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

Ca2+ accumulation and Ca2+ overloading in mitochondria are responsible for the cell abnormality associated with ischemia and reperfusion injury. The present study was aimed at evaluating the efficacy of the Ca2+ channel blocker amlodipine on the mitochondrial Ca2+ accumulation, mitochondrial antioxidant status and mitochondrial respiratory enzymes in ischemia and reperfusion (I/R) induced liver injury. I/R injury induced mitochondrial damage in rats was assessed in terms of the decrease in activities (p < 0.05) of respiratory marker enzymes (malate dehydrogenase, succinate dehydrogenase and NADH dehydrogenase), mitochondrial antioxidant enzymes (glutathione, superoxide dismutase, catalase), and significant increase (p < 0.05) in the level of lipid peroxidation (LPO) and Ca2+ content.Mitochondrial damage was confirmed by transmission electron microscopic (TEM) examination. Pretreatment with amlodipine effectively counteracted the alteration in mitochondrial enzymes induced by ischemia-reperfusion liver damage. TEM study confirms the restoration of cellular normalcy and the cytoprotective role of amlodipine against I/R induced hepatic injury. On the basis of our findings it may be concluded that amlodipine not only possesses Ca2+ channel antagonist properties but it may also reduce the extent of mitochondrial damage by its antioxidant activity.
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PMID:Protective role of the calcium channel blocker amlodipine against mitochondrial injury in ischemia and reperfusion injury of rat liver. 1910 76

Patients with a chronic brain ischemia of stages I-II on the background of hypertension and/or cerebral atherosclerosis are characterized by energy insufficiency of the metabolism, as estimated by the activity of succinate dehydrogenase in peripheral blood lymphocytes. Within the framework of randomized comparative investigation of the efficiency of actovegin and mexidol in the complex therapy of a chronic brain ischemia, positive dynamics in reduction of the clinical semiology, restoration of cognitive processes in the brain, and reduction of the expression of subjective manifestations of the disease is established. On this background, the administration of mexidol led to restoration of the energy exchange due to substrate effects of the Krebs cycle intermediates present in its structure.
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PMID:[Metabolic effects of mexidol in complex treatment of chronic brain ischemia]. 1914 May 8

The cardioprotective effects of ischemic preconditioning (IPC) can be mimicked or blocked by pharmacologic agents, which modulate the mitochondrial ATP-sensitive potassium (mK(ATP)) channel, thereby implicating this channel in the mechanism of IPC. Cardioprotection can also be achieved via inhibition of mitochondrial respiratory complex II, and significant pharmacologic overlap exists between complex II inhibitors and mK(ATP) channel agonists. However, the relationship between complex II and the mK(ATP) channel remains unclear. Atpenin A5 (AA5) is a potent and specific complex II inhibitor, and herein we report that AA5 (1 nM) also activates the mK(ATP) channel and protects against simulated ischemia-reperfusion (IR) injury in isolated cardiomyocytes. Similar to known mK(ATP) agonists, AA5-mediated protection was sensitive to the mK(ATP) antagonists 5-hydroxydecanoate (5HD) and glyburide. Notably, the optimal mK(ATP) opening and protective concentration of AA5 had no effect on complex II enzymatic activity, suggesting an interaction of AA5 with complex II, but not inhibition of the complex per se, is necessary for protection. A cardioprotective effect of AA5 was also observed in isolated perfused hearts, wherein AA5 increased post-IR contractile function and decreased infarct size, in a 5HD-sensitive manner. In conclusion, the specific complex II inhibitor AA5 is the most potent mK(ATP) activator discovered to date, and provides a novel method of activating mK(ATP) channels and protecting the heart from IR injury.
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PMID:The complex II inhibitor atpenin A5 protects against cardiac ischemia-reperfusion injury via activation of mitochondrial KATP channels. 1924 45

The effect of ageing and the relationships between the catalytic properties of enzymes linked to Krebs' cycle, electron transfer chain, glutamate and aminoacid metabolism of cerebral cortex, a functional area very sensitive to both age and ischemia, were studied on mitochondria of adult and aged rats, after complete ischemia of 15 minutes duration. The maximum rate (Vmax) of the following enzyme activities: citrate synthase, malate dehydrogenase, succinate dehydrogenase for Krebs' cycle; NADH-cytochrome c reductase as total (integrated activity of Complex I-III), rotenone sensitive (Complex I) and cytochrome oxidase (Complex IV) for electron transfer chain; glutamate dehydrogenase, glutamate-oxaloacetate-and glutamate-pyruvate transaminases for glutamate metabolism were assayed in non-synaptic, perikaryal mitochondria and in two populations of intra-synaptic mitochondria, i.e., the light and heavy mitochondrial fraction. The results indicate that in normal, steady-state cerebral cortex, the value of the same enzyme activity markedly differs according (a) to the different populations of mitochondria, i.e., non-synaptic or intra-synaptic light and heavy, (b) and respect to ageing. After 15 min of complete ischemia, the enzyme activities of mitochondria located near the nucleus (perikaryal mitochondria) and in synaptic structures (intra-synaptic mitochondria) of the cerebral tissue were substantially modified by ischemia. Non-synaptic mitochondria seem to be more affected by ischemia in adult and particularly in aged animals than the intra-synaptic light and heavy mitochondria. The observed modifications in enzyme activities reflect the metabolic state of the tissue at each specific experimental condition, as shown by comparative evaluation with respect to the content of energy-linked metabolites and substrates. The derangements in enzyme activities due to ischemia is greater in aged than in adult animals and especially the non-synaptic and the intra-synaptic light mitochondria seems to be more affected in aged animals. These data allow the hypothesis that the observed modifications of catalytic activities in non-synaptic and intra-synaptic mitochondrial enzyme systems linked to energy metabolism, amino acids and glutamate metabolism are primary responsible for the physiopathological responses of cerebral tissue to complete cerebral ischemia for 15 min duration during ageing.
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PMID:Effect of ageing and ischemia on enzymatic activities linked to Krebs' cycle, electron transfer chain, glutamate and aminoacids metabolism of free and intrasynaptic mitochondria of cerebral cortex. 1949 70

Age-related decline in the capacity to withstand stress, such as ischemia and reperfusion, results in congestive heart failure. Though the mechanisms underlying cardiac decay are not clear, age dependent somatic damages to mitochondrial DNA (mtDNA), loss of mitochondrial function, and a resultant increase in oxidative stress in heart muscle cells may be responsible for the increased risk for cardiovascular diseases. The effect of a safe nutritional supplement, POLY-MVA, containing the active ingredient palladium alpha-lipoic acid complex, was evaluated on the activities of the Krebs cycle enzymes such as isocitrate dehydrogenase, alpha-ketoglutarate dehydrogenase, succinate dehydrogenase, and malate dehydrogenase as well as mitochondrial complexes I, II, III, and IV in heart mitochondria of aged male albino rats of Wistar strain. Administration of 0.05 ml/kg of POLY-MVA (which is equivalent to 0.38 mg complexed alpha-lipoic acid/kg, p.o), once daily for 30 days, was significantly (p<0.05) effective to enhance the Krebs cycle dehydrogenases, and mitochondrial electron transport chain complexes. The unique electronic and redox properties of palladium alpha-lipoic acid complex appear to be a key to this physiological effectiveness. The results strongly suggest that this formulation might be effective to protect the aging associated risk of cardiovascular and neurodegenerative diseases.
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PMID:Palladium alpha-lipoic acid complex formulation enhances activities of Krebs cycle dehydrogenases and respiratory complexes I-IV in the heart of aged rats. 1950 Jun 41

Oxidative stress has been implicated in the cell death that occurs after ischemia-reperfusion of the brain, which causes the production of reactive oxygen species and a decrease in antioxidants, leading to mitochondrial dysfunction. However, the invasive methods used to collect much of this evidence are themselves stress inducing, which could skew the results. In this study, we aimed at demonstrating brain redox alterations after ischemia-reperfusion noninvasively, using Overhauser-enhanced magnetic resonance imaging. The reduction rate of 3-methoxycarbonyl-2,2,5,5-tetramethylpyrrolidine-L-oxyl (methoxycarbonyl-PROXYL), a redox-sensitive contrast agent, was used as an index of the redox status in vivo. No changes were observed in the antioxidant concentration, the mitochondrial complex activity, or in the redox status image intensity after 3 h of reperfusion, following transient middle cerebral artery occlusion; however, after 24 h of reperfusion, the methoxycarbonyl-PROXYL reduction rate, calculated from continuous images, had decreased significantly. Concordantly, biochemical assays showed that the concentration of ascorbic acid in the ischemic hemisphere and the activity of mitochondrial complex II had also decreased. Thus, the noninvasive imaging of the brain redox alterations faithfully reflected changes in antioxidant levels and in mitochondrial complex II activity after ischemia-reperfusion.
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PMID:Noninvasive assessment of the brain redox status after transient middle cerebral artery occlusion using Overhauser-enhanced magnetic resonance imaging. 1955 9

Diazoxide, a mitochondrial ATP-sensitive potassium (mitoK(ATP)) channel opener, protects the heart from ischemia-reperfusion injury. Diazoxide also inhibits mitochondrial complex II-dependent respiration in addition to its preconditioning effect. However, there are no prior studies of the role of diazoxide on post-ischemic myocardial oxygenation. In the current study, we determined the effect of diazoxide on the suppression of post-ischemic myocardial tissue hyperoxygenation in vivo, superoxide (O(2)(-*)) generation in isolated mitochondria, and impairment of the interaction between complex II and complex III in purified mitochondrial proteins. It was observed that diazoxide totally suppressed the post-ischemic myocardial hyperoxygenation. With succinate but not glutamate/malate as the substrate, diazoxide significantly increased ubisemiquinone-dependent O(2)(-*) generation, which was not blocked by 5-HD and glibenclamide. Using a model system, the super complex of succinate-cytochrome c reductase (SCR) hosting complex II and complex III, we also observed that diazoxide impaired complex II and its interaction with complex III with no effect on complex III. UV-visible spectral analysis revealed that diazoxide decreased succinate-mediated ferricytochrome b reduction in SCR. In conclusion, our results demonstrated that diazoxide suppressed the in vivo post-ischemic myocardial hyperoxygenation through opening the mitoK(ATP) channel and ubisemiquinone-dependent O(2)(-*) generation via inhibiting mitochondrial complex II-dependent respiration.
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PMID:Opening of the mitoKATP channel and decoupling of mitochondrial complex II and III contribute to the suppression of myocardial reperfusion hyperoxygenation. 1985 35

Promethazine (PMZ), an FDA-approved antihistaminergic drug, was identified as a potentially neuroprotective compound in a NINDS screening program. It was shown to protect against ischemia in mice, to delay disease onset in a mouse model of amyotrophic lateral sclerosis and to inhibit Ca(2+)-induced mitochondrial permeability transition in rat liver mitochondria. We investigated whether PMZ could protect against the neurotoxic effects induced by 3-nitropropionic acid (3-NP), an inhibitor of the succinate dehydrogenase, used to model Huntington's disease (HD) in rats. Lewis rats receiving chronic subcutaneous infusion of 3-NP were treated with PMZ. The findings indicate that chronic PMZ treatment significantly reduced 3-NP-induced striatal lesion volume, loss of GABAergic neurons and number of apoptotic cells in the striatum. PMZ showed a strong neuroprotective effect against 3-NP toxicity in vivo.
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PMID:Promethazine protects against 3-nitropropionic acid-induced neurotoxicity. 1985 92

Asperosaponin VI is a saponin of the medicinal herb Dipsacus asper (Xuduan), and no pharmacological activity has been reported yet. In this study, we investigated the anti-myocardial ischemia effects of Asperosaponin VI (ASA VI) both in vivo and in vitro. An animal model of myocardial ischemia(MI) injury was induced by coronary occlusion, pretreatment with ASA VI (10 and 20mg/kg, i.v.) could protect the heart from ischemia injury by decreasing the levels of creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH), glutamic oxalacetic transaminase (GOT) and cardiac troponin T (cTnT) in serum, increasing the levels of catalase, glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) levels in heart, and decreasing that of malondialdehyde (MDA) level in acute MI rats. ASA VI also raised the activities of mitochondrial enzymes (succinate dehydrogenase (SDH), isocitrate dehydrogenase (ICDH), malate dehydrogenase (MDH) and alpha-ketoglutarate dehydrogenase (alpha-KGDH)) and those of adenosine triphosphate (ATP) content, but lowered Ca(2+) level. Electrocardiograph parameters and histopathological observations demonstrated the same protective effects. In vitro experiment, neonatal rat cardiomyocytes were incubated to test the direct cytoprotective effect of ASA VI against H(2)O(2) exposure. Pretreatment with ASA VI (30 and 60 microg/ml) prior to H(2)O(2) exposure increased cell viability and inhibited H(2)O(2)-induced reactive oxygen species increase. ASA VI (15, 30 and 60 microg/ml) also increased the activities of LDH in the cultured supernatant and SOD in cardiomyocytes, but decreased the cardiomyocytes MDA level. Our results suggested that ASA VI could provide significant cardioprotective effects against acute MI in rats. The mechanisms might be attributed to scavenging lipid peroxidation products and reactive oxygen species, increasing antioxidant defense enzymes and preventing mitochondrial damage.
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PMID:Protective roles of Asperosaponin VI, a triterpene saponin isolated from Dipsacus asper Wall on acute myocardial infarction in rats. 1990 36

Since the anti-epileptic drug Zonisamide (ZNS) seems to exert beneficial effects in Parkinson's (PD) disease, we have investigated the electrophysiological effects of ZNS in a rat corticostriatal slice preparation. ZNS affected neither the resting membrane potential nor the input resistance of the putative striatal spiny neurons. In contrast, this drug depressed in a dose-dependent manner the current-evoked repetitive firing discharge with a EC(50) value of 16.38 microM. ZNS also reduced the amplitude of glutamatergic excitatory postsynaptic potentials (EPSPs) with a EC(50) value of 32.5 microM. Reduced activity of the mitochondrial respiratory chain, particularly complex I and II, is implicated in the pathophysiology of PD and Huntington's (HD) diseases, respectively. Thus, ZNS was also tested in two different in vitro neurotoxic models obtained by acutely exposing corticostriatal slices either to rotenone, a selective inhibitor of mitochondrial complex I, or to 3-nitropropionic acid (3-NP), an inhibitor of complex II. Additionally, we also investigated the effect of ZNS in an in vitro model of brain ischemia. Interestingly, low concentrations of ZNS (0.3, 1, 3 and 10 microM) significantly reduced the rotenone-induced toxicity protecting striatal slices from the irreversible loss of corticostriatal field potential (FP) amplitude via a GABA-mediated mechanism. Conversely, this drug showed no protection against 3-NP and ischemia-induced toxicity. Our data indicate that relatively high doses of ZNS are required to decrease striatal neuronal excitability while low concentrations of this drug are sufficient to protect striatum against mitochondrial impairment suggesting its possible use in the therapy of basal ganglia neurodegenerative diseases.
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PMID:Electrophysiological actions of zonisamide on striatal neurons: Selective neuroprotection against complex I mitochondrial dysfunction. 2045 Sep 11


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