Inhibition of NADH oxidation by 1‐methyl‐4‐phenylpyridinium analogs as the basis for the prediction of the inhibitory potency of novel compounds

Sablin, Sergey O.; Krueger, Matthew J.; Yankovskaya, Victoria; Ткаченко, С. Е.; Razdolsky, Alexander N.; Бачурин, С. О.; Ramsay, Rona R.; Singer, Thomas P.

doi:10.1002/(sici)1522-7146(1996)11:1<33::aid-jbt5>3.3.co;2-8

Cited by 5 publications

(5 citation statements)

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“…These data suggest that glucose metabolism beyond pyruvate (i.e., a decreased oxidative phosphorylation or an altered mitochondrial ROS production) is responsible for the inhibition of sustained HPV. This explanation is well in line with our study, as all inhibitors of the mitochondrial electron transport chain are suggested to result in a reduced oxidative phosphorylation in the concentrations applied (29)(30)(31)(32)(33)(34). In accordance with the observations of Wiener and Sylvester (9,13) low glucose also suppressed sustained HPV in isolated rat intrapulmonary arteries (6).…”

Section: Pharmacologic Interventions In the Isolated Rabbit Lungsupporting

confidence: 92%

Impact of Mitochondria and NADPH Oxidases on Acute and Sustained Hypoxic Pulmonary Vasoconstriction

Weißmann

Zeller

Schäfer

et al. 2006

Am J Respir Cell Mol Biol

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Hypoxic pulmonary vasoconstriction (HPV) matches lung perfusion with ventilation to optimize pulmonary gas exchange. However, it remains unclear whether acute HPV (occurring within seconds) and the vasoconstrictor response to sustained alveolar hypoxia (developing over several hours) are triggered by identical mechanisms. We investigated the effect of mitochondrial and NADPH oxidase inhibitors on both phases of HPV in intact rabbit lungs. These studies revealed that the sustained HPV is largely dependent on mitochondrial complex I and totally dependent on complex IV, whereas NADPH oxidase dependence was only observed for acute HPV. These findings were reinforced by an alternative approach employing lungs from mice deficient in the NADPH oxidase subunit p 47(phox). In these mice (which lack a subunit suggested to be important for the function of most NADPH oxidase isoforms), but not in gp 91(phox)-deficient mice (which represent only one isoform of NADPH oxidases), acute HPV was significantly reduced, while non-hypoxia-induced vasoconstrictions elicited by the thromboxane mimetic U46619 were not affected. We concluded that the acute phase and the sustained phase of HPV are differentially regulated, with NADPH oxidase activity predominating in the acute phase, while a strong dependence on mitochondrial participation was observed for the second phase.

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Section: Pharmacologic Interventions In the Isolated Rabbit Lungsupporting

confidence: 92%

Impact of Mitochondria and NADPH Oxidases on Acute and Sustained Hypoxic Pulmonary Vasoconstriction

Weißmann

Zeller

Schäfer

et al. 2006

Am J Respir Cell Mol Biol

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“…MPP ϩ binds to one of two ubiquinone binding sites of the NADH multienzyme complex (17,25), which is in the same domain as the rotenone and piericidin A sites. Inhibition of NADH dehydrogenase, in addition to decreasing cell respiration, decreases mitochondrial proton pumping (16) and increases free radical production, the latter effect being correlated with cell death (26).…”

Section: Discussionmentioning

confidence: 99%

d -β-Hydroxybutyrate protects neurons in models of Alzheimer's and Parkinson's disease

Kashiwaya

Takeshima

Mori

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

475

364

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The heroin analogue 1-methyl-4-phenylpyridinium, MPP + , both in vitro and in vivo , produces death of dopaminergic substantia nigral cells by inhibiting the mitochondrial NADH dehydrogenase multienzyme complex, producing a syndrome indistinguishable from Parkinson's disease. Similarly, a fragment of amyloid protein, Aβ 1–42 , is lethal to hippocampal cells, producing recent memory deficits characteristic of Alzheimer's disease. Here we show that addition of 4 mM d -β-hydroxybutyrate protected cultured mesencephalic neurons from MPP + toxicity and hippocampal neurons from Aβ 1–42 toxicity. Our previous work in heart showed that ketone bodies, normal metabolites, can correct defects in mitochondrial energy generation. The ability of ketone bodies to protect neurons in culture suggests that defects in mitochondrial energy generation contribute to the pathophysiology of both brain diseases. These findings further suggest that ketone bodies may play a therapeutic role in these most common forms of human neurodegeneration.

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“…Fortunately it is treatable for a period by administration of dopamine, but eventually continued free radical damage lessens the effectiveness of this therapy. The meperidine analogue MPP C , when taken by humans causes increased oxygen radical formation (30) and inhibition of NADH dehydrogenase (31). Recent reports show that primary cultures of mesencephalic dopaminergic neurons exposed to MPP C could be protected from death by addition of 4 mM D-¯-hydroxybutyrate (25).…”

Section: Parkinson's Diseasementioning

confidence: 94%

Ketone Bodies, Potential Therapeutic Uses

Veech¹

2001

IUBMB Life

363

129

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SummaryKetosis, meaning elevation of D-¯-hydroxybutyrate (R-3-hydroxybutyrate) and acetoacetate, has been central to starving man's survival by providing nonglucose substrate to his evolutionarily hypertrophied brain, sparing muscle from destruction for glucose synthesis. Surprisingly, D-¯-hydroxybutyrate (abbreviated "¯OHB") may also provide a more ef cient source of energy for brain per unit oxygen, supported by the same phenomenon noted in the isolated working perfused rat heart and in sperm. It has also been shown to decrease cell death in two human neuronal cultures, one a model of Alzheimer's and the other of Parkinson's disease. These observations raise the possibility that a number of neurologic disorders, genetic and acquired, might bene t by ketosis. Other bene cial effects from¯OHB include an increased energy of ATP hydrolysis (1G 0 ) and its linked ionic gradients. This may be signi cant in drug-resistant epilepsy and in injury and anoxic states. The ability of¯OHB to oxidize co-enzyme Q and reduce NADP + may also be important in decreasing free radical damage. Clinical maneuvers for increasing blood levels of¯OHB to 2 -5 mmol may require synthetic esters or polymers of¯OHB taken orally, probably 100 to 150 g or more daily. This necessitates advances in food-science technology to provide at least enough orally acceptable synthetic material for animal and possibly subsequent clinical testing. The other major need is to bring the technology for the analysis of multiple metabolic "phenotypes" up to the level of sophistication of the instrumentation used, for example, in gene science or in structural biology. This technical strategy will be critical to the characterization of polygenic disorders by enhancing the knowledge gained from gene analysis and from the subsequent steps and modi cations of the protein products themselves.

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Inhibition of NADH oxidation by 1‐methyl‐4‐phenylpyridinium analogs as the basis for the prediction of the inhibitory potency of novel compounds

Cited by 5 publications

References 0 publications

Impact of Mitochondria and NADPH Oxidases on Acute and Sustained Hypoxic Pulmonary Vasoconstriction

Impact of Mitochondria and NADPH Oxidases on Acute and Sustained Hypoxic Pulmonary Vasoconstriction

d -β-Hydroxybutyrate protects neurons in models of Alzheimer's and Parkinson's disease

Ketone Bodies, Potential Therapeutic Uses

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