作者：ZHONG; Jia-hong; XIE; Jin-feng; XIAO; ...phosphodiesterase4fcpr16oxidativestressmitochondrialmembranepotentialparkinsondisease
摘要：OBJECTIVE The cause of Parkinson disease (PD) is generally not clear, but it is considered to be related to excessive oxidative damage. Therefore, the identification of therapeutic targets and compounds with antioxidant damage is a reasonable strategy to slow down the progress of PD. FCPR16 is a novel phosphodiesterase4 inhibitor with little emetic potential. Our previous studies showed that FCPR16 was an effective compound for blocking 1-methyl-4-phenylpyridine(MPP+)-induced oxidative damage in SH-SY5Y cells and neurons. However, the detailed mechanisms underlying its protective effect have not been investigated. The level of oxidative stress in neurons is closely related to the balance of mitochondria mass, while autophagy strongly regulates mitochondrial activity in neurons. Our previous study indicated that inhibition of PDE4 or PDE4 knockdown enhanced the activation of autophagy in microglial cells. While whether PDE4 inhibition mediates autophagy in neurons is largely unknown. As described above, autophagy plays a pivotal role in maintaining redox and mitochondrial homeostasis. We were interested in exploring the impact of PDE4 inhibition on autophagy in neurons. METHODS SH-SY5Y cells and neurons was induced with MPP+to mimic PD cell injury in vitro, and MTT assay was used to investigate the viability effects of FCPR16 (50μmol·L-1) with or without different autophagy inhibitors on MPP+-injured SH-SY5Y cells. Detection of apoptosis was performed by PI staining fluorescence. Lysosomes are essential in autophagy, so LYT Red Stain was used to detect lysosomes in SY5Y cells and neurons. Cells were exposed to Cell ROX Deep Red Reagent to detect intracellular reactive oxygen species (ROS). Mitochondrial membrane potential (Δψm)measurement was executed by 5, 5′, 6, 6′-tetrachloro-1, 1′, 3, 3′-tetraethylbenzimidazolyl-carbocyanineiodide (JC-1).To better detect intracellular autophagy, we used the CYTO-ID Autophagy detection kit to detect the autophagic vacuoles and monitor autophagic flux. The expression
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