Several studies have shown that the accumulation of ROS is associated with a variety of diseases, including Alzheimer's disease (AD), PD, and other neurodegenerative diseases that can lead to motor and cognitive dysfunction [10–12]. MPP+ was formed through MPTP,the neurotoxin, oxidation by monoamine oxidase-B (MAO-B) in vivo, and MPP+ undergoes a redox reaction in neurons, forming oxygen radicals that eventually lead to neuronal death [13]. This study found that the cell viability changes and the accumulation of ROS induced by MPP+ and the results demonstrated that MPP+ cause evident cytotoxicity effects. However, the toxicity level showed a concentration-dependent manner, with the high concentration of MPP+ resulting in sever toxicity.
Research on antioxidant enzymes related to human neurodegenerative diseases has always attracted considerable attention. Prdx-2, a member of the Prdxs family, is most abundant in the nervous system, where it is expressed in neurons of the cerebral cortex, hippocampus, cerebellum, basal ganglia, substantia nigra, and spinal cord, mainly in the cytoplasm and nucleus, but not in glial cells [14–15]. The study has previously demonstrated that the Prdx-2 levels in the plasma were reduced in PD patients compared with healthy controls [6]. This outcome compelled us to learn more about the mechanism of action. In the present study, the findings indicate that SH-SY5Y cells are indeed vulnerable to MPP+ toxicity and that MPP+ can cause a decrease in Prdx-2 and increase the accumulation of ROS in cells. Furthermore, overexpression of Prdx-2 reduces MPP+-induced toxicity in SH-SY5Y cells. These findings are in keeping with a previous study that found overexpression of Prdx-2 protected neurons from death after an MPP+ treatment, while downregulation of Prdx-2 increased oxidative stress, resulting in neuronal death. Moreover, Prdx-2 overexpression prevented the loss of dopaminergic neurons in the MPTP mouse model of PD [16]. But studies on the mechanism of action of Prdx-2 are limited. According to Hu et al., Prdx2 prevented 6-hydroxydopamine (6-OHDA)-induced dopaminergic neurodegeneration in MN9D dopamine neurons by controlling Trx's redox status and preventing the activation of the JNK/p38 signaling pathway and ASK1 downstream [17]. The comprehensive literature search identified SIRT1 as being in a crucial position in the signaling pathway network, and it can activate multiple signaling pathways to enable the body to exert antioxidant, anti-inflammatory, and anti-apoptotic effects [8]. This study also revealed that overexpression of Prdx-2 increased the level of SIRT1.
SIRT1 is a deacetylase, and the benefit of SIRT1 in neurodegenerative diseases was first reported by Graff [18]. There was a study that found that in SH-SY5Y cells, SIRT1 can directly deacetylate the histone residue H3K9 in the p53 promoter as a way to prevent apoptosis. In addition, resveratrol activates SIRT1 to regulate p53 to exert anti-inflammatory effects and protect against rotenone-induced dopaminergic neurodegeneration [19]. In contrast, Kitao et al. used SIRT1 overexpression mice to study PD models, SIRT1 overexpression mice did not protect against MPTP toxicity in nigrostriatal DA neurons compared to controls [20]. This may suggests that SIRT1 needs to function in both the signaling network and the deacetylase activity network to provide protection against PD pathology. However, the relationship between Prdx-2 and SIRT1 in PD has not been reported.
Bax aids in promoting cell death, while Bcl-2 plays a significant role in discouraging it. The ratio of Bax/Bcl-2 was usually used as a ruler to measure cell apoptosis [21–22]. From this study, after the cells were treated with MPP+, the ratio of Bax/Bcl-2 was increased. Then the expression of Bax and Bcl-2 was affected by the overexpression of Prdx-2. This result suggests that MPP+ promotes cell apoptosis, and overexpression of Prdx-2 prevents this alteration. Based on the results, a hypothesis is formed that the effects of Prdx-2 on MPP+-induced apoptosis may be partly mediated by regulating the expression of Bcl-2 and Bax.
Taken together, this study suggests that MPP+ could cause severe neurotoxicity. Overexpression of Prdx-2 protected SH-SY5Y cells against MPP+-induced toxicity by reducing the level of SIRT1, accumulation of reactive oxygen species, and decreasing the ratio of Bax/Bcl-2. In the future, it will be important to determine whether Prdx-2 affects the downstream signaling factors of SIRT1.