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.