Dapoxetine induces neuroprotective effects against glutamate-induced neuronal cell death by inhibiting calcium signaling and mitochondrial depolarization in cultured rat hippocampal neurons

Jeong, Imju; Yang, Ji Seon; Hong, Yi Jae; Kim, Hee Jung; Hahn, Sang June; Yoon, Shin Hee

doi:10.1016/j.ejphar.2017.03.033

Cited by 7 publications

(6 citation statements)

References 35 publications

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“…The SSRI-mediated increase in brain-derived neurotrophic factors and activation of neurogenesis might explain their neuroprotective effects in stroke (Do Hoon Kim et al 2007ab ). A recent report illustrated the neuroprotective effects of DAP against glutamate-induced cell death through mitochondrial depolarization in cultured primary rat hippocampal neurons (Jeong et al 2017 ). On the other hand, the possible in vivo neuroprotection by DAP against stroke has not been fully elucidated.…”

Section: Introductionmentioning

confidence: 99%

Dapoxetine prevents neuronal damage and improves functional outcomes in a model of ischemic stroke through the modulation of inflammation and oxidative stress

Abdel-Hameed,

El-Daly,

Ahmed

et al. 2023

Naunyn-Schmiedeberg's Arch Pharmacol

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Stroke is a medical emergency that is associated with substantial mortality and functional disability in adults. The most popular class of antidepressants, selective serotonin reuptake inhibitors SSRIs, have recently been shown in studies to have positive effects on post-stroke motor and cognitive function. Thus, we hypothesized that dapoxetine (DAP), a short-acting SSRI, would be effective against cerebral ischemia/reperfusion injury. Adult male Wister rats (200–250 g) were subjected to a sham operation or bilateral common carotid artery occlusion (BCCAO) for 30 min followed by 24 h of reperfusion to induce global cerebral ischemia/reperfusion (I/R) injury. Rats were treated with vehicle or DAP (30 or 60 mg/kg, i.p.) 1 h before BCCAO. The neurobehavioral performance of rats was assessed. The infarct volume, histopathological changes, oxidative stress parameters, and apoptotic and inflammatory mediators were determined in the brain tissues of euthanized rats. Our results confirmed that DAP significantly ameliorated cerebral I/R-induced neurobehavioral deficits, reduced cerebral infarct volume, and histopathological damage. Moreover, DAP pretreatment reduced lipid peroxidation, caspase-3, and inflammatory mediators (TNF-α and iNOS) compared to I/R-injured rats. Thus, DAP pretreatment potentially improves neurological function, and cerebral damage in cerebral ischemic rats may be partly related to the reduction in the inflammatory response, preservation of oxidative balance, and suppression of cell apoptosis in brain tissues.

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Section: Introductionmentioning

confidence: 99%

Dapoxetine prevents neuronal damage and improves functional outcomes in a model of ischemic stroke through the modulation of inflammation and oxidative stress

Abdel-Hameed,

El-Daly,

Ahmed

et al. 2023

Naunyn-Schmiedeberg's Arch Pharmacol

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“…Since transient depolarization considerably alters mitochondrial function for a short period, it has been intensively studied. Several mechanisms underlying this process have been elucidated ( Buckman and Reynolds, 2001 ; Jacobson and Duchen, 2002 ; Aon et al, 2003 ; Vergun et al, 2003 ; Hattori et al, 2005 ; Azarias et al, 2008 ; Hu et al, 2008 ; Lee and Yoon, 2014 ; Jeong et al, 2017 ; Higashi et al, 2020 ). Among transient depolarization, spontaneous depolarization of individual mitochondria are physiological phenomena widely observed from plants to mammals ( Wang et al, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

Effects of Matrix pH on Spontaneous Transient Depolarization and Reactive Oxygen Species Production in Mitochondria

Aklima

Onojima

Kimura

et al. 2021

Front. Cell Dev. Biol.

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Reactive oxygen species (ROS) oxidize surrounding molecules and thus impair their functions. Since mitochondria are a major source of ROS, suppression of ROS overproduction in the mitochondria is important for cells. Spontaneous transient depolarization of individual mitochondria is a physiological phenomenon widely observed from plants to mammals. Mitochondrial uncoupling can reduce ROS production; therefore, it is conceivable that transient depolarization could reduce ROS production. However, transient depolarization has been observed with increased ROS production. Therefore, the exact contribution of transient depolarization to ROS production has not been elucidated. In this study, we examined how the spontaneous transient depolarization occurring in individual mitochondria affected ROS production. When the matrix pH increased after the addition of malate or exposure of the isolated mitochondria to a high-pH buffer, transient depolarization was stimulated. Similar stimulation by an increased matrix pH was also observed in the mitochondria in intact H9c2 cells. Modifying the mitochondrial membrane potential and matrix pH by adding K+ in the presence of valinomycin, a K+ ionophore, clarified that an increase in the matrix pH is a major cause of ROS generation. When we added ADP in the presence of oligomycin to suppress the transient depolarization without decreasing the matrix pH, we observed the suppression of mitochondrial respiration, increased matrix pH, and enhanced ROS production. Based on these results, we propose a model where spontaneous transient depolarization occurs during increased proton influx through proton channels opened by increased matrix pH, leading to the suppression of ROS production. This study improves our understanding of mitochondrial behavior.

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“…[5][6][7][8][9] Due to the sensitivity of neurons towards intracellular calcium-ion concentration, disruption of calcium homeostasis can lead to destructive consequences, such as damage to cell dendrites or neuronal cell death, in part, by activating calpain, a cysteine protease, that degrades a variety of substrates, such as cytoskeletal proteins, membrane receptors and metabolic enzymes. [10][11][12][13] Therefore, molecules capable of modulating calcium influx via the NMDA receptor and/or VGCC could provide protection against calcium overload mediated by prolonged glutamate activity. MK-801 has been shown to uncompetitively block NMDA receptors, but is marked by undesirable psychotomimetic side effects such as hallucination, psychosis, dysphoria and amnesia.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of 4-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione derivatives as lead scaffolds for neuroprotective agents

Egunlusi¹,

Malan²,

Joubert³

2020

Arkivoc

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Neurodegenerative disorders are characterised by progressive loss of neuronal functions. Of the proposed mechanisms, excitotoxicity, mediated by prolonged glutamate activation and calcium overload, is prominent. NGP1-01, a polycyclic cage amine, and tricyclo[6.2.1.0 2,7 ]undec-9-ene-3,6-dione have been shown to display calcium-modulating properties. In this study, we synthesised structurally-related 4-oxatricyclo[5.2.1.0 2,6 ]dec-8ene-3,5-dione as the base scaffold, and incorporated various functional moieties through aminolysis, to afford a series of imide derivatives. All final compounds were obtained in yields between 47-97% and their structures were confirmed by NMR, IR and MS. These structurally-related derivatives could potentially act as neuroprotective agents. Additionally, their synthetic versatilities could make them precursors, as lead compounds, to potential pharmacologically-active agents.

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Dapoxetine induces neuroprotective effects against glutamate-induced neuronal cell death by inhibiting calcium signaling and mitochondrial depolarization in cultured rat hippocampal neurons

Cited by 7 publications

References 35 publications

Dapoxetine prevents neuronal damage and improves functional outcomes in a model of ischemic stroke through the modulation of inflammation and oxidative stress

Dapoxetine prevents neuronal damage and improves functional outcomes in a model of ischemic stroke through the modulation of inflammation and oxidative stress

Effects of Matrix pH on Spontaneous Transient Depolarization and Reactive Oxygen Species Production in Mitochondria

Synthesis of 4-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione derivatives as lead scaffolds for neuroprotective agents

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