Decynium-22 Enhances SSRI-Induced Antidepressant-Like Effects in Mice: Uncovering Novel Targets to Treat Depression

Horton, Rebecca E.; Apple, Deana M.; Owens, William A.; Baganz, Nicole L.; Cano, Sonia; Mitchell, Nathan C.; Vitela, Melissa; Gould, Georgianna G.; Koek, Wouter; Daws, Lynette C.

doi:10.1523/jneurosci.5687-11.2013

Cited by 82 publications

(103 citation statements)

References 64 publications

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“…26) Furthermore, Horton et al 27) have reported that, while decynium-22 (D22, a potent inhibitor of "uptake 2 " 28) ) alone does not effectively work as an anti-depressant, the compound significantly enhances the anti-depressant effects of fluvoxamine (a selective serotonin reuptake inhibitor, SSRI). Furthermore, this incremental effect was significantly attenuated in OCT3 knock-out mouse, indicating that OCT3 participates in D22's pharmacological action.…”

Section: Organic Cation Transporter 3 (Oct3)mentioning

confidence: 99%

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Functional Expression of Organic Ion Transporters in Astrocytes and Their Potential as a Drug Target in the Treatment of Central Nervous System Diseases

Furihata

Anzai

2017

Biological & Pharmaceutical Bulletin

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It has become widely acknowledged that astrocytes play essential roles in maintaining physiological central nervous system (CNS) activities. Astrocytes fulfill their roles partly through the manipulation of their plasma membrane transporter functions, and therefore these transporters have been regarded as promising drug targets for various CNS diseases. A representative example is excitatory amino acid transporter 2 (EAAT2), which works as a critical regulator of excitatory signal transduction through its glutamate uptake activity at the tripartite synapse. Thus, enhancement of EAAT2 functionality is expected to accelerate glutamate clearance at synapses, which is a promising approach for the prevention of over-excitation of glutamate receptors. In addition to such well-known astrocyte-specific transporters, cumulative evidence suggests that multi-specific organic ion transporters (i.e., organic cation/anion transporters [OCTs/OATs], carnitine/organic cation transporters [OCTNs], and organic anion transporting polypeptides [OATPs]) are also functionally expressed in astrocytes. Even though identification and characterization of their physiological/pathophysiological roles in astrocytes are in the initial stage, the findings obtained so far indicate that OCT3 and plasma membrane monoamine transporter are significantly involved in the clearance of biogenic amine neurotransmitters in the synaptic cleft, and that OCTN2 and OATP1C1 provide a cellular entry gate for carnitine/acetyl-L-carnitine and thyroxine, respectively. Therefore, organic ion transporters, including those mentioned above, are expected to become emerging pharmacological targets for various CNS diseases. With such expectations in mind, this review will briefly summarize the functional expression of organic ion transporters in astrocytes.

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Section: Organic Cation Transporter 3 (Oct3)mentioning

confidence: 99%

“…For example, in addition to OCT3, the functional inhibition of PMAT by D22 may also be involved in its anti-depressant augmenting effects. 27) However, currently it is difficult to separately evaluate the contribution of each transporter to the action of D22.…”

Section: Plasma Membrane Monoamine Transporter (Pmat)mentioning

confidence: 99%

Functional Expression of Organic Ion Transporters in Astrocytes and Their Potential as a Drug Target in the Treatment of Central Nervous System Diseases

Furihata

Anzai

2017

Biological & Pharmaceutical Bulletin

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“…However, unlike OCT1 and OCT2, OCT3 is expressed ubiquitously in most tissues. Originally thought to be a major component of the extraneuronal monoamine transporter system, scavenging neurotransmitters that escaped reuptake in the central nervous system, OCT3 has been shown to play an important role in the homeostasis and neuropharmacology of monoamines (Zwart et al, 2001;Wultsch et al, 2009;Zhu et al, 2010;Horton et al, 2013). Although OCT3 is widely expressed in many tissues and has been shown to be the most highly expressed organic cation transporter in skeletal muscle and adipose tissue (Bleasby et al, 2006), little is known about its biologic or pharmacologic roles in peripheral tissues.…”

Section: Introductionmentioning

confidence: 99%

Targeted Disruption of Organic Cation Transporter 3 Attenuates the Pharmacologic Response to Metformin

et al. 2015

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Metformin, the most widely prescribed antidiabetic drug, requires transporters to enter tissues involved in its pharmacologic action, including liver, kidney, and peripheral tissues. Organic cation transporter 3 (OCT3, SLC22A3), expressed ubiquitously, transports metformin, but its in vivo role in metformin response is not known. Using Oct3 knockout mice, the role of the transporter in metformin pharmacokinetics and pharmacodynamics was determined. After an intravenous dose of metformin, a 2-fold decrease in the apparent volume of distribution and clearance was observed in knockout compared with wild-type mice (P , 0.001), indicating an important role of OCT3 in tissue distribution and elimination of the drug. After oral doses, a significantly lower bioavailability was observed in knockout compared with wild-type mice (0.27 versus 0.58, P , 0.001). Importantly, metformin's effect on the plasma glucose concentration-time curve was reduced in knockout compared with wild-type mice (12 versus 30% reduction, respectively, P , 0.05) along with its accumulation in skeletal muscle and adipose tissue (P , 0.05). Furthermore, the effect of metformin on phosphorylation of AMP activated protein kinase, and expression of glucose transporter type 4 was absent in the adipose tissue of Oct3 2/2 mice. Additional analysis revealed that an OCT3 39 untranslated region variant was associated with reduced activity in luciferase assays and reduced response to metformin in 57 healthy volunteers. These findings suggest that OCT3 plays an important role in the absorption and elimination of metformin and that the transporter is a critical determinant of metformin bioavailability, clearance, and pharmacologic action.

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“…Usually, proteins that comprise uptake 2 will also transport other neurotransmitters like dopamine and noradrenaline [63]. Uptake 2 is usually inhibited by cortisone (but also by synthetic dexamethasone, by aldosterone, and by budesonide) via unknown mechanisms and divergent specificity for OCT1-3 and PMAT [63,74]) and more specifically by decynium 22 [57,63]. At higher concentrations of 5-HT (10 μM), it is mainly transported via uptake 2 (in synaptosomes, regarding decynium 22 as uptake 2-specific [57]).…”

Section: Uptake 2 Of 5-ht In the Heartmentioning

confidence: 99%

Production and Function of Serotonin in Cardiac Cells

Neumann¹,

Hofmann²,

Gergs³

2017

Serotonin - A Chemical Messenger Between All Types of Living Cells

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Serotonin [5-hydroxy-tryptamine (5-HT)] exerts a number of effects in the mammalian heart: increase in heart rate, increase in force of contraction, fibrosis of cardiac valves, coronary constriction, arrhythmias and thrombosis. These effects are, in part, mediated by 5-HT-receptors, in part, directly by 5-HT action on intracellular proteins. In the beginning, 5-HT was thought to be only produced in the gut and then transported into the heart via platelets, because platelets can take up 5-HT in the gut and enter the capillaries and thus the mammalian heart. 5-HT is to a large extent metabolized in the liver and excreted via the urine. Here, we will also overview data that argue for additional pathways, namely production and degradation of 5-HT in the cells of the heart itself.

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Decynium-22 Enhances SSRI-Induced Antidepressant-Like Effects in Mice: Uncovering Novel Targets to Treat Depression

Cited by 82 publications

References 64 publications

Functional Expression of Organic Ion Transporters in Astrocytes and Their Potential as a Drug Target in the Treatment of Central Nervous System Diseases

Functional Expression of Organic Ion Transporters in Astrocytes and Their Potential as a Drug Target in the Treatment of Central Nervous System Diseases

Targeted Disruption of Organic Cation Transporter 3 Attenuates the Pharmacologic Response to Metformin

Production and Function of Serotonin in Cardiac Cells

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