Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

After nigrostriatal dopaminergic denervation, the output nuclei of the basal ganglia, the medial globus pallidus and substantia nigra pars reticulata (Snr), become overactive, in part, because of increased activity of excitatory afferents from the subthalamic nucleus (STN). Because STN uses glutamate as a transmitter, we examined whether there are regulatory changes in glutamate receptor binding in the basal ganglia. Rats received unilateral 6-hydroxydopamine lesions of the medial forebrain bundle and substantia nigra pars compacta that were confirmed by apomorphine-induced rotation and 3H-GBR-12935 binding. As an indirect index of relative synaptic activity, succinate dehydrogenase and cytochrome oxidase activities were assayed histochemically in sections adjacent to those used for receptor binding. There were increases in enzymatic activity in entopeduncular nucleus (EP; the rodent homolog of medial globus pallidus), SNr, and globus pallidus (GP, the rodent homolog of lateral globus pallidus) in the lesioned hemisphere, suggesting increased synaptic activity, perhaps due to increased firing of the STN. Ipsilateral to the lesion, and postsynaptic to the STN, there were profound decreases in the binding of 3H-AMPA (alpha-amino-3-hydroxy-5-methylisoxazole propionic acid) in EP and SNr (45% and 30%, respectively); there were no alterations in the striatum, globus pallidus, or STN, and binding throughout the unlesioned hemisphere was equivalent to that in unlesioned control animals. In contrast, 3H-MK-801 binding to the NMDA receptor ion channel was not reduced in SNr, and was too low to be measured reliably in EP and STN. 3H-MK-801 binding was reduced by 6% in striatum and 39% in globus pallidus.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Polysynaptic regulation of glutamate receptors and mitochondrial enzyme activities in the basal ganglia of rats with unilateral dopamine depletion. 796 8

Consistent with the notion that a defect in cellular energy metabolism is a cause of human neurodegenerative disease, systemic treatment with the mitochondrial complex II inhibitor 3-nitropropionic acid (3-NPA) can model the striatal neurodegeneration seen in Huntington's disease. Previously, we have found that nerve growth factor (NGF), delivered biologically by the implantation of a genetically altered fibroblast cell-line, can protect locally against striatal degeneration induced by infusions of high doses of glutamate receptor agonists. We now report that implantation of NGF-secreting fibroblasts reduces the size of adjacent striatal 3-NPA lesions by an average of 64%. We conclude that biologically delivered NGF protects neurons against excitotoxicity and mitochondrial blockade--both energy-depleting processes--implying that appropriate neurotrophic support in the adult brain could protect against neurodegenerative diseases caused in part by energy depletion.
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PMID:Striatal degeneration induced by mitochondrial blockade is prevented by biologically delivered NGF. 810 16

There may be important relationships between glutamate receptor activation and neurotoxicity in neurodegenerative diseases. Previous experiments using cultured neurons have demonstrated a correlation between the metabolic status of neurons and their sensitivity to glutamate receptor-mediated cytotoxicity (Novelli et al. Brain Res. 451, 205, 1988). To examine such a relationship in vivo, we first established a dose-response curve for N-methyl-D-aspartate (NMDA)-induced neuronal death in the rat striatum. We then examined the interaction between metabolic impairment and infusion of NMDA at a dose below the threshold for neurotoxicity. Metabolic impairment was induced by intraperitoneal delivery of 3-nitropropionic acid (3-NP), an inhibitor of mitochondrial complex II (succinic dehydrogenase). Twelve hours after 3-NP delivery we performed stereotactic infusion of NMDA or vehicle into the striatum. During mitochondrial impairment, a relatively nonneurotoxic dose of NMDA (15 nmol) produced a lesion that was significantly larger than that caused by this dose under normal metabolic conditions. At a dose normally below the threshold for neurotoxicity, metabolic impairment significantly increased the likelihood of neuronal death in the striatum by a factor of 5. Lesions were characterized by neuronal loss with gliosis and sparing of traversing fiber bundles. These results demonstrate that metabolic impairment reduces the threshold for glutamate receptor-mediated neurotoxicity in vivo. This potentiation may have implications for understanding the role of "neuronal stress" produced by glutamate receptor activation in neurodegenerative diseases and normal aging.
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PMID:Mitochondrial impairment reduces the threshold for in vivo NMDA-mediated neuronal death in the striatum. 849 11

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

Glutamate receptor involvement and oxidative stress have both been implicated in damage to neurons due to impairment of energy metabolism. Using two different neuronal in vitro model systems, an ex vivo chick retinal preparation and dopamine neurons in mesencephalic culture, the involvement and interaction of these events as early occurring contributors to irreversible neuronal damage have been examined. Consistent with previous reports, the early acute changes in the retinal preparation, as well as irreversible loss of dopamine neurons due to inhibition of metabolism, can be prevented by blocking NMDA receptors during the time of energy inhibition. Oxidative stress was suggested to be a downstream consequence and contributor to neuronal cell loss due to either glutamate receptor overstimulation or metabolic inhibition since trapping of free radicals with the cyclic nitrone spin-trapping agent MDL 102,832 (1 mM) attenuated acute excitotoxicity in the retinal preparation or loss of mesencephalic dopamine neurons due to either metabolic inhibition by the succinate dehydrogenase inhibitor, malonate, or exposure to excitotoxins. In mesencephalic culture, malonate caused an enhanced efflux of both oxidized and reduced glutathione into the medium, a significant reduction in total reduced glutathione and a significant increase in total oxidized glutathione at time points that preceded those necessary to cause toxicity. These findings provide direct evidence for early oxidative events occurring following malonate exposure and suggest that the glutathione system is important for protecting neurons during inhibition of energy metabolism. Consistent with this, lowering of glutathione by buthionine sulfoxamine (BSO) pretreatment greatly potentiated malonate toxicity in the mesencephalic dopamine population. In contrast, BSO pretreatment did not potentiate glutamate toxicity. This latter finding indicates dissimilarities in the type of oxidative stress that is generated by the two insults and suggests that the oxidative challenge during energy inhibition is not solely a downstream consequence of glutamate receptor overstimulation.
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PMID:Excitotoxicity and oxidative stress during inhibition of energy metabolism. 977 83

Methylmalonic acidurias are biochemically characterized by an accumulation of methylmalonate (MMA) and alternative metabolites. There is growing evidence for basal ganglia degeneration in these patients. The pathomechanisms involved are still unknown, a contribution of toxic organic acids, in particular MMA, has been suggested. Here we report that MMA induces neuronal damage in cultures of embryonic rat striatal cells at a concentration range encountered in affected patients. MMA-induced cell damage was reduced by ionotropic glutamate receptor antagonists, antioxidants, and succinate. These results suggest the involvement of secondary excitotoxic mechanisms in MMA-induced cell damage. MMA has been implicated in inhibition of respiratory chain complex II. However, MMA failed to inhibit complex II activity in submitochondrial particles from bovine heart. To unravel the mechanism underlying neuronal MMA toxicity, we investigated the formation of intracellular metabolites in MMA-loaded striatal neurons. There was a time-dependent intracellular increase in malonate, an inhibitor of complex II, and 2-methylcitrate, a compound with multiple inhibitory effects on the tricarboxylic acid cycle, suggesting their putative implication in MMA neurotoxicity. We propose that neuropathogenesis of methylmalonic aciduria may involve an inhibition of complex II and the tricarboxylic acid cycle by accumulating toxic organic acids, and synergistic secondary excitotoxic mechanisms.
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PMID:Neurodegeneration in methylmalonic aciduria involves inhibition of complex II and the tricarboxylic acid cycle, and synergistically acting excitotoxicity. 1184 33

Previous studies showed that 3-nitropropionic acid, an irreversible inhibitor of succinate dehydrogenase, produced neuronal death secondary to perturbed intracellular calcium homeostasis. However, the response of intramitochondrial calcium ([Ca(2+)](m)) to 3-nitropropionic acid remains unknown. In this study, we investigated the roles of and relationships among [Ca(2+)](m) overload, mitochondrial reactive oxygen species, and mitochondrial membrane depolarization in 3-nitropropionic acid-induced neuronal death. Following 1 mM 3-nitropropionic acid treatment on primary rat neuronal cultures, there was a gradual increase of [Ca(2+)](m) beginning at 2-4 h post 3-nitropropionic acid application, and a twofold increase of mitochondrial reactive oxygen species at 4 h. These were followed by mitochondrial membrane depolarization at 6-8 h post-treatment. By inhibiting [Ca(2+)](m) uptake, Ruthenium Red attenuated the production of reactive oxygen species, and prevented the 3-nitropropionic acid-induced mitochondrial membrane depolarization and 70% of apoptotic neuronal death (P<0.001). Inhibition of caspase activation attenuated the elevation of [Ca(2+)](m) (P<0.001), indicating that caspase activation plays a role in the elevation of [Ca(2+)](m). MK-801, an antagonist of N-methyl-D-aspartate (NMDA) glutamate receptors, prevented 3-nitropropionic acid-induced [Ca(2+)](m) elevation, caspase-3 activation, mitochondrial depolarization, and neuronal death. We conclude that the activation of NMDA glutamate receptor contributes to mitochondrial alterations induced by 3-nitropropionic acid. Inhibition of its activation and [Ca(2+)](m) overload with subsequent mitochondrial membrane depolarization can therefore attenuate the neuronal death induced by 3-nitropropionic acid.
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PMID:The mechanisms of neuronal death produced by mitochondrial toxin 3-nitropropionic acid: the roles of N-methyl-D-aspartate glutamate receptors and mitochondrial calcium overload. 1207 12

3-Nitropropionic acid (3-NP), an irreversible inhibitor of succinate dehydrogenase, induced ATP depletion and both necrosis and apoptosis in human NT2-N neurons. Necrosis occurred predominantly within the first two days, and increased in a dose-dependent fashion with the concentration of 3-NP, whereas apoptosis was observed after 24 h or later at a similar rate in 0.1 mM and 5 mM 3-NP. We focused our efforts on intracellular calcium homeostasis during the first 48 h in 1 mM 3-NP, a period during which 10% of the neurons died by necrosis and 3% by apoptosis. All NT2-N neurons showed a stereotyped [Ca(2+)](i) rise, from 48+/-2 to 140+/-12 nM (mean +/-S.E.M.), during the first 2 h in 3-NP. Despite severe ATP depletion, however, [Ca(2+)](i) remained above 100 nM in only 17% and 25% of the NT2-N neurons after 24 and 48 h in 3-NP, respectively, indicating that most neurons were able to recover from acute [Ca(2+)](i) rise, and suggesting that chronic [Ca(2+)](i) dysregulation is a better indicator of subsequent necrosis. Blockade of N-methyl-D-aspartate-glutamate receptor by MK-801 substantially ameliorated 3-NP-induced ATP depletion, subsequent chronic [Ca(2+)](i) elevation, and survival. Moreover, xestospongin C, an inhibitor of endoplasmic reticulum Ca(2+) release, enhanced the capacity of NT2-N neurons to maintain [Ca(2+)](i) homeostasis and resist necrosis while subjected to sustained energy deprivation. As far as we know, this report is the first to employ human neurons to study the pathophysiology of 3-NP neurotoxicity.
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PMID:Acute and chronic alterations in calcium homeostasis in 3-nitropropionic acid-treated human NT2-N neurons. 1215 Jul 90

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder typically affecting individuals in midlife. HD is characterized by the selective loss of striatal spiny neurons, while large cholinergic interneurons are spared. An impaired mitochondrial complex II (succinate dehydrogenase, SD) activity is known as a prominent metabolic alteration in HD. Accordingly, chronic treatment with 3-nitropropionic acid (3-NP), an irreversible SD inhibitor, mimics motor abnormalities and pathology of HD in several animal models. We have previously shown that in vitro application of 3-NP induces a long-term potentiation (LTP) of corticostriatal synaptic transmission through NMDA glutamate receptor. Since this 3-NP-induced LTP (3-NP-LTP) is shown by striatal spiny neurons, but not by cholinergic interneurons, it might play a role in the regional and cell type-specific neuronal death observed in HD. Here we investigate the role of group I metabotropic glutamate receptors (mGluRs) in the induction of 3-NP-LTP. We report that selectively blocking mGluR1, but not mGluR5, suppresses 3-NP-LTP induction. Moreover, we show that a PKC-mediated mechanism is involved in the formation of 3-NP-LTP. Characterizing the cellular mechanisms underlying 3-NP-LTP may provide new insights to better understand the processes leading to the selective neuronal loss observed in HD.
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PMID:Induction of corticostriatal LTP by 3-nitropropionic acid requires the activation of mGluR1/PKC pathway. 1503 36

Glutamate-induced excitotoxicity is implicated as playing a key role in the pathogenesis of amyotrophic lateral sclerosis (ALS), and mitochondrial dysfunction is also found in ALS patients. We investigated the relationship between glutamate excitotoxicity and mitochondrial dysfunction elicited by rotenone (a complex I inhibitor), malonate (a complex II inhibitor), or antimycin (a complex III inhibitor), in primary cultures of the embryonic rat spinal cord. Rotenone and malonate induced relatively selective toxicity against motor neurons as compared to non-motor neurons, whereas antimycin caused non-selective toxicity. The toxicity of rotenone was prevented by a non-N-methyl-D-aspartate (NMDA) receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) but not by an NMDA receptor antagonist, 5-methyl-10, 11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate (MK-801). The toxicity of malonate was blocked by both CNQX and MK-801. The toxicity of antimycin was affected by neither CNQX nor MK-801. When mitochondrial complex I was mildly inhibited by a sub-lethal concentration of rotenone, AMPA-induced motor neuron death was significantly exacerbated. A sub-lethal concentration of malonate exacerbated both NMDA- and AMPA-induced motor neuron death. These data suggest that mitochondrial dysfunction predisposes motor neurons to ionotropic glutamate receptor-mediated excitotoxicity.
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PMID:Effects of mitochondrial dysfunction on glutamate receptor-mediated neurotoxicity in cultured rat spinal motor neurons. 1522 68


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