MC1568 Inhibits Thimerosal-Induced Apoptotic Cell Death by Preventing HDAC4 Up-Regulation in Neuronal Cells and in Rat Prefrontal Cortex

Guida, Natascia; Laudati, Giusy; Mascolo, Luigi; Cuomo, Ornella; Anzilotti, Serenella; Sirabella, Rossana; Santopaolo, Marianna; Galgani, Mario; Montuori, Paolo; Renzo, Gianfranco Di; Canzoniero, Lorella M.T.; Formisano, Luigi

doi:10.1093/toxsci/kfw157

Cited by 26 publications

(30 citation statements)

References 48 publications

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“…In fact, MeHg exposure increased HDAC4 gene and protein expression causing also in the nucleus an increase of its binding to the BDNF gene promoter IV sequence with consequent mRNA and protein reduction of this neuroprotective factor. These results are in accordance with recent in vivo studies demonstrating that intramuscular injection of the organomercury compound thimerosal induces neuronal cell death by increasing HDAC4 expression in rat prefrontal cortex (Guida et al, 2015b, 2016), and that in cortical neurons HDAC4 knockdown improves neuronal survival after oxygen glucose deprivation (OGD, Yuan et al, 2016). Furthermore, we found that of the three main branches of the MAPK cascade (ERK, p38, and JNK), only p38 was involved in regulating HDAC4 gene expression in cells exposed to MeHg.…”

Section: Discussionsupporting

confidence: 91%

“…In particular, siRNAs against Sp1 reduced Sp1 protein expression respectively of 80 and 68% in SH-SY5Y cells and rat cortical neurons, as already published (Formisano et al, 2015b). Whereas, siRNAs against HDAC4 reduced HDAC4 protein expression respectively of 75 and 71% in SH-SY5Y cells and rat cortical neurons, as already published (Guida et al, 2016). They were also transfected with siRNAs against human and rat Sp4 (siSp4; SI04333588) at 20 nM, both purchased from Quiagen.…”

Section: Methodssupporting

confidence: 71%

“…To this aim, we knocked down p38, Sp1, Sp4 and HDAC4, by transfecting neurons with specific siRNAs named sip38, siSp1, siSp4, and siHDAC4 and increased BDNF with a plasmid overexpressing BDNF named pBDNF. Notably, the efficiency of sip38, siSp1, and siHDAC4 to reduce respectively p38, Sp1, and HDAC4 protein expression was previously published (Sirabella et al, 2012; Formisano et al, 2015b; Guida et al, 2015b, 2016). Instead, siSp4 significantly reduced Sp4 expression by 65%, whereas pBDNF increased BDNF expression by 54%, both compared to the respective control (Figures 5G,H).…”

Section: Resultsmentioning

confidence: 85%

“…For SB239063 experiments cells were pre-treated for 2 h with the drug at 10 μM followed with MeHg 1 μM for 24 h. All transfection experiments in SH-SY5Y and cortical neurons were performed 24 h before MeHg treatment (1 μM/24 h) with HiPerFect Transfection Reagent (Quiagen) in accordance with the manufacture's protocol, as previously reported (Vinciguerra et al, 2014). In SH-SY5Y cells and cortical neurons the synthetic small interfering RNA (siRNA) transfections for Sp1 (siSp1), HDAC4 (siHDAC4), and negative control (siCTL) were performed as already reported (Formisano et al, 2015b; Guida et al, 2016). In particular, siRNAs against Sp1 reduced Sp1 protein expression respectively of 80 and 68% in SH-SY5Y cells and rat cortical neurons, as already published (Formisano et al, 2015b).…”

Section: Methodsmentioning

confidence: 99%

“…On the other hand a pan HDAC inhibition has been found to be neuroprotective in vitro against the neurotoxicity of bis (2-ethylhexyl) phthalate (DEHP) (Guida et al, 2014), Polychlorinated Biphenyls (PCB) (Formisano et al, 2011, 2015a), and MeHg (Guida et al, 2015b). Recently, it has also been shown that the mercury-containing organic compound Thimerosal induces an increase of the HDAC4 isoform (Guida et al, 2015b, 2016) determining neuronal cell death, but the molecular mechanism of this effect is still unrevealed. On the other hand, it is known that HDAC4 mRNA expression is regulated by the transcription factors specificity proteins 1 (Sp1) and 3 (Sp3) (Liu et al, 2006), that have been also associated in vivo to neuronal cell death after stroke (Formisano et al, 2015b), and in vitro to cell death after PCB exposure, through the up-regulation of RE1-Silencing Transcription factor (REST) (Formisano et al, 2015c).…”

Section: Introductionmentioning

confidence: 99%

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p38/Sp1/Sp4/HDAC4/BDNF Axis Is a Novel Molecular Pathway of the Neurotoxic Effect of the Methylmercury

et al. 2017

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The molecular pathways involved in methylmercury (MeHg)-induced neurotoxicity are not fully understood. Since pan-Histone deacetylases (HDACs) inhibition has been found to revert the neurodetrimental effect of MeHg, it appeared of interest to investigate whether the pattern of HDACs isoform protein expression is modified during MeHg-induced neurotoxicity and the transcriptional/transductional mechanisms involved. SH-SY5Y neuroblastoma cells treated with MeHg 1 μM for 12 and 24 h showed a significant increase of HDAC4 protein and gene expression, whereas the HDACs isoforms 1–3, 5, and 6 were unmodified. Furthermore, MeHg-induced HDAC4 increase was reverted when cells were transfected with siRNAs against specificity protein 1 (Sp1) and Sp4, that were both increased during MeHg exposure. Next we studied the role of extracellular-signal-regulated kinases 1/2 (ERK1/2), c-Jun N-terminal kinases (JNK), and p38 mitogen-activated protein kinases (MAPKs) in MeHg—induced increase of Sp1, Sp4, and HDAC4 expression. As shown by Western Blot analysis MeHg exposure increased the phosphorylation of p38, but not of ERK and JNK. Notably, when p38 was pharmacologically blocked, MeHg-induced Sp1, Sp4 protein expression, and HDAC4 protein and gene expression was reverted. In addition, MeHg exposure increased the binding of HDAC4 to the promoter IV of the Brain-derived neurotrophic factor (BDNF) gene, determining its mRNA reduction, that was significantly counteracted by HDAC4 knocking down. Furthermore, rat cortical neurons exposed to MeHg (1 μM/24 h) showed an increased phosphorylation of p38, in parallel with an up-regulation of Sp1, Sp4, and HDAC4 and a down-regulation of BDNF proteins. Importantly, transfection of siRNAs against p38, Sp1, Sp4, and HDAC4 or transfection of vector overexpressing BDNF significantly blocked MeHg-induced cell death in cortical neurons. All these results suggest that p38/Sp1-Sp4/HDAC4/BDNF may represent a new pathway involved in MeHg-induced neurotoxicity.

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Section: Discussionsupporting

confidence: 91%

Section: Methodssupporting

confidence: 71%

Section: Resultsmentioning

confidence: 85%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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p38/Sp1/Sp4/HDAC4/BDNF Axis Is a Novel Molecular Pathway of the Neurotoxic Effect of the Methylmercury

et al. 2017

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Modification of the toxic effects of methylmercury and thimerosal by testosterone and estradiol in SH‐SY5Y neuroblastoma cell line

Erdemli-Köse

Yirün

Balci‐Özyurt

et al. 2021

J of Applied Toxicology

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Short-chained alkyl mercury compounds accumulate in particularly in the brain. Exposure to these compounds is associated with various neurotoxic effects. Gender-based differences are observed in neurodevelopmental disorders, and testosterone and estradiol may alter the toxic effect of the compounds. The present study aimed to investigate the toxic effects of methylmercury and thimerosal on SH-SY5Y cells in high testosterone/low estradiol and high estradiol/low testosterone containing cellular environment and estimate whether male and female brains react differently to the toxic effects of methylmercury and thimerosal. Study groups (n = 3) were designed as control: growth medium, thimerosal (T): 1.15-μM thimerosal, methylmercury (M): 2.93-μM methylmercury, high testosterone/low estradiol + thimerosal (TT): 1-μM testosterone + 0.75-μM estradiol + 1.15-μM thimerosal, high estradiol/low testosterone + thimerosal (ET): 0.1-μM testosterone + 7.5-μM estradiol + 1.15-μM thimerosal, high testosterone/low estradiol + methylmercury (TM): 1-μM testosterone + 0.75-μM estradiol + 2.93-μM methylmercury and high estradiol/low testosterone + methylmercury (EM): 0.1-μM testosterone + 7.5-μM estradiol + 2.93-μM methylmercury. While a significant decrease in glutathione levels was observed in M group, it was not seen in EM group. A significant increase in the protein carbonyl levels was detected in T group. A similar increase was observed in the TM and TT groups in which testosterone was dominant. It was determined that methylmercury, but not thimerosal, caused significant DNA damage and in TT group.The results showed that both thimerosal and methylmercury are toxic on SH-SY5Y cells and toxic effects of methylmercury are more severe than thimerosal. It has been determined that testosterone and estradiol alter the toxic effects of thimerosal and methylmercury.

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Insights into the Potential Role of Mercury in Alzheimer’s Disease

et al. 2019

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MC1568 Inhibits Thimerosal-Induced Apoptotic Cell Death by Preventing HDAC4 Up-Regulation in Neuronal Cells and in Rat Prefrontal Cortex

Cited by 26 publications

References 48 publications

p38/Sp1/Sp4/HDAC4/BDNF Axis Is a Novel Molecular Pathway of the Neurotoxic Effect of the Methylmercury

p38/Sp1/Sp4/HDAC4/BDNF Axis Is a Novel Molecular Pathway of the Neurotoxic Effect of the Methylmercury

Modification of the toxic effects of methylmercury and thimerosal by testosterone and estradiol in SH‐SY5Y neuroblastoma cell line

Insights into the Potential Role of Mercury in Alzheimer’s Disease

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