Neuroprotective effects of disubstituted dithiolethione ACDT against manganese-induced toxicity in SH-SY5Y cells

Kulkarni, Neha; Gadde, Rajitha; Gugnani, Kuljeet S.; Vu, Nguyen Tuan; Yoo, Claude; Zaveri, Rohan; Betharia, Swati

doi:10.1016/j.neuint.2021.105052

Cited by 4 publications

(2 citation statements)

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“…For example, organotellurium diethyl-2-phenyl-2-telluropheny vinyl phosphonate (DPTVP) exerted neuroprotection against Mn-induced neurotoxicity and behavioral deficits in rats, attributing to its antioxidant activity ( Avila et al, 2010 ) and attenuated Mn-induced reduction in survival in C. elegans ( Avila et al, 2012 ). Dithiolethiones, lipophilic organosulfur compounds that activate Nrf2, upregulated various phase II antioxidant enzymes, and its disubstituted dithiolethione (ACDT) exerted protection against Mn toxicity by increasing GSH, NAD(P)H dehydrogenase in SH-SY5Y cells ( Kulkarni et al, 2021 ).…”

Section: Neurotherapeutics and Their Potential Underlying Mechanisms ...mentioning

confidence: 99%

Mechanisms of manganese-induced neurotoxicity and the pursuit of neurotherapeutic strategies

et al. 2022

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Chronic exposure to elevated levels of manganese via occupational or environmental settings causes a neurological disorder known as manganism, resembling the symptoms of Parkinson’s disease, such as motor deficits and cognitive impairment. Numerous studies have been conducted to characterize manganese’s neurotoxicity mechanisms in search of effective therapeutics, including natural and synthetic compounds to treat manganese toxicity. Several potential molecular targets of manganese toxicity at the epigenetic and transcriptional levels have been identified recently, which may contribute to develop more precise and effective gene therapies. This review updates findings on manganese-induced neurotoxicity mechanisms on intracellular insults such as oxidative stress, inflammation, excitotoxicity, and mitophagy, as well as transcriptional dysregulations involving Yin Yang 1, RE1-silencing transcription factor, transcription factor EB, and nuclear factor erythroid 2-related factor 2 that could be targets of manganese neurotoxicity therapies. This review also features intracellular proteins such as PTEN-inducible kinase 1, parkin, sirtuins, leucine-rich repeat kinase 2, and α-synuclein, which are associated with manganese-induced dysregulation of autophagy/mitophagy. In addition, newer therapeutic approaches to treat manganese’s neurotoxicity including natural and synthetic compounds modulating excitotoxicity, autophagy, and mitophagy, were reviewed. Taken together, in-depth mechanistic knowledge accompanied by advances in gene and drug delivery strategies will make significant progress in the development of reliable therapeutic interventions against manganese-induced neurotoxicity.

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Section: Neurotherapeutics and Their Potential Underlying Mechanisms ...mentioning

confidence: 99%

Mechanisms of manganese-induced neurotoxicity and the pursuit of neurotherapeutic strategies

et al. 2022

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“…Additionally, D3T has displayed protection in models of neuroin ammation [15], stroke [16], and amyloid beta-induced toxicity [17]. ACDT, a disubstituted dithiolethione with pharmacokinetically favorable functional groups (Munday 2010) has exhibited protection against neuroin ammation [18], a 6-hydroxydopamine model of PD [19], and manganese-induced neurotoxicity [20]. Overlap in the toxicity pro les of manganese and iron as well as the strong association of iron with neurodegenerative diseases including PD and AD led us to explore the protective role of these dithiolethiones against iron-induced toxicity in human astrocytoma (U-87 MG) cells.…”

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confidence: 99%

Dithiolethiones D3T and ACDT Protect Against Iron Overload-Induced Cytotoxicity and Serve as Ferroptosis Inhibitors in U-87 MG Cells

2023

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Iron overload-induced oxidative stress is implicated in various neurodegenerative disorders. Given the numerous adverse effects associated with current iron chelators, natural antioxidants are being explored as alternative therapeutic options. Dithiolethiones found in cruciferous vegetables have emerged as promising candidates against a wide range of toxicants owing to their lipophilic and cytoprotective properties. Here, we test the dithiolethiones D3T and ACDT against ferric ammonium citrate (FAC)induced toxicity in U-87 MG astrocytoma cells. Exposure to 15 mM FAC for 24 hours resulted in 54% cell death. A 24-hour pretreatment with 50 µM D3T and ACDT prevented this cytotoxicity. Both dithiolethiones exhibited antioxidant effects by activating the Nrf2 transcription factor and upregulating levels of intracellular glutathione (GSH). This resulted in the successful inhibition of FAC-induced reactive oxygen species, lipid peroxidation, and cell death. Additionally, D3T and ACDT upregulated expression of the Nrf2-mediated iron storage protein ferritin which consequently reduced the total labile iron pool. A 24-hour pretreatment with D3T and ACDT also prevented cell death induced by the ferroptosis inducer erastin by upregulating the xCT transporter expression. The resulting increase in intracellular GSH and alleviation of lipid peroxidation was comparable to that caused by ferrostatin-1, a speci c ferroptosis inhibitor. Collectively, our ndings demonstrate that dithiolethiones may show promise as potential therapeutic options for the treatment of iron overload disorders.

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Dithiolethiones D3T and ACDT protect against iron overload-induced cytotoxicity and serve as ferroptosis inhibitors in U-87 MG cells

Kulkarni

Gadde

Betharia

2023

Preprint

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Iron overload-induced oxidative stress is implicated in various neurodegenerative disorders. Given the numerous adverse effects associated with current iron chelators, natural antioxidants are being explored as alternative therapeutic options. Dithiolethiones found in cruciferous vegetables have emerged as promising candidates against a wide range of toxicants owing to their lipophilic and cytoprotective properties. Here, we test the dithiolethiones D3T and ACDT against ferric ammonium citrate (FAC)-induced toxicity in U-87 MG astrocytoma cells. Exposure to 15 mM FAC for 24 hours resulted in 54% cell death. A 24-hour pretreatment with 50 µM D3T and ACDT prevented this cytotoxicity. Both dithiolethiones exhibited antioxidant effects by activating the Nrf2 transcription factor and upregulating levels of intracellular glutathione (GSH). This resulted in the successful inhibition of FAC-induced reactive oxygen species, lipid peroxidation, and cell death. Additionally, D3T and ACDT upregulated expression of the Nrf2-mediated iron storage protein ferritin which consequently reduced the total labile iron pool. A 24-hour pretreatment with D3T and ACDT also prevented cell death induced by the ferroptosis inducer erastin by upregulating the xCT transporter expression. The resulting increase in intracellular GSH and alleviation of lipid peroxidation was comparable to that caused by ferrostatin-1, a specific ferroptosis inhibitor. Collectively, our findings demonstrate that dithiolethiones may show promise as potential therapeutic options for the treatment of iron overload disorders.

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Neuroprotective effects of disubstituted dithiolethione ACDT against manganese-induced toxicity in SH-SY5Y cells

Cited by 4 publications

References 60 publications

Mechanisms of manganese-induced neurotoxicity and the pursuit of neurotherapeutic strategies

Mechanisms of manganese-induced neurotoxicity and the pursuit of neurotherapeutic strategies

Dithiolethiones D3T and ACDT Protect Against Iron Overload-Induced Cytotoxicity and Serve as Ferroptosis Inhibitors in U-87 MG Cells

Dithiolethiones D3T and ACDT protect against iron overload-induced cytotoxicity and serve as ferroptosis inhibitors in U-87 MG cells

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