Protective Effects of Probucol on Different Brain Cells Exposed to Manganese

Silva, Erica Blenda da; Eichwald, Tuany; Glaser, Viviane; Varela, Karina Giacomini; Baptistella, Antuani Rafael; Carvalho, Diego de; Remor, Aline Pertile

doi:10.1007/s12640-021-00458-3

Cited by 7 publications

(7 citation statements)

References 49 publications

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“…This could be attributed to the fact that the MZ structure has around 15% of Mn, which may also explain why Mn is the metal most strongly with the pathophysiological outcomes associated with the pesticide. Also, Mn exposure showed oxidative stress' parameters alterations, indicating that Mn cytotoxicity causes mitochondrial dysfunction, as shown in SH-SY5Y cells (da Silva et al, 2022) andC6 cells (da Silva et al, 2022;Maddirala et al, 2015) exposed to this metal, and probucol was able to prevent these deleterious events.…”

Section: Discussionmentioning

confidence: 85%

“…In addition, the protein autophagy seems to be compromised, accelerating the accumulation of protein aggregates, which is a characteristic of neurological disorders (Angeli et al, 2014). Consequently, damaged astrocytes and neurons have a hampered ability to respond to the brain’s dynamically changing environment (da Silva et al, 2022; Erikson and Aschner, 2019).…”

Section: Introductionmentioning

confidence: 99%

“…Probucol prevented oxidative damage and improved cognition in experimental models of neuropathologies (Santos et al, 2020), such as Huntington’s disease (Colle et al, 2012), Alzheimer’s disease (Santos et al, 2012), and PD (Moreira et al, 2013). Moreover, this compound showed increased antioxidant activity and protective effects against neurological damage caused by methylmercury (Farina et al, 2009) and more recently protects oxidative damage in different brain cells against Mn exposure (da Silva et al, 2022).…”

Section: Introductionmentioning

confidence: 99%

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Probucol neuroprotection against manganese-induced damage in adult Wistar rat brain slices

Del Rio Naiz,

Varela,

de Carvalho

et al. 2023

Toxicol Ind Health

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Manganese (Mn) is an abundant element used for commercial purposes and is essential for the proper function of biological systems. Chronic exposure to high Mn concentrations causes Manganism, a Parkinson's-like neurological disorder. The pathophysiological mechanism of Manganism remains unknown; however, it involves mitochondrial dysfunction and oxidative stress. This study assessed the neuroprotective effect of probucol, a hypolipidemic agent with anti-inflammatory and antioxidant properties, on cell viability and oxidative stress in slices of the cerebral cortex and striatum from adult male Wistar rats. Brain structure slices were kept separately and incubated with manganese chloride (MnCl2) and probucol to evaluate the cell viability and oxidative parameters. Probucol prevented Mn toxicity in the cerebral cortex and striatum, as evidenced by the preservation of cell viability observed with probucol (10 and 30 μM) pre-treatment, as well as the prevention of mitochondrial complex I inhibition in the striatum (30 μM). These findings support the protective antioxidant action of probucol, attributed to its ability to prevent cell death and mitigate Mn-induced mitochondrial dysfunction.

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Section: Discussionmentioning

confidence: 85%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Probucol neuroprotection against manganese-induced damage in adult Wistar rat brain slices

Del Rio Naiz,

Varela,

de Carvalho

et al. 2023

Toxicol Ind Health

Self Cite

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“…Probucol contains two easily oxidizable phenolic hydroxyl groups that can form stable phenolic oxygen groups by binding to oxygen free radicals, exhibiting potent effects such as lipid-lowering, anti-inflammatory, and anti-oxidative properties. There is increasing evidence that probucol has therapeutic potential for neurodegenerative diseases [ 20 , 21 ]. However, it is not clear whether probucol exerts a protective effect against VD by affecting Syk.…”

Section: Discussionmentioning

confidence: 99%

Probucol protects against brain damage caused by intra-neural pyroptosis in rats with vascular dementia through inhibition of the Syk/Ros pathway

Zhu,

Du,

Kou

et al. 2024

Aging

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Background: Neuronal injury in chronic cerebral hypoperfusion (CCH) is the main pathogenic factor of vascular dementia (VD). Clinically, there isn’t a drug specifically for VD; instead, the majority of medications used to treat Alzheimer’s disease (AD) are also used to treat VD. Based on the proven anti-inflammatory and antioxidant effects of Probucol, we hypothesized that it may have therapeutic effects on VD, but more research is required to determine its exact mechanism of action. Methods: In vivo experiment: We used SD rats and most commonly used bilateral carotid artery occlusion (2-VO) in VD for modeling. After successful modeling, SD rats were given Probucol 3.5 mg/kg/day for 8 weeks to evaluate the therapeutic effect. In vitro experiment: BV-2 microglia of rats were cultured and divided into Control group and Probucol group. Each group was treated with hypoxia-hypoglycemia, hypoxia-hypoglycemia hydrogen peroxide and hypoxia-hypoglycemia hydrogen peroxide Syk inhibitor respectively. Results: The results of immunofluorescence and Western blot showed that Probucol could significantly improve the cognitive impairment induced by CCH, and the neuronal damage was also attenuated. On the one hand, the underlying mechanism of Probucol was to reduce oxidative stress and cell apoptosis of hippocampal neurons by inhibiting the expression of phosphorylated spleen tyrosine kinase (P-Syk); On the other hand, it exerted a protective effect by reducing NLRP3-dependent cell pyroptosis and inhibiting neuroinflammation induced by microglia activation. Conclusion: Probucol could reduce oxidative stress and cell apoptosis by inhibiting the Syk/ROS signaling pathway, thereby improving CCH-induced cognitive impairment in vitro and in vivo .

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“…Trolox, a water-soluble vitamin E analog, attenuated Mn-induced ROS, F2-isoprostanes, and caspase activity in the rat striatum and rat primary neurons ( Milatovic et al, 2011 ; Cordova et al, 2013 ). Probucol, an anti-hyperlipidemic drug, showed powerful antioxidative effects, attenuating Mn-induced ROS production, mitochondrial dysfunction, and cell death in SH-SY5Y neuronal and C6 glial cells ( da Silva et al, 2022 ). Minocycline, a tetracycline antibiotic, exerted antioxidative effects against Mn-induced oxidative stress by decreasing lipid peroxidation and increasing antioxidant enzymes such as SOD in Drosophila ( Bonilla et al, 2012 ; Mora et al, 2014 ).…”

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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Protective Effects of Probucol on Different Brain Cells Exposed to Manganese

Cited by 7 publications

References 49 publications

Probucol neuroprotection against manganese-induced damage in adult Wistar rat brain slices

Probucol neuroprotection against manganese-induced damage in adult Wistar rat brain slices

Probucol protects against brain damage caused by intra-neural pyroptosis in rats with vascular dementia through inhibition of the Syk/Ros pathway

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

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