Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:1.3.5.1 (succinate dehydrogenase)
 8,177 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

3-Nitropropionic acid (1 mM), which inhibits succinate dehydrogenase activity and reduces cellular energy, produces in the pyramidal cell layer of the hippocampal region CA1 a hyperpolarization for variable lengths of time before evoking an irreversible depolarization. Hyperpolarization is caused by an increased potassium conductance that is attenuated by glibenclamide (1-10 microM), a selective antagonist of ATP-sensitive potassium channels; in contrast, diazoxide (0.5 mM), an agonist at this channel, induces a hyperpolarization in CA1 neurons of rat hippocampal slices. The transient hyperpolarization after prolonged (ca. 1 h) application of 3-NPA is followed by a depolarization that is incompletely reversed by brief application of the glutamate antagonists (D-2-amino-5-phosphonopentanoic acid (APV), 6,7-dichloroquinoxaline-2,3-dione (CNQX), 3-(+/-)-2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP), 7-chloro-kynurenic acid (7Cl-KYN)). Early application of glibenclamide (within the initial 5 min) blocked or reduced hyperpolarization and accelerated the depolarization. These data suggest that metabolic inhibition by 3-NPA initially activates ATP-sensitive potassium channels. Events other than activation of glutamate receptors participate in the final depolarization resulting from uncoupling of oxidative phosphorylation.
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PMID:Inhibition of energy metabolism by 3-nitropropionic acid activates ATP-sensitive potassium channels. 135 4

3-Nitropropionic acid (3-NPA)--a suicide inhibitor of succinate dehydrogenase--is a widely distributed plant and fungal neurotoxin known to induce a damage to basal ganglia, hippocampus, spinal tracts and peripheral nerves in animals. Recent reports from Northern China indicate that 3-NPA is also likely to be responsible for the development of putaminal necrosis with delayed dystonia in children after ingestion of mildewed sugar cane. This article discusses the role of 3-NPA in the causation of the disease in China, its neurotoxic effects in animals and the potential role for this compound as a probe of selective neuronal vulnerability.
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PMID:3-Nitropropionic acid-exogenous animal neurotoxin and possible human striatal toxin. 178 16

3-Nitropropionic acid (NPA), a toxin which irreversibly inhibits the Krebs cycle enzyme succinate dehydrogenase, causes severe neurologic disease and a specific pattern of morphologic brain damage when given subcutaneously to rats. To determine whether hypotension or hypoxemia were necessary for development of morphologic brain lesions in NPA neurotoxicity, systemic blood pressure and arterial blood gases were measured in NPA-intoxicated rats. The extent and distribution of albumin extravasation was examined by immunohistochemistry, and was compared to the extent and severity of morphological injury in the caudate-putamen. Neither hypotension nor hypoxemia were necessary for the development of morphologic injury in the brains of NPA-intoxicated rats. In fact, intoxicated rats had significantly higher systolic blood pressure and arterial blood oxygen than did controls. Arterial bicarbonate and pH were significantly lower in intoxicated rats than controls, however, suggesting that acidosis may be involved in the pathogenesis of NPA toxicity. When morphologic injury was severe, albumin extravasation was extensive occupying approximately 30%-80% of the lesion area in the caudate-putamen of NPA-intoxicated rats. When morphologic injury was mild, albumin extravasation was absent, or limited to small cuffs around individual capillaries (less than 1% of the lesion area). There was no leakage of albumin in the cerebral cortex, which was resistant to morphologic injury. It was concluded that leakage of protein-rich fluid into cerebral parenchyma from blood-brain barrier impairment is not responsible for the initiation of morphologic injury in NPA toxicity, but may contribute to the severity of injury later in the evolution of brain lesions.
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PMID:Correlation of morphologic brain lesions with physiologic alterations and blood-brain barrier impairment in 3-nitropropionic acid toxicity in rats. 311 20

3-Nitropropionic acid (3-NPA), an irreversible inhibitor of succinate dehydrogenase, was administered to rats and the characteristics of the neuronal damage were investigated. Injections of 3-NPA (15 mg/kg s.c.) every 2 or 3 days for 1-2 weeks induced a mild neuronal loss and neutrophil invasions in the striatum (STR). The same administration for 4 weeks induced specific symmetric lesions in the lateral STR although the size was variable in each animal. Inside the lesions, strong neutrophil invasions and a strong immunoreaction for IgG, C3 as well as complement factor C3b/C4b receptor (C3b/C4br) were detected. Lesioned sites lost the immunoreaction for GFAP while the marginal areas contained abundant GFAP-labeled astrocytes around the vessels. In intoxicated animals, there was a weak but stout immunoreaction for IgG and C3b/C4br localizing around vessels in the STR even when there were no lesions or neuronal loss. The data suggest that the blood-brain barrier dysfunction is responsible for the specific vulnerability of the STR for the toxin.
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PMID:Chronically administered 3-nitropropionic acid induces striatal lesions attributed to dysfunction of the blood-brain barrier. 777 87

3-Nitropropionic acid (3-NP) irreversibly inhibits the activity of the mitochondrial enzyme succinate dehydrogenase, leading to selective striatal lesions when administered in vivo. We studied the effects of 3-NP on dissociated cultures of neurons and glia with the following findings: (a) 3-NP killed cultured striatal neurons with a median lethal dose of 2.5 mM after 20 h of incubation in 20.0 mM glucose medium. Despite its selective toxicity in vivo, cultured striatal, hippocampal, septal, and hypothalamic neurons were similarly sensitive to 3-NP incubation. (b) 3-NP's effects were remarkably energy substrate dependent, with the median lethal dose dropping over an order of magnitude when glucose concentrations were lowered to 3.0 mM, a condition that was itself nontoxic. Cultures exposed to 3-NP had a far greater sensitivity to energy availability than those exposed to glutamate. (c) Recent work suggests that 3-NP toxicity may be partially mediated by excitotoxins. Our experiments show that neither kynurenic acid, a nonspecific glutamate receptor antagonist, nor the NMDA-receptor antagonist, DL-2-amino-7-phosphonoheptanoic acid, either in combination or alone, reduced 3-NP toxicity in striatal cultures. However, the noncompetitive NMDA antagonist MK-801 did attenuate 3-NP toxicity.
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PMID:Energy and glutamate dependency of 3-Nitropropionic acid neurotoxicity in culture. 862 Sep 28

3-Nitropropionic acid (3-NPA) is a selective and irreversible inhibitor of succinate dehydrogenase. The effect of this compound on the metabolism of [U-13C]glutamate was studied in astrocytes using 13C nuclear magnetic resonance spectroscopy. The appearance of [1,2,3-13C]glutamate in cell extracts and [1,2,3-13C]glutamine and [U-13C]lactate in cell media demonstrated the metabolism of labeled glutamate via the tricarboxylic acid cycle. Such labeling was observed in the control situation and also in cells treated with 3 mM 3-NPA. In the cells treated with 3 mM 3-NPA, however, the labeling was significantly reduced, and with 10 mM 3-NPA no such labeling was observed. Labeled aspartate was observed in untreated cells only. Labeled succinate was not detectable under control conditions, but increased dose dependently in the presence of 3-NPA. Glutamate uptake and conversion of [U-13C]glutamate to [U-13C]glutamine was largely unaffected by 3-NPA, and ATP content was unchanged. In a previous study using cerebellar neurons, tricarboxylic acid cycle metabolism was blocked with 3 mM 3-NPA. The present results show that astrocyte metabolism is more adaptable to blockade of the tricarboxylic acid cycle by 3-NPA than neuronal metabolism.
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PMID:NMR spectroscopy study of the effect of 3-nitropropionic acid on glutamate metabolism in cultured astrocytes. 908 13

3-Nitropropionic acid, a potent inhibitor of succinate dehydrogenase which thus compromises cellular energy metabolism, evoked convulsions in mice in a dose-dependent manner. CD50 for clonic seizures was 158.5 (144.1-174.3) mg/kg. Tonic seizures were not observed. Broad-spectrum anticonvulsants, namely diazepam, phenobarbital and valproate, prevented the occurrence of 3-nitropropionic acid-induced seizures with ED50 of 4.9 (3.1-7.6), 33.1 (17.9-61.0) and 389.7 (351.2-432.3) mg/kg, respectively. Diphenylhydantoin-like drugs (diphenylhydantoin, and carbamazepine), anti-absence drugs (trimethadione and ethosuximide) and acetazolamide were ineffective. The characteristics of 3-nitropropionic acid-induced seizures resembled those of convulsions evoked by another mitochondrial toxin, aminooxyacetic acid.
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PMID:Mitochondrial toxin 3-nitropropionic acid evokes seizures in mice. 983 Dec 93

3-Nitropropionic acid (NPA), an inhibitor of succinate dehydrogenase, is dietary neurotoxin. It is not known if neurons and astrocytes differ in their vulnerability to NPA, therefore, we investigated its toxicity in primary cultures of cerebellar granule cells and astrocytes. NPA inhibited succinate dehydrogenase and tricarboxylic acid cycle activity to the same degree in neurons and astrocytes. Even so NPA acid was 16 times more toxic to neurons than to astrocytes (LC50: 0.7 and 11 mM, respectively). The neurotoxicity of NPA was mediated by NMDA-receptor activation, calcium influx, and formation of reactive oxygen species, as revealed by the protective effect of NMDA-receptor blockade, the accumulation of 45Ca, and the protective effect of N-t-butyl-alpha-phenylnitron (PBN), a scavenger of reactive oxygen species. Cytotoxic concentrations of NPA caused a reduction in the intracellular level of glutathione, which probably contributed to the oxidative damage in both neurons and astrocytes. The relative resistance of astrocytes to NPA appeared to be related to their low tricarboxylic acid cycle activity (5%-10% of that in neurons) and to the inability of NPA to cause astrocytic calcium overload. We conclude that NPA acid predominantly is an astrocyte-sparing neurotoxin.
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PMID:3-Nitropropionic acid: an astrocyte-sparing neurotoxin in vitro. 1062 58

A number of data concerning the central action of mitochondrial toxins, substances impairing mitochondrial synthesis of ATP and thus compromising cellular energy status, has emerged within last years. 3-Nitropropionic acid (3-NPA) is an irreversible inhibitor of succinate dehydrogenase and mitochondrial complex II. The experimental administration of 3-NPA may lead to selective neuronal loss and chorea-like behavioral alterations but, as was recently shown, it also evokes clonic convulsions in rodents. The gathered data suggest that disturbed mitochondrial energy metabolism might initiate the chain of events culminating in seizure episode and that 3-NPA might become a useful tool in studying "mitochondrial" seizures. It has been hypothesized that the resistance to standard anticonvulsive therapy occurring among high proportion of epilepsy sufferers may result from the impairment of mitochondrial energy status due to either genetic predispositions or environmental influences.
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PMID:Seizures evoked by mitochondrial toxin, 3-nitropropionic acid: new mechanism of epileptogenesis? 1094 22

3-Nitropropionic acid (3-NP) is an irreversible inhibitor of complex II in the mitochondria. 3-NP toxicity has gained acceptance as an animal model of Huntington's disease (HD). In the present study, we confirmed that rats injected with 3-NP (20 mg/kg, i.p., daily for 4 days) exhibit increased oxidative stress in both striatum and cortical synaptosomes as well as lesions in the striatum. Synaptosomal membrane proteins from rats injected with 3-NP exhibited a decrease in W/S ratio, the relevant electron paramagnetic resonance (EPR) parameter used to determine levels of protein oxidation, and western blot analysis for protein carbonyls revealed direct evidence of increased synaptosomal protein oxidation. Treatment of rats with the brain-accessible free radical spin trap 5-diethoxyphosphoryl-5-methyl-1-pyrroline N-oxide (DEPMPO; 30 mg/kg, i.p., daily 2 h before 3-NP injection) or with N-acetylcysteine (NAC; 100 mg/kg, i.p., daily 2 h before 3-NP injection), a known glutathione precursor, before 3-NP treatments protects against oxidative damage induced by 3-NP as measured by EPR and western blot analysis for protein carbonyls. Furthermore, both DEMPMPO and NAC treatments before 3-NP administration significantly reduce striatal lesion volumes. These data suggest oxidative damage is a prerequisite for striatal lesion formation and that antioxidant treatment may be a useful therapeutic strategy against 3-NP neurotoxicity and perhaps against HD as well.
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PMID:Effect of exogenous and endogenous antioxidants on 3-nitropionic acid-induced in vivo oxidative stress and striatal lesions: insights into Huntington's disease. 1098 54


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