Effect of the anti-anginal agent, perhexiline, on neutrophil, valvular and vascular superoxide formation

Kennedy, Jennifer A.; Beck-Oldach, Konstanz; McFadden-Lewis, Kate; Murphy, Geraldine A.; Wong, Y.; Zhang, Yi; Horowitz, John D.

doi:10.1016/j.ejphar.2005.11.058

Cited by 39 publications

(19 citation statements)

References 22 publications

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“…Mechanistically, it was suggested to inhibit carnitine palmitoyl transferase-1 (86), resulting in a shift in myocardial energy usage from fatty acid to glucose metabolism. However, a part of its beneficial effects was also attributed to the inhibition of NOX2 in neutrophils (IC 50 1.5-3.6 lM) as well as in different cardiovascular tissues and cells (85). A later study confirmed the inhibition of NOX2 in neutrophils and in an assay measuring purified semi-recombinant NOX2 activity (IC 50 13.2 lM).…”

supporting

confidence: 48%

Evolution of NADPH Oxidase Inhibitors: Selectivity and Mechanisms for Target Engagement

Altenhöfer

Radermacher

Kleikers

et al. 2015

Antioxidants & Redox Signaling

448

417

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Significance: Oxidative stress, an excess of reactive oxygen species (ROS) production versus consumption, may be involved in the pathogenesis of different diseases. The only known enzymes solely dedicated to ROS generation are nicotinamide adenine dinucleotide phosphate (NADPH) oxidases with their catalytic subunits (NOX). After the clinical failure of most antioxidant trials, NOX inhibitors are the most promising therapeutic option for diseases associated with oxidative stress. Recent Advances: Historical NADPH oxidase inhibitors, apocynin and diphenylene iodonium, are un-specific and not isoform selective. Novel NOX inhibitors stemming from rational drug discovery approaches, for example, GKT137831, ML171, and VAS2870, show improved specificity for NADPH oxidases and moderate NOX isoform selectivity. Along with NOX2 docking sequence (NOX2ds)-tat, a peptide-based inhibitor, the use of these novel small molecules in animal models has provided preliminary in vivo evidence for a pathophysiological role of specific NOX isoforms. Critical Issues: Here, we discuss whether novel NOX inhibitors enable reliable validation of NOX isoforms' pathological roles and whether this knowledge supports translation into pharmacological applications. Modern NOX inhibitors have increased the evidence for pathophysiological roles of NADPH oxidases. However, in comparison to knockout mouse models, NOX inhibitors have limited isoform selectivity. Thus, their use does not enable clear statements on the involvement of individual NOX isoforms in a given disease. Future Directions: The development of isoform-selective NOX inhibitors and biologicals will enable reliable validation of specific NOX isoforms in disease models other than the mouse. Finally, GKT137831, the first NOX inhibitor in clinical development, is poised to provide proof of principle for the clinical potential of NOX inhibition. Antioxid. Redox Signal. 23, 406-427.

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supporting

confidence: 48%

Evolution of NADPH Oxidase Inhibitors: Selectivity and Mechanisms for Target Engagement

Altenhöfer

Radermacher

Kleikers

et al. 2015

Antioxidants & Redox Signaling

448

417

View full text Add to dashboard Cite

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“…Additional effects of perhexiline include blockade of the NAD(P)H oxidase 2 (Nox2) complex, conveying beneficial anti-inflammatory effects (Gatto, et al, 2013;Kennedy, et al, 2006;Liberts, et al, 2007), and reduced expression of TXNIP (Ngo, et al, 2011). Moreover, a recent study reports that perhexiline activates Krüppel-like factor 14 (KLF14), which regulates lipid metabolism, reducing atherosclerotic lesion development in a mouse model .…”

Section: Carnitine Palmitoyltransferase 1 (Cpt1) Inhibitionmentioning

confidence: 99%

Cardiac metabolism — A promising therapeutic target for heart failure

Noordali

Loudon

Frenneaux

et al. 2018

Pharmacology & Therapeutics

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Both heart failure with reduced ejection fraction (HFrEF) and with preserved ejection fraction (HFpEF) are associated with high morbidity and mortality. Although many established pharmacological interventions exist for HFrEF, hospitalization and death rates remain high, and for those with HFpEF (approximately half of all heart failure patients), there are no effective therapies. Recently, the role of impaired cardiac energetic status in heart failure has gained increasing recognition with the identification of reduced capacity for both fatty acid and carbohydrate oxidation, impaired function of the electron transport chain, reduced capacity to transfer ATP to the cytosol, and inefficient utilization of the energy produced. These nodes in the genesis of cardiac energetic impairment provide potential therapeutic targets, and there is promising data from recent experimental and early-phase clinical studies evaluating modulators such as carnitine palmitoyltransferase 1 inhibitors, partial fatty acid oxidation inhibitors and mitochondrial-targeted antioxidants.Metabolic modulation may provide significant symptomatic and prognostic benefit for patients suffering from heart failure above and beyond guideline-directed therapy, but further clinical trials are needed.

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“…Subsequent studies demonstrated that perhexiline reversibly inhibited CPT-1 and -2 in the liver and cardiac mitochondria 55 and that the toxicity was attributable to phospholipid accumulation in liver and peripheral nerves related to chronic exposure to high plasma levels of the drug related in large part to polymorphic variation in the activity of the Cytochrome P450 2D enzyme predominantly responsible for its metabolism and preventable by monitoring of plasma levels with appropriate dose titration. In a randomized placebo-controlled trial in 56 patients with chronic heart failure, perhexiline increased exercise capacity, LV ejection fraction, and quality of life.…”

Section: Cpt-1 Inhibitors Perhexiline (Reversible Cpt-1 Inhibitor)mentioning

confidence: 99%

“…59 Perhexiline also reduces generation of superoxide by NADPH oxidase enzymes, 55 reduces expression of thioredoxin-interacting protein, an inhibitor of thioredoxin (a potent intracellular antioxidant) and of glycolysis, 60 and inhibits mammalian target of rapamycin C1 (potentially leading to improved cell survival via increased autophagy). 61 In a metabolomic and proteomic study, perhexiline not only caused the known shift from fatty acid β-oxidation to glucose oxidation (via CPT-1 and -2 inhibition), but also induced a complex rebalancing of carbon and nucleotide phosphate fluxes via augmented lactate and amino acid uptake.…”

Section: Cpt-1 Inhibitors Perhexiline (Reversible Cpt-1 Inhibitor)mentioning

confidence: 99%

Cardiac Energetic Impairment in Heart Disease and the Potential Role of Metabolic Modulators

Singh

Schwarz

Horowitz

et al. 2014

Circ Cardiovasc Genet

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Effect of the anti-anginal agent, perhexiline, on neutrophil, valvular and vascular superoxide formation

Cited by 39 publications

References 22 publications

Evolution of NADPH Oxidase Inhibitors: Selectivity and Mechanisms for Target Engagement

Evolution of NADPH Oxidase Inhibitors: Selectivity and Mechanisms for Target Engagement

Cardiac metabolism — A promising therapeutic target for heart failure

Cardiac Energetic Impairment in Heart Disease and the Potential Role of Metabolic Modulators

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