Abstract
BackgroundThe Paeonia lactiflora extract (PLE) has been reported to have neuroprotective effect against neurodegeneration that are induced by cellular stress such as oxidative stress. Its underlying mechanisms, however, remain unclear. In latest decades, emerging evidence has suggested that epigenetic mechanisms play a key role in gene regulation in response to the cellular stress. We investigated whether epigenetic modulation was involved in neuronal cell death by the neurotoxicant, 1-Methyl-4-phenylpyridinium (MPP+), and the neuroprotective effect of PLE.MethodsDifferentiated SH-SY5Y, which is a well-established dopaminergic cell line model, was treated with 0 ~ 200 μg/ml PLE for 4 h prior to MPP+ treatment. The effect of PLE on cell viability was determined by MTT assays. Gene expression levels of oxidative stress responsive genes, such as Heme oxygenase 1 (HMOX1), and histone modifiers, such as histone acetyltransferases (HATs) and deacetylases (HDACs) were measured by quantitative RT PCR. In order to investigate the changes in epigenetic modifications, the acetylated lysine 9 (H3K9ac) and lysine 27 (H3K27ac) of Histone H3 were measured by western blot using histones extracted from the cells.ResultsMPP+-induced cell death in SH-SY5Y cells was significantly reduced by PLE pretreatment in a dose-dependent manner, indicating the potent neuroprotective effects of PLE. It was accompanied by induced expression of HMOX1. MPP+ treatment increased the expression of HATs and consistently increased H3K9ac and H3K27ac of Histone H3. PLE pretreatment impeded the changes in H3K9ac and H3K27ac, coincided with increased expression of HDAC5 without changes in HAT expression.ConclusionsThe results suggested that MPP+-induced cell death in the dopaminergic SH-SY5Y cells was related with transcriptional induction of HATs and increased histone H3 acetylation and that PLE might prevent the cells from MPP+-induced cell death via tempering histone H3 acetylation.
Highlights
The Paeonia lactiflora extract (PLE) has been reported to have neuroprotective effect against neurodegeneration that are induced by cellular stress such as oxidative stress
The results indicated that MPP+ acted as a neurotoxicant in dopaminergic neuronal cells by inducing oxidative stress-mediated cell death
MPP+-induced cell death in differentiated SH-SY5Y cells was significantly reduced by PLE pretreatment in a dosedependent manner, accompanied by induced expression of Heme oxygenase 1 (HMOX1)
Summary
The Paeonia lactiflora extract (PLE) has been reported to have neuroprotective effect against neurodegeneration that are induced by cellular stress such as oxidative stress. We investigated whether epigenetic modulation was involved in neuronal cell death by the neurotoxicant, 1-Methyl-4-phenylpyridinium (MPP+), and the neuroprotective effect of PLE. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its metabolite, MPP+, has been used as oxidative stressors that induce cell death in dopaminergic neurons in vivo and in vitro, which mimic Parkinson’s disease [2]. MPP+ enters dopaminergic neuronal cells via dopamine transporters and induces mitochondria dysfunction. It produces ROS [3] and releases cytochrome C (Cyt-C), which activates caspase-3 and eventually, leads dopaminergic neuronal cells to apoptosis [4]. MPP+-induced cell system serves as a useful model to study the molecular mechanism underlying loss of dopaminergic neurons and therapeutic potentials
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