model flies subjected to high oxidative insult, and this improvement was abolished by the autophagy inhibitor 3-methyladenine. These results point to the TORC1 pathway as a new potential therapeutic target for FRDA and as a guide to finding new promising molecules for disease treatment.
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PMID:TORC1 Inhibition by Rapamycin Promotes Antioxidant Defences in a Drosophila Model of Friedreich's Ataxia. 2615 31