Studies on the Respiratory Chain-linked Reduced Nicotinamide Adenine Dinucleotide Dehydrogenase

Palmer, Graham; Horgan, Douglas J.; Tisdale, H.D.; Singer, Thomas P.; Beinert, Helmut

doi:10.1016/s0021-9258(19)81742-8

Cited by 155 publications

(27 citation statements)

References 13 publications

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“…ROT has become interesting for PD study because it has high lipophilicity, which allows it to easily penetrate biological membranes, including the blood-brain barrier [14]. As mentioned above, this pesticide acts as a potent inhibitor of mitochondrial complex I, leading to incomplete electron transfer from the centers of iron-sulfur complex I to ubiquinone, which blocks oxidative phosphorylation with limited ATP synthesis [15], promoting the formation of free oxygen radicals and causes oxidative stress and apoptosis in cells. Mitochondrial dysfunction and increased oxidative stress were demonstrated in a subgroup of patients with PD [16].…”

Section: Resultsmentioning

confidence: 99%

Corrective effects of benzodiazepine derivative – diazepinone on purine and lipid metabolism in the liver of rats with Parkinson’s disease

Shtanova¹,

Yanchuk²,

Veselsky³

et al. 2021

Fiziol Zh

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Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra. The cause of PD is not fully understood, and effective treatments still do not exist. It is believed that oxidative stress, mitochondrial dysfunction, and impaired lipid metabolism may underlie the pathogenesis of PD. Bile contains the breakdown products of various compounds that form in hepatocytes. This study aimed to evaluate the effect of a new benzodiazepine derivative - diazepinone (DP) on purine and lipid metabolism in the liver of rats with PD caused by rotenone (ROT) by studying the composition of bile. The concentration of ATP, ADP, AMP, xanthine, hypoxanthine, phospholipids (PL), cholesterol (CHOL), cholesterol esters (ECHOL), free fatty acids (FFA), and triglycerides (TG) was quantified in bile samples by thin-layer chromatography. Our findings suggested that the ratio of AMP/ ATP in bile increased almost threefold under the influence of ROT, and with DP, it exceeded the norm by only 1.6 times. ROT also increased the content of xanthine and hypoxanthine by 28.6% and 66.7%, respectively. DP did not affect the increased xanthine content relative to control but significantly reduced the level of hypoxanthine (up to 22.2%, above normal). In addition, ROT reduced the content of bile PL, CHOL, ECHOL, TG by 23.9%, 38.6%, 47.5%, 39.2 %, respectively. Under the influence of the DP, all the above indicators returned to the level of control. Thus, diazepinone improves both the metabolism of purines and lipids in the liver of rats with ROT-simulated PD. This drug may become a therapeutic agent for treating PD and possibly other neurodegenerative diseases in the future.

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Section: Resultsmentioning

confidence: 99%

Corrective effects of benzodiazepine derivative – diazepinone on purine and lipid metabolism in the liver of rats with Parkinson’s disease

Shtanova¹,

Yanchuk²,

Veselsky³

et al. 2021

Fiziol Zh

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“…The fraction of active cells in the population increased from 14.9% under control, normoxic, conditions to 32.4% after application of 3 mM metformin. In order to check that this effect is due to metformin inhibition of complex I of the respiratory chain in mitochondria [25], we tested canonical inhibitor rotenone [39]. Treatment of microglial cells with 5 nM and concentrations up to 1 µM of rotenone for 24 h had no statistically significant effect on cell viability under normoxic and mild hypoxic conditions (data not shown).…”

Section: Resultsmentioning

confidence: 99%

“…Thus, if ROS production is regulating spontaneous Ca 2+ signaling, the observed increased spontaneous Ca 2+ activity in our experiments could be quite expected. In order to check that this effect is brought about by action of metformin only on complex I, we tested a canonical complex I inhibitor rotenone, which blocks NADH oxidation by mitochondria [39], and its evoked neuronal degeneration is thought to be mediated by microglial NADPH oxidase [47]. Rotenone also has much faster inhibitory effect on mitochondrial respiration comparing to metformin or phenformin [26].…”

Section: Discussionmentioning

confidence: 99%

Effects of Metformin on Spontaneous Ca2+ Signals in Cultured Microglia Cells under Normoxic and Hypoxic Conditions

Jankevičiūtė¹,

Svirskienė²,

Svirskis³

et al. 2021

IJMS

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Microglial functioning depends on Ca2+ signaling. By using Ca2+ sensitive fluorescence dye, we studied how inhibition of mitochondrial respiration changed spontaneous Ca2+ signals in soma of microglial cells from 5–7-day-old rats grown under normoxic and mild-hypoxic conditions. In microglia under normoxic conditions, metformin or rotenone elevated the rate and the amplitude of Ca2+ signals 10–15 min after drug application. Addition of cyclosporin A, a blocker of mitochondrial permeability transition pore (mPTP), antioxidant trolox, or inositol 1,4,5-trisphosphate receptor (IP3R) blocker caffeine in the presence of rotenone reduced the elevated rate and the amplitude of the signals implying sensitivity to reactive oxygen species (ROS), and involvement of mitochondrial mPTP together with IP3R. Microglial cells exposed to mild hypoxic conditions for 24 h showed elevated rate and increased amplitude of Ca2+ signals. Application of metformin or rotenone but not phenformin before mild hypoxia reduced this elevated rate. Thus, metformin and rotenone had the opposing fast action in normoxia after 10–15 min and the slow action during 24 h mild-hypoxia implying activation of different signaling pathways. The slow action of metformin through inhibition of complex I could stabilize Ca2+ homeostasis after mild hypoxia and could be important for reduction of ischemia-induced microglial activation.

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“…It is a strong inhibitor of mitochondrial complex 1 and has been linked to the higher incidences of PD in agricultural areas [71,72]. Rotenone inhibits electron transfer from the iron-sulphur clusters in complex I to ubiquinone which blocks oxidative phosphorylation and limits ATP synthesis [73]. Such incomplete electron transfer also results in the excessive formation of ROS and together eventually leads to apoptosis of the affected cells [74][75][76].…”

Section: Discussionmentioning

confidence: 99%

Micellar Nanocarriers of Hydroxytyrosol Are Protective against Parkinson’s Related Oxidative Stress in an In Vitro hCMEC/D3-SH-SY5Y Co-Culture System

Mursaleen

Noble

Somavarapu³

et al. 2021

Antioxidants

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Hydroxytyrosol (HT) is a natural phenolic antioxidant which has neuroprotective effects in models of Parkinson’s disease (PD). Due to issues such as rapid metabolism, HT is unlikely to reach the brain at therapeutic concentrations required for a clinical effect. We have previously developed micellar nanocarriers from Pluronic F68® (P68) and dequalinium (DQA) which have suitable characteristics for brain delivery of antioxidants and iron chelators. The aim of this study was to utilise the P68 + DQA nanocarriers for HT alone, or in combination with the iron chelator deferoxamine (DFO), and assess their physical characteristics and ability to pass the blood–brain barrier and protect against rotenone in a cellular hCMEC/D3-SH-SY5Y co-culture system. Both HT and HT + DFO formulations were less than 170 nm in size and demonstrated high encapsulation efficiencies (up to 97%). P68 + DQA nanoformulation enhanced the mean blood–brain barrier (BBB) passage of HT by 50% (p < 0.0001, n = 6). This resulted in increased protection against rotenone induced cytotoxicity and oxidative stress by up to 12% and 9%, respectively, compared to the corresponding free drug treatments (p < 0.01, n = 6). This study demonstrates for the first time the incorporation of HT and HT + DFO into P68 + DQA nanocarriers and successful delivery of these nanocarriers across a BBB model to protect against PD-related oxidative stress. These nanocarriers warrant further investigation to evaluate whether this enhanced neuroprotection is exhibited in in vivo PD models.

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Studies on the Respiratory Chain-linked Reduced Nicotinamide Adenine Dinucleotide Dehydrogenase

Cited by 155 publications

References 13 publications

Corrective effects of benzodiazepine derivative – diazepinone on purine and lipid metabolism in the liver of rats with Parkinson’s disease

Corrective effects of benzodiazepine derivative – diazepinone on purine and lipid metabolism in the liver of rats with Parkinson’s disease

Effects of Metformin on Spontaneous Ca2+ Signals in Cultured Microglia Cells under Normoxic and Hypoxic Conditions

Micellar Nanocarriers of Hydroxytyrosol Are Protective against Parkinson’s Related Oxidative Stress in an In Vitro hCMEC/D3-SH-SY5Y Co-Culture System

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