Cell-Based Screening Identifies Paroxetine as an Inhibitor of Diabetic Endothelial Dysfunction

Gerö, Domokos; Szoleczky, Petra; Suzuki, Kunihiro; Módis, Katalin; Oláh, Gabor; Coletta, Ciro; Szabó, Csaba

doi:10.2337/db12-0789

Cited by 42 publications

(73 citation statements)

References 33 publications

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“…Data of the present investigation showed that paroxetine didn't significantly alter the blood glucose level. This finding is in accordance with that of Gerö et al [51]. Results of the present study showed that paroxetine moderately decreased the gene expression of the enzyme GSK-3b in the hippocampal tissues as proved by RT-qPCR test, a result which reflects a decrease in the level and/or activity of the enzyme.…”

Section: Discussionsupporting

confidence: 94%

Effect of Imipramine, Paroxetine, and Lithium Carbonate on Neurobehavioral Changes of Streptozotocin in Rats: Impact on Glycogen Synthase Kinase-3 and Blood Glucose Level

Nadeem¹,

Ahmed

El-Denshary

2015

Neurochem Res

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Recent studies have demonstrated a scrutinized association of diabetes mellitus with depressive symptoms and major depression. Glycogen synthase kinase-3 (GSK-3) is a protein kinase enzyme constitutively active in non-stimulated cells and in multiple signalings. Independent lines of research provide a converging evidence for an involvement of GSK-3 in the regulation of behavior and hyperglycemia. The present study revealed that streptozotocin (STZ)-induced diabetic rats were found to show lengthened duration of immobility in the forced-swimming test (FST) and reduced locomotor and exploratory activities in the open-field test (OFT). Imipramine (15 mg/kg), Paroxetine (10 mg/kg) and lithium carbonate (36.94 mg/kg) for 14 days reduced immobility behavior in FST. Paroxetine and lithium carbonate increased the locomotor and exploratory activities, while imipramine decreased the locomotor activity in the OFT. Imipramine and lithium carbonate reduced the blood glucose level while paroxetine didn't alter it. STZ-induced diabetes increased GSK-3 gene expression which was determined using the reverse transcription-quantitative polymerase chain reaction test, while the three drugs decreased its expression. It can be concluded that lithium carbonate and imipramine can control both hyperglycemia and the associated symptoms of depression at the same time by inhibiting GSK-3 activity. On the other hand, paroxetine may only manage the depressive-like symptoms associated with diabetes through modulating the enzyme GSK-3, without changing blood glucose levels.

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Section: Discussionsupporting

confidence: 94%

Effect of Imipramine, Paroxetine, and Lithium Carbonate on Neurobehavioral Changes of Streptozotocin in Rats: Impact on Glycogen Synthase Kinase-3 and Blood Glucose Level

Nadeem¹,

Ahmed

El-Denshary

2015

Neurochem Res

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“…The MTT method was performed as described [28]. Briefly, 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) was added to the cells at a final concentration of 0.5 mg/ml and cells were cultured at 37 °C for 1 hour.…”

Section: Methodsmentioning

confidence: 99%

AP39, a novel mitochondria-targeted hydrogen sulfide donor, stimulates cellular bioenergetics, exerts cytoprotective effects and protects against the loss of mitochondrial DNA integrity in oxidatively stressed endothelial cells in vitro

et al. 2014

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The purpose of the current study was to investigate the effect of the recently synthesized mitochondrially-targeted H2S donor, AP39 [10-oxo-10-(4-(3-thioxo-3H-1,2-dithiol-5yl)phenoxy)decyl) triphenylphosphonium bromide], on bioenergetics, viability, and mitochondrial DNA integrity in bEnd.3 murine microvascular endothelial cells in vitro, under normal conditions, and during oxidative stress. Intracellular H2S was assessed by the fluorescent dye 7-azido-4-methylcoumarin. For the measurement of bioenergetic function, the XF24 Extracellular Flux Analyzer was used. Cell viability was estimated by the combination of the MTT and LDH methods. Oxidative protein modifications were measured by the Oxyblot method. Reactive oxygen species production was monitored by the MitoSOX method. Mitochondrial and nuclear DNA integrity were assayed by the Long Amplicon PCR method. Oxidative stress was induced by addition of glucose oxidase. AP39 (30 – 300 nM) to bEnd.3 cells increased intracellular H2S levels, with a preferential response in the mitochondrial regions. AP39 exerted a concentration-dependent effect on mitochondrial activity, which consisted of a stimulation of mitochondrial electron transport and cellular bioenergetic function at lower concentrations (30–100 nM) and an inhibitory effect at the higher concentration of 300 nM. Under oxidative stress conditions induced by glucose oxidase, an increase in oxidative protein modification and an enhancement in MitoSOX oxidation was noted, coupled with an inhibition of cellular bioenergetic function and a reduction in cell viability. AP39 pretreatment attenuated these responses. Glucose oxidase induced a preferential damage to the mitochondrial DNA; AP39 (100 nM) pretreatment protected against it. In conclusion, the current paper documents antioxidant and cytoprotective effects of AP39 under oxidative stress conditions, including a protection against oxidative mitochondrial DNA damage.

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“…U937 cells were incubated with MitoSox Red (5 mM; Life Technologies, Grand Island, NY) 10 minutes at 37°C in dark or with 29,79-dichlorofluorescein (5 mM; 29,79-dichlorofluorescein H 2 DCF) 30 minutes at 37°C before hydrogen peroxide (H 2 O 2 ) challenge. Fluorescence signal was measured as described (Gerö et al, 2013b) on Synergy 2 (Ex/Em of MitoSox Red: 510/580 nm; Ex/Em of reactive oxygen species detection reagent: 490/520 nm) (BioTek, Winooski, VT).…”

Section: Introductionmentioning

confidence: 99%

Regulation of Mitochondrial Poly(ADP-Ribose) Polymerase Activation by theβ-Adrenoceptor/cAMP/Protein Kinase A Axis during Oxidative Stress

et al. 2014

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We investigated the regulation of mitochondrial poly(ADP-ribose) polymerase 1 (PARP1) by the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) system during oxidative stress in U937 monocytes. Oxidative stress induced an early (10 minutes) mitochondrial DNA damage, and concomitant activation of PARP1 in the mitochondria. These early events were followed by a progressive mitochondrial oxidant production and nuclear PARP1 activation (by 6 hours). These processes led to a functional impairment of mitochondria, culminating in cell death of mixed (necrotic/apoptotic) type. b-Adrenoceptor blockade with propranolol or inhibition of its downstream cAMP/PKA signaling attenuated, while b-adrenoceptor agonists and cAMP/PKA activators enhanced, the oxidant-mediated PARP1 activation. In the presence of cAMP, recombinant PKA directly phosphorylated recombinant PARP1 on serines 465 (in the automodification domain) and 782 and 785 (both in the catalytic domain). Inhibition of the b-adrenergic receptor/cAMP/PKA axis protected against the oxidant-mediated cell injury. Propranolol also suppressed PARP1 activation in peripheral blood leukocytes during bacterial lipopolysaccharide (LPS)-induced systemic inflammation in mice. We conclude that the activation of mitochondrial PARP1 is an early, active participant in oxidant-induced cell death, which is under the control of b-adrenoceptor/cAMP/PKA axis through the regulation of PARP1 activity by PARP1 phosphorylation.

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Cell-Based Screening Identifies Paroxetine as an Inhibitor of Diabetic Endothelial Dysfunction

Cited by 42 publications

References 33 publications

Effect of Imipramine, Paroxetine, and Lithium Carbonate on Neurobehavioral Changes of Streptozotocin in Rats: Impact on Glycogen Synthase Kinase-3 and Blood Glucose Level

Effect of Imipramine, Paroxetine, and Lithium Carbonate on Neurobehavioral Changes of Streptozotocin in Rats: Impact on Glycogen Synthase Kinase-3 and Blood Glucose Level

AP39, a novel mitochondria-targeted hydrogen sulfide donor, stimulates cellular bioenergetics, exerts cytoprotective effects and protects against the loss of mitochondrial DNA integrity in oxidatively stressed endothelial cells in vitro

Regulation of Mitochondrial Poly(ADP-Ribose) Polymerase Activation by theβ-Adrenoceptor/cAMP/Protein Kinase A Axis during Oxidative Stress

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