D609-mediated inhibition of ATP synthesis in neural progenitor cells

Kalluri, Haviryaji S. G.; Dempsey, Robert J.

doi:10.1097/wnr.0000000000000176

Cited by 6 publications

(3 citation statements)

References 21 publications

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“…Even though studies have shown that NSCs function at a lower metabolic rate when compared to other cells, a decreased level of intracellular NSC ATP can inhibit the overall process of NSC proliferation 39 . Recent studies have shown how various molecules that inhibit the actions of ATP, such as tricyclodecan-9-yl-xanthogenate (D609), decrease the rate of proliferation among NSCs, therefore opposing the process of proliferation 40 . Moreover in vitro results indicated that EFV lowered NSC MMP (Fig.…”

Section: Discussionmentioning

confidence: 99%

HIV Non-Nucleoside Reverse Transcriptase Inhibitor Efavirenz Reduces Neural Stem Cell Proliferation in Vitro and in Vivo

et al. 2016

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The prevalence of HIV-associated neurocognitive disorders (HAND) remains high despite combination antiretroviral therapy (cART). There is evidence that neural stem cells (NSCs) can migrate to sites of brain injury such as those caused by inflammation and oxidative stress, which are pathological features of HAND. Thus, reductions in NSCs may contribute to HAND pathogenesis. Since the HIV non-nucleoside reverse transcriptase inhibitor efavirenz (EFV) has previously been associated with cognitive deficits and promotion of oxidative stress pathways, we examined its effect on NSCs in vitro as well as in C57BL/6J mice. Here we report that EFV induced a decrease in NSC proliferation in vitro as indicated by MTT assay, as well as BrdU and nestin immunocytochemistry. In addition, EFV decreased intracellular NSC adenosine triphosphate (ATP) stores and NSC mitochondrial membrane potential (MMP). Further, we found that EFV promoted increased lactate dehydrogenase (LDH) release, activation of p38 mitogen-activated protein kinase (MAPK), and increased Bax expression in cultured NSCs. Moreover, EFV reduced the quantity of proliferating NSCs in the subventricular zone (SVZ) of C57BL/6J mice as suggested by BrdU, and increased apoptosis as measured by active caspase-3 immunohistochemistry. If these in vitro and in vivo models translate to the clinical syndrome, then a pharmacological or cell-based therapy aimed at opposing EFV-mediated reductions in NSC proliferation may be beneficial to prevent or treat HAND in patients receiving EFV.

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Section: Discussionmentioning

confidence: 99%

HIV Non-Nucleoside Reverse Transcriptase Inhibitor Efavirenz Reduces Neural Stem Cell Proliferation in Vitro and in Vivo

et al. 2016

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“…Modulating COX activity can thus interfere with ATP production, influencing cell proliferation. After the incubation of D609 neural progenitor cells, cytochrome C oxidase activity was found to decrease, supporting this hypothesis [ 128 , 129 ]. According to these findings, D609 can inhibit cytochrome C oxidase activity and, as a result, ATP synthesis in neural progenitor cells [ 129 ].…”

Section: Pharmacological Properties Of D609mentioning

confidence: 66%

Tricyclodecan-9-yl-Xanthogenate (D609): Mechanism of Action and Pharmacological Applications

Bhat

Dar

Khan

et al. 2022

IJMS

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Tricyclodecan-9-yl xanthogenate (D609) is a synthetic tricyclic compound possessing a xanthate group. This xanthogenate compound is known for its diverse pharmacological properties. Over the last three decades, many studies have reported the biological activities of D609, including antioxidant, antiapoptotic, anticholinergic, anti-tumor, anti-inflammatory, anti-viral, anti-proliferative, and neuroprotective activities. Its mechanism of action is extensively attributed to its ability to cause the competitive inhibition of phosphatidylcholine (PC)-specific phospholipase C (PC-PLC) and sphingomyelin synthase (SMS). The inhibition of PCPLC or SMS affects secondary messengers with a lipidic nature, i.e., 1,2-diacylglycerol (DAG) and ceramide. Various in vitro/in vivo studies suggest that PCPLC and SMS inhibition regulate the cell cycle, block cellular proliferation, and induce differentiation. D609 acts as a pro-inflammatory cytokine antagonist and diminishes Aβ-stimulated toxicity. PCPLC enzymatic activity essentially requires Zn2+, and D609 might act as a potential chelator of Zn2+, thereby blocking PCPLC enzymatic activity. D609 also demonstrates promising results in reducing atherosclerotic plaque formation, post-stroke cerebral infarction, and cancer progression. The present compilation provides a comprehensive mechanistic insight into D609, including its chemistry, mechanism of action, and regulation of various pharmacological activities.

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“…Tricyclodecan-9-yl-xanthogenate (D609), an inhibitor for phosphatidylcholine-specific phospholipase C, exhibits diverse potent biological functions 8 , 9 . It has been shown that D609 can act as a GSH mimetic compound to scavenge hydrogen peroxide and hydroxyl free radicals 10 .…”

Section: Introductionmentioning

confidence: 99%

Glutathione-mimetic D609 alleviates memory deficits and reduces amyloid-β deposition in an AβPP/PS1 transgenic mouse model

et al. 2018

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Excessive extracellular deposition of amyloid-β-peptide (Aβ) in the brain is a pathological hallmark of Alzheimer’s disease (AD). Oxidative stress is associated with the onset and progression of AD and contributes to Aβ generation. Tricyclodecan-9-yl-xanthogenate (D609) is a glutathione (GSH)-mimetic compound. Although the antioxidant properties of D609 have been well-studied, its potential therapeutic significance on AD remains unclear. In the present study, we used a mouse model of AD to investigate the effects and the mechanism of action of D609 on AD. We found that D609 treatment significantly improved the spatial learning and alleviated the memory decline in the mice harboring amyloid precursor protein (APP) and presenilin-1 (PS1) double mutations (AβPP/PS1 mice). D609 treatment also increased GSH level, GSH and oxidative glutathione ratio, and superoxide dismutase activity, whereas decreased malondialdehyde and protein carbonyl levels, suggesting that D609 alleviated oxidative stress in AβPP/PS1 mice. In addition, D609 reduced β-secretase 1 level and decreased amyloidogenic processing of AβPP, consequently reducing Aβ deposition in the mice. Thus, our findings suggest that D609 might produce beneficial effects on the prevention and treatment of AD.

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D609-mediated inhibition of ATP synthesis in neural progenitor cells

Cited by 6 publications

References 21 publications

HIV Non-Nucleoside Reverse Transcriptase Inhibitor Efavirenz Reduces Neural Stem Cell Proliferation in Vitro and in Vivo

HIV Non-Nucleoside Reverse Transcriptase Inhibitor Efavirenz Reduces Neural Stem Cell Proliferation in Vitro and in Vivo

Tricyclodecan-9-yl-Xanthogenate (D609): Mechanism of Action and Pharmacological Applications

Glutathione-mimetic D609 alleviates memory deficits and reduces amyloid-β deposition in an AβPP/PS1 transgenic mouse model

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