The synthesis and functional evaluation of a mitochondria-targeted hydrogen sulfide donor, (10-oxo-10-(4-(3-thioxo-3H-1,2-dithiol-5-yl)phenoxy)decyl)triphenylphosphonium bromide (AP39)

Trionnaire, Sophie Le; Perry, Alexis; Szczesny, Bartosz; Szabó, Csaba; Winyard, Paul G.; Whatmore, Jacqueline L.; Wood, Mark E.; Whiteman, Matthew

doi:10.1039/c3md00323j

Cited by 114 publications

(108 citation statements)

References 59 publications

Supporting

Mentioning

104

Contrasting

Order By: Relevance

“…It has been reported that AP39 increased H 2 S generation in mitochondria, protected mitochondrial membrane potential and inhibited oxidative-stress induced cell death in cultured human endothelial cells [21, 23]. In our experiments, administration of AP39 before CPR also attenuated the increase of hydrogen peroxide levels in serum after reperfusion (Fig.…”

Section: Discussionsupporting

confidence: 71%

“…To evaluate effects of AP39, we assigned mice randomly to four groups (AP39 at 10, 100 or 1000 nmol kg −1 , and vehicle) in which the study drug was administered 2 min before the initiation of CPR (Experiment 1) and three groups (AP39 at 10 or 1000 nmol kg −1 , and vehicle) in which the study drug was administered 1 min after return of spontaneous circulation (ROSC) (Experiment 2). AP39 was synthesized in-house as described [23]. …”

Section: Methodsmentioning

confidence: 99%

“…AP39 or vehicle was administered at 2 min before CPR in Experiment 1 and 1 min after ROSC in Experiment 2, respectively. Synthesis and structure of AP39 was described elsewhere [23]. …”

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Mitochondria-targeted hydrogen sulfide donor AP39 improves neurological outcomes after cardiac arrest in mice

et al. 2015

Self Cite

View full text Add to dashboard Cite

Aims Mitochondria-targeted hydrogen sulfide donor AP39, [(10-oxo-10-(4-(3-thioxo-3H-1,2-dithiol-5yl)phenoxy)decyl) triphenylphosphonium bromide], exhibits cytoprotective effects against oxidative stress in vitro. We examined whether or not AP39 improves neurological function and long term survival in mice subjected to cardiac arrest (CA) and cardiopulmonary resuscitation (CPR). Methods Adult C57BL/6 male mice were subjected to 8 min of CA and subsequent CPR. We examined the effects of AP39 (10, 100, 1000 nmol kg−1) or vehicle administered intravenously at 2 min before CPR (Experiment 1). Systemic oxidative stress levels, mitochondrial permeability transition, and histological brain injury were assessed. We also examined the effects of AP39 (10, 1000 nmol kg−1) or vehicle administered intravenously at 1 min after return of spontaneous circulation (ROSC) (Experiment 2). ROSC was defined as the return of sinus rhythm with a mean arterial pressure > 40 mm Hg lasting at least 10 seconds. Results Vehicle treated mice subjected to CA/CPR had poor neurological function and 10-day survival rate (Experiment 1; 15%, Experiment 2; 23%). Administration of AP39 (100 and 1000 nmol kg−1) 2 min before CPR significantly improved neurological function and 10-day survival rate (54% and 62%, respectively) after CA/CPR. Administration of AP39 before CPR attenuated mitochondrial permeability transition pore opening, reactive oxygen species generation, and neuronal degeneration after CA/CPR. Administration of AP39 1 min after ROSC at 10 nmol kg−1, but not at 1000 nmol kg−1, significantly improved neurological function and 10 day-survival rate (69%) after CA/CPR. Conclusion The current results suggest that administration of mitochondria-targeted sulfide donor AP39 at the time of CPR or after ROSC improves neurological function and long term survival rates after CA/CPR by maintaining mitochondrial integrity and reducing oxidative stress.

show abstract

Section: Discussionsupporting

confidence: 71%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Mitochondria-targeted hydrogen sulfide donor AP39 improves neurological outcomes after cardiac arrest in mice

et al. 2015

Self Cite

View full text Add to dashboard Cite

show abstract

“…These studies suggest that H 2 S-based therapeutic strategies may help maintain BBB integrity and decrease EDF-related stroke damage. In the same line, studies on human cerebral microvascular endothelial cells, used frequently as an in vitro model of the BBB, showed that slow-release and mitochondria-targeted H 2 S donors such as GYY4137 and AP39, respectively, prevented cellular and mitochondrial oxidative damage [72, 73]. …”

Section: H2s-related Edf In Strokementioning

confidence: 99%

The role of H2S bioavailability in endothelial dysfunction

Wang

Szabó

Ichinose

et al. 2015

Trends in Pharmacological Sciences

Self Cite

144

View full text Add to dashboard Cite

Endothelial dysfunction reflects pathophysiological changes in the phenotype and functions of endothelial cells that result from and/or contribute to a plethora of cardiovascular diseases. Here we review the role of hydrogen sulfide (H2S) in the pathogenesis of endothelial dysfunction, one of the fastest advanced and hottest research topics. Conventionally treated as an environment pollutant, H2S is also produced in endothelial cells and participates in the fine regulation of endothelial integrity and functions. Disturbed H2S bioavailability has been suggested to be a novel indicator of the progress and prognosis of endothelial dysfunction. Endothelial dysfunction appears to exhibit in different forms in different pathologies but therapeutics aimed at remedying the altered H2S bioavailability may benefit all.

show abstract

“…Various H 2 S donation strategies have been developed and tested in vitro and in vivo (5,6), including renal I/R injury. The goal of the current study was to evaluate the therapeutic effect of the mitochondrially targeted H 2 S donor AP39 (7,8) in renal epithelial cells subjected to oxidative stress in vitro and in a rat model of renal ischemia in vivo . AP39 consists of a mitochondria-targeting motif, triphenyl phosphonium (TPP + ), coupled to a H 2 S-donating moiety (dithiolethione) by an aliphatic linker.…”

Section: Introductionmentioning

confidence: 99%

AP39, A Mitochondrially Targeted Hydrogen Sulfide Donor, Exerts Protective Effects in Renal Epithelial Cells Subjected to Oxidative Stress in Vitro and in Acute Renal Injury in Vivo

Ahmad

Oláh²,

Szczesny³

et al. 2016

Shock

Self Cite

107

View full text Add to dashboard Cite

This study evaluated the effects of AP39 [(10-oxo-10-(4-(3-thioxo-3H-1,2-dithiol-5yl) phenoxy)decyl) triphenyl phosphonium bromide], a mitochondrially targeted donor of hydrogen sulfide (H2S) in an in vitro model of hypoxia/oxidative stress injury in NRK-49F rat kidney epithelial cells (NRK cells) and in a rat model of renal ischemia-reperfusion injury. Renal oxidative stress was induced by the addition of glucose oxidase, which generates hydrogen peroxide in the culture medium at a constant rate. Glucose oxidase (GOx)-induced oxidative stress led to mitochondrial dysfunction, decreased intracellular ATP content, and, at higher concentrations, increased intracellular oxidant formation (estimated by the fluorescent probe 2, 7-dichlorofluorescein, DCF) and promoted necrosis (estimated by the measurement of lactate dehydrogenase release into the medium) of the NRK cells in vitro. Pretreatment with AP39 (30-300 nM) exerted a concentration-dependent protective effect against all of the above effects of GOx. Most of the effects of AP39 followed a bell-shaped concentration-response curve; at the highest concentration of GOx tested, AP39 was no longer able to afford cytoprotective effects. Rats subjected to renal ischemia/reperfusion responded with a marked increase (over 4-fold over sham control baseline) blood urea nitrogen and creatinine levels in blood, indicative of significant renal damage. This was associated with increased neutrophil infiltration into the kidneys (assessed by the myeloperoxidase assay in kidney homogenates), increased oxidative stress (assessed by the malondialdehyde assay in kidney homogenates) and an increase in plasma levels of IL-12. Pretreatment with AP39 (0.1, 0.2 and 0.3 mg/kg) provided a dose-dependent protection against these pathophysiological alterations; the most pronounced protective effect was observed at the 0.3 mg/kg dose of the H2S donor; nevertheless AP39 failed to achieve a complete normalization of any of the injury markers measured. The partial protective effects of AP39 correlated with a partial improvement of kidney histological scores and reduced TUNEL staining (an indicator of DNA damage and apoptosis). In summary, the mitochondria-targeted H2S donor AP39 exerted dose-dependent protective effects against renal epithelial cell injury in vitro and renal ischemia-reperfusion injury in vivo. We hypothesize that the beneficial actions of AP39 are related to the reduction of cellular oxidative stress, and subsequent attenuation of various positive feed-forward cycles of inflammatory and oxidative processes.

show abstract

The synthesis and functional evaluation of a mitochondria-targeted hydrogen sulfide donor, (10-oxo-10-(4-(3-thioxo-3H-1,2-dithiol-5-yl)phenoxy)decyl)triphenylphosphonium bromide (AP39)

Abstract: Mitochondrial dysfunction is observed in many diseases. Targeting H2S generation to mitochondria may be cytoprotective.

Cited by 114 publications

References 59 publications

Mitochondria-targeted hydrogen sulfide donor AP39 improves neurological outcomes after cardiac arrest in mice

Mitochondria-targeted hydrogen sulfide donor AP39 improves neurological outcomes after cardiac arrest in mice

The role of H2S bioavailability in endothelial dysfunction

AP39, A Mitochondrially Targeted Hydrogen Sulfide Donor, Exerts Protective Effects in Renal Epithelial Cells Subjected to Oxidative Stress in Vitro and in Acute Renal Injury in Vivo

Contact Info

Product

Resources

About