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)

3-Nitropropionic acid (3-NP), an irreversible inhibitor of succinate dehydrogenase, produces selective lesions in striatal neurons that resemble those observed in Huntington's disease neuropathology. In this study, we evaluated the role of peripheral bone marrow-derived cells (BMDCs) in the 3-NP-induced striatal damage by transplanting bone marrow cells with human SOD1 G93A mutation (mSOD1(G93A)) which induces amyotrophic lateral sclerosis through an unknown gain of toxicity and mitochondrial dysfunction. We assessed striatal damage after 3-NP treatment in the recipient C57BL/6 wild-type (WT) mice that received bone marrow cells from WT or mSOD1(G93A) transgenic donor mice (WT-->WT or mSOD(G93A)-->WT). After intraperitoneal injection of 3-NP, six of the eight mSOD1(G93A)-->WT mice had bilateral striatal lesions while only one out of eight WT-->WT mice had a striatal lesion. The lesion volume was significantly higher in the mSOD1(G93A)-->WT mice than in the WT-->WT mice. However, following an intrastriatal injection of 3-NP, there was no significant difference in the lesion volumes between the WT-->WT mice and mSOD1(G93A)-->WT mice. Thus, the exacerbation of 3-NP-induced striatal damage in mSOD(G93A)-->WT mice was only seen after systemic administration of 3-NP, but not after intrastriatal injection. These results demonstrate that altered SOD1 activity (mSOD(G93A)) in BMDCs affects striatal damage probably through a mechanism involving a systemic factor.
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PMID:Mutant SOD1G93A in bone marrow-derived cells exacerbates 3-nitropropionic acid induced striatal damage in mice. 1741 47

3-Nitropropionic acid (3-NP) is a neurotoxin that inhibits mitochondrial complex II and is used in an experimental model of Huntington's disease. Treatment of rats with 3-NP 30mgkg(-1) i.p. once a day for 5 days induced an increase in calpain activation in rat striatum, measured by the formation of 145kDa fragment of alpha-spectrin breakdown and by an increase in enzymatic calpain activity. In this neurotoxic model, Western blot studies revealed that calpain activity increase was followed by changes in cyclin-dependent kinase 5 (cdk5) and its activator p25. Our results indicated, after 10 days of treatment with 3-NP, a decrease in myocyte enhancer factor phosphorylation, a neuronal prosurvival factor. Thus, a decrease in its expression indicates a new potential mechanism of neuronal cell death mediated by the neurotoxin 3-NP. Accordingly, in our study we demonstrated in rat striatum the activation of the calpain/cdk5/p25 pathway in the 3-NP model. Previous studies have linked the deregulation of cdk5 with neurodegenerative diseases, such as Alzheimer's and Parkinson's. We suggest that calpain/cdk5 activation could also be a common pathway activated in other neurodegenerative diseases, which is liable to be targeted.
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PMID:3-Nitropropionic acid activates calpain/cdk5 pathway in rat striatum. 1756 44

3-Nitropropionic acid (3-NP), an inhibitor of the mitochondrial enzyme succinate dehydrogenase, induces neuronal degeneration in the striatum. It is known that dopamine (DA) enhances this toxic effect. In this work, we study how the increase of DA influences the toxic effect of 3-NP on DAergic terminals, GABAergic neurons, astroglia and microglia in the striatum. We increased the content of DA through the inhibition of its uptake by nomifensine or the inhibition of its catabolism by deprenyl. We found that although nomifensine and deprenyl enhanced the DA overflow produced by 3-NP perfusion, they protected against the damage induced by 3-NP in the DAergic terminals and the GABAergic neurons in the striatum. Moreover, there was a decrease of apoptotic cells, astrogliosis and activation of microglia as index of damage. We also found that depletion of DA by reserpine and alpha-methyl-p-tyrosine produced a significant reduction of the inhibition of the respiratory rate and of the production of superoxide radical induced by 3-NP in synaptosomes from the striatum. All these results suggest that endogenous dopamine within the dopaminergic terminals of the striatum enhances the mitochondrial production of radical oxygen species along with the respiratory inhibition produced by 3-NP and thus increases the toxicity produced by 3-NP in the striatum.
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PMID:Endogenous dopamine enhances the neurotoxicity of 3-nitropropionic acid in the striatum through the increase of mitochondrial respiratory inhibition and free radicals production. 1809 58

3-Nitropropionic acid (3-NP) is an irreversible inhibitor of the electron transport enzyme succinate dehydrogenase, a mitochondrial Complex II enzyme. Minocycline is a semi-synthetic second-generation tetracycline with neuroprotective activity and has the capability to effectively cross the blood-brain barrier. We investigated the effects of minocycline on behavioral, biochemical, inflammation related and neurochemical alterations induced by the sub-chronic administration of 3-nitropropionic acid to rats. Chronic pre-administration of minocycline (50 and 100mg/kg) dose dependently prevented 3-NP-induced dysfunction behavioral (hypoactivity, memory retention, locomotor and rota-rod activity). In addition, 3-NP produced a marked increase in lipid peroxidation levels whereas decreased the activities of catalase and succinate dehydrogenase. In contrast, pretreatment of 3-NP injected rats with minocycline resulted in the attenuation of all these alterations. A marked increase in an inflammatory cytokine TNF-alpha by 3-NP was also decreased by minocycline treatment. Neurochemically, the administration of 3-NP significantly decreased the levels of catecholamines in the brain homogenates (dopamine, norepinephrine and serotonin) which were reversed by pretreatment of minocycline. The present finding explains the neuroprotective effect of minocycline against 3-NP toxicity by virtue of its antioxidant and anti-inflammatory activity.
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PMID:Protective effect of minocycline, a semi-synthetic second-generation tetracycline against 3-nitropropionic acid (3-NP)-induced neurotoxicity. 1816 15

Recent evidence suggests that unscheduled cell cycle activity leads to neuronal cell death. 3-Nitropropionic acid (3-NP) is an irreversible inhibitor of succinate dehydrogenase and induces cell death in both striatum and cerebral cortex. Here we analyzed the involvement of aberrant cell cycle progression in 3-NP-induced cell death in these brain regions. 3-NP reduced the level of cyclin-dependent kinase inhibitor p27 in striatum but not in cerebral cortex. 3-NP also induced phosphorylation of retinoblastoma protein, a marker of cell cycle progression at late G(1) phase, only in striatum. Pharmacological experiments revealed that cyclin-dependent kinase activity and N-methyl-d-aspartate (NMDA) receptor were cooperatively involved in cell death by 3-NP in striatal neurons, whereas only NMDA receptor was involved in 3-NP-induced neurotoxicity in cortical neurons. Death of striatal neurons was preceded by elevation of somatic Ca(2+) and activation of calpain, a Ca(2+)-dependent protease. Both striatal p27 down-regulation and cell death provoked by 3-NP were dependent on calpain activity. Moreover, transfection of p27 small interfering RNA reduced striatal cell viability. In cortical neurons, however, there was no change in somatic Ca(2+) and calpain activity by 3-NP, and calpain inhibitors were not protective. These results suggest that 3-NP induces aberrant cell cycle progression and neuronal cell death via p27 down-regulation by calpain in striatum but not in the cerebral cortex. This is the first report for differential involvement of cell cycle reactivation in different brain regions and lightens the mechanism for region-selective vulnerability in human disease, including Huntington disease.
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PMID:Differential involvement of cell cycle reactivation between striatal and cortical neurons in cell death induced by 3-nitropropionic acid. 1818 90

Despite the increasing popularity of Centella asiatica (a well known plant in ayurvedic medicine) globally, evidence demonstrating its protective efficacy against neurotoxicants in animal models is limited. 3-Nitropropionic acid (3-NPA), a fungal toxin is a well known neurotoxicant which induces selective striatal pathology similar to that seen in Huntington's disease. The present study aimed to understand the neuroprotective efficacy of a standardized aqueous extract of C. asiatica (CA) against 3-NPA-induced early oxidative stress and mitochondrial dysfunctions in striatum and other brain regions. We determined the extent of oxidative stress in cytosol and mitochondria of brain regions of male mice (4wk old) given CA prophylaxis (5mg/kgbw) for 10 days followed by 3-NPA administration (i.p., 75mg/kgbw/d) on the last 2 days. The neurotoxicant elicited marked oxidative stress in the untreated mice as evidenced by elevated levels of malondialdehyde, ROS levels and hydroperoxides in the striatum (cytosol and mitochondria), while CA prophylaxis completely attenuated the 3-NPA-induced oxidative stress. 3-NPA also caused significant oxidative stress and protein oxidation in cytosol/mitochondria of other brain regions as well which were predominantly abolished by CA prophylaxis. Significant depletion of GSH levels, total thiols and perturbations in antioxidant enzymic defences in striatum and other brain regions discernible among 3-NPA administered mice were also protected with CA prophylaxis. Interestingly, CA prophylaxis offered varying degree of protection against 3-NPA-induced mitochondrial dysfunctions viz., reduction in the activity of succinic dehydrogenase, ETC enzymes and decreased mitochondrial viability. Collectively these findings clearly suggest that short-term oral intake of a standardized aqueous extract of CA confers marked resistance against the 3-NPA-induced oxidative stress and mitochondrial dysfunctions in brain. Although the precise mechanism/s underlying the prophylactic efficacy of CA merit further investigation, based on these findings, it is hypothesized that it may be wholly or in part related to the enhancement of GSH, thiols and antioxidant machinery in the brain regions of prepubertal mice.
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PMID:Prophylactic neuroprotective property of Centella asiatica against 3-nitropropionic acid induced oxidative stress and mitochondrial dysfunctions in brain regions of prepubertal mice. 1893 Jul 62

3-Nitropropionic acid (3NP) functions as an irreversible inhibitor of succinic acid dehydrogenase (complex II) and induces neuronal disorders in rats similar to those in patients with Huntington's disease. It is well known that L-carnitine (LC), a carrier of long chain fatty acid into the mitochondrial matrix, attenuates the neuronal degeneration in 3NP-treated rats. From these findings it has been suggested that 3NP induces certain neuronal cell death through mitochondrial dysfunction and that LC preserves the neurons against the dysfunction of mitochondria caused by 3NP. However, the detailed mechanism of cell death by 3NP and the protective actions of LC against the mitochondrial dysfunction have not been fully elucidated yet. Thus, we studied the molecular mechanism of the effects of 3NP and LC on isolated rat liver mitochondria. 3NP inhibited succinate respiration and the decreased respiratory control ratio of isolated mitochondria without affecting oxidative phosphorylation. 3NP induced a membrane permeability transition (MPT), which plays an important role in the mechanism of apoptotic cell death. 3NP stimulated Ca2+ release from mitochondria, decreased membrane potential, induced mitochondrial swelling, and stimulated cytochrome c release from mitochondria. 3NP-induced swelling was suppressed by bovine serum albumin, inhibitors of phospholipase A(2) and by an inhibitor of classic MPT, cyclosporin A. Furthermore, LC suppressed the changes brought about by 3NP in mitochondrial functions in the presence of ATP. These results suggest that MPT underlies the mechanism of 3NP-induced cell death, and that LC attenuates mitochondrial MPT by decreasing long chain fatty acids generated by phospholipase A(2).
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PMID:Mechanism of 3-nitropropionic acid-induced membrane permeability transition of isolated mitochondria and its suppression by L-carnitine. 1894 62

3-Nitropropionic acid (3-NP)-induced neurotoxicity can be used as a model for the genetic neurodegenerative disorder Huntington's disease (HD). A metabolic profiling strategy was adopted to explore the biochemical consequences of 3-NP administered to rats in specific brain regions. (1)H NMR spectroscopy was used to characterize the metabolite composition of several brain regions following 3-NP-intoxication. Dose-dependent increases in succinate levels were observed in all neuroanatomical regions, resulting from the 3-NP-induced inhibition of succinate dehydrogenase. Global decreases in taurine and GABA were observed in the majority of brain regions, whereas altered lipid profiles were observed only in the globus pallidus and dorsal striatum. Depleted phosphatidylcholine and elevated glycerol levels, which are indicative of apoptosis, were also observed in the frontal cortex of the 3-NP model. Many of the metabolic anomalies are consistent with those reported in HD. The 3-NP-induced model of HD provides a means of monitoring potential mechanisms of pathology and therapeutic response for drug interventions, which can be efficiently assessed using metabolic profiling strategies.
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PMID:Metabonomic characterization of the 3-nitropropionic acid rat model of Huntington's disease. 1914 50

Brain-derived neurotrophic factor (BDNF) deficiency has been implicated in pathogenesis of Huntington's disease (HD). 3-Nitropropionic acid (3-NP), an irreversible mitochondrial complex II inhibitor, has been commonly used as a pharmacological model recapitulating HD phenotypes in rodents and nonhuman primates. Herein we test whether BDNF may exert neuroprotective effects against mitochondrial dysfunction caused by 3-NP in primary culture of fetal rat cortical neurons. Preconditioning of neuronal cells with BDNF (100 ng/ml for 8h) attenuated 3-NP toxicity (2.5 mM for additional 24h) based on Hoechst and propidium iodide (PI) staining. BDNF effects can be inhibited by the nitric oxide synthase (NOS) inhibitor L-nitroarginine methylester (L-NAME, 100 microM), the cGMP-dependent protein kinase (PKG) inhibitor KT5823 (2 microM), the thioredoxin reductase inhibitor 1-chloro-2,4-dinitrobenzene (DNCB, 5 microM), and a membrane-permeable Bcl-2 inhibitor (12.5 microM). 8-Br-cGMP is a cGMP analogue capable of activating PKG independent of NO. Exogenous application of 8-Br-cGMP (3-30 microM) and purified thioredoxin (3-5 microM) partially mimicked BDNF effects in conferring 3-NP resistance to cortical cells. These results, together with our previous report showing NO donor S-nitrosoglutathione (GSNO)-mediated neuroprotective effects against 3-NP toxicity, suggest that BDNF may protect neurons from mitochondrial dysfunction at least partly via activation of the signaling cascades involving NOS/NO, PKG, thioredoxin and Bcl-2.
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PMID:Protective effects of brain-derived neurotrophic factor against neurotoxicity of 3-nitropropionic acid in rat cortical neurons. 1942 12

3-Nitropropionic acid inhibits succinate dehydrogenase, complex II enzyme in the mitochondrial respiratory chain that leads to cellular energy deficit and oxidative stress. Huntington's disease is characterized by abnormal body movements (chorea) and cognitive dysfunctions. Rivastigmine, a well known cholinesterase inhibitor used in the management of Alzheimer's disease in a clinical practice. Recent clinical studies suggest the potential role of rivastigmine in the management of Huntington's disease. The present study has been designed to explore the possible role of rivastigmine against 3-nitropropionic acid induced behavioral, biochemical and cellular alterations. Intraperitoneal administration of 3-nitropropionic acid (10 mg/kg for 14 days) caused significant loss in body weight, motor in coordination (locomotor activity and rota rod performance) and poor memory retention in Morris water maze and elevated plus maze performance tasks as compared to vehicle treated animals. Biochemical analysis revealed significant increase in lipid peroxidation, nitrite concentration and depleted superoxide dismutase, catalase levels and alterations in mitochondrial complex enzymes (I, II, IV and MTT assay) in the different regions (striatum, cortex and hippocampus) of rat brain. Rivastigmine (0.5, 1 and 2 mg/kg, orally) once daily treatment for a period of 14 days significantly improved motor performance and cognitive task in both Morris water maze and elevated plus maze tests. Further, rivastigmine treatment significantly attenuated oxidative damage and improved mitochondrial complexes enzyme activities in different regions (striatum, cortex and hippocampus) of rat brain. The results show that rivastigmine could be used as an effective therapeutic agent in the management of Huntington's disease and related conditions.
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PMID:Protective effect of rivastigmine against 3-nitropropionic acid-induced Huntington's disease like symptoms: possible behavioural, biochemical and cellular alterations. 1944 28


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