title: MC1568 Inhibits Thimerosal-Induced Apoptotic Cell Death by Preventing HDAC4 Up-Regulation in Neuronal Cells and in Rat Prefrontal Cortex.
abstract: Ethylmercury thiosalicylate (thimerosal) is an organic mercury-based compound commonly used as an antimicrobial preservative that has been found to be neurotoxic. In contrast, histone deacetylases (HDACs) inhibition has been found to be neuroprotective against several environmental contaminants, such as polychlorinated biphenyls, di-2-ethylhexyl phthalate, and methylmercury. The aim of this study was to investigate the effect of HDAC inhibition on thimerosal-induced neurotoxicity in neuroblastoma cells and cortical neurons. Interestingly, we found that thimerosal, at 0.5 μM in SH-SY5Y cells and at 1 μM in neurons, caused cell death by activation of apoptosis, which was prevented by the HDAC class IIA inhibitor MC1568 but not the class I inhibitor MS275. Furthermore, thimerosal specifically increased HDAC4 protein expression but not that of HDACs 5, 6, 7, and 9. Western blot analysis revealed that MC1568 prevented thimerosal-induced HDAC4 increase. In addition, both HDAC4 knocking-down and MC1568 inhibited thimerosal-induced cell death in SH-SY5Y cells and cortical neurons. Importantly, intramuscular injection of 12 μg/kg thimerosal on postnatal days 7, 9, 11, and 15 increased HDAC4 levels in the prefrontal cortex (PFC), which decreased histone H4 acetylation in infant male rats, in parallel increased motor activity changes. In addition, coadministration of 40 mg/kg MC1568 (intraperitoneal injection) moderated the HDAC4 increase which reduced histone H4 deacetylation and caspase-3 cleavage in the PFC. Finally, open-field testing showed that thimerosal-induced motor activity changes are reduced by MC1568. These findings indicate that HDAC4 regulates thimerosal-induced cell death in neurons and that treatment with MC1568 prevents thimerosal-induced activation of caspase-3 in the rat PFC.
authors.affiliation: IRCCS SDN, Naples 80131, Italy.
authors.forename: Natascia
authors.initials: N
authors.lastname: Guida
authors.affiliation: Division of Pharmacology, Department of Neuroscience, Reproductive and Dentistry Sciences, School of Medicine, "Federico II" University of Naples, Naples 80131, Italy.
authors.forename: Giusy
authors.initials: G
authors.lastname: Laudati
authors.affiliation: Division of Pharmacology, Department of Neuroscience, Reproductive and Dentistry Sciences, School of Medicine, "Federico II" University of Naples, Naples 80131, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Mascolo
authors.affiliation: Division of Pharmacology, Department of Neuroscience, Reproductive and Dentistry Sciences, School of Medicine, "Federico II" University of Naples, Naples 80131, Italy.
authors.forename: Ornella
authors.initials: O
authors.lastname: Cuomo
authors.affiliation: IRCCS SDN, Naples 80131, Italy.
authors.forename: Serenella
authors.initials: S
authors.lastname: Anzilotti
authors.affiliation: Division of Pharmacology, Department of Neuroscience, Reproductive and Dentistry Sciences, School of Medicine, "Federico II" University of Naples, Naples 80131, Italy.
authors.forename: Rossana
authors.initials: R
authors.lastname: Sirabella
authors.affiliation: Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli "Federico II" Napoli, Naples 80131, Italy.
authors.forename: Marianna
authors.initials: M
authors.lastname: Santopaolo
authors.affiliation: Laboratorio di Immunologia, Istituto di Endocrinologia e Oncologia Sperimentale, Consiglio Nazionale delle Ricerche (IEOS-CNR), Napoli 80131, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Galgani
authors.affiliation: Department of Preventive Medical Sciences, University Federico II, Via Pansini 5, Naples, 80131, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Montuori
authors.affiliation: Division of Pharmacology, Department of Neuroscience, Reproductive and Dentistry Sciences, School of Medicine, "Federico II" University of Naples, Naples 80131, Italy.
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Di Renzo
authors.affiliation: Division of Pharmacology, Department of Neuroscience, Reproductive and Dentistry Sciences, School of Medicine, "Federico II" University of Naples, Naples 80131, Italy.|Division of Pharmacology, Department of Science and Technology, University of Sannio, Benevento 82100, Italy.
authors.forename: Lorella M T
authors.initials: LM
authors.lastname: Canzoniero
authors.affiliation: Division of Pharmacology, Department of Neuroscience, Reproductive and Dentistry Sciences, School of Medicine, "Federico II" University of Naples, Naples 80131, Italy cformisa@unisannio.it.|Division of Pharmacology, Department of Science and Technology, University of Sannio, Benevento 82100, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Formisano
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001522:Behavior, Animal / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D019610:Cytoprotection; D004305:Dose-Response Relationship, Drug; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D011758:Pyrroles / Q000494:pharmacology*; D034622:RNA Interference; D017208:Rats, Wistar; D012097:Repressor Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D025842:SUMO-1 Protein / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013849:Thimerosal / Q000633:toxicity*; D014162:Transfection; D015854:Up-Regulation
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C577554:MC1568; D018696:Neuroprotective Agents; D011758:Pyrroles; D012097:Repressor Proteins; D025842:SUMO-1 Protein; D013849:Thimerosal; C505410:Casp3 protein, rat; D053148:Caspase 3; C400300:HDAC4 protein, human; C559944:HDAC4 protein, rat; D006655:Histone Deacetylases
keywords: HDAC; MC1568; thimerosal.