Inhibition of PDE4 by FCPR16 induces AMPK-dependent autophagy and confers neuroprotection in SH-SY5Y cells and neurons exposed to MPP+-induced oxidative insult

The etiology of Parkinson's disease (PD) is generally not well understood, but it is believed to involve excessive oxidative insult. Hence, identifying therapeutic targets and compounds that exhibit protective effects against oxidative damage is a reasonable strategy to slow down the progression of PD. FCPR16 is a novel phosphodiesterase 4 inhibitor with little emetic potential. Our previous studies showed that FCPR16 was able to block 1-Methyl-4-phenylpyridine (MPP+)-induced oxidative damage in SH-SY5Y cells and neurons. However, the detailed mechanism of this is unknown. Here, we found that FCPR16 triggered autophagy in SH-SY5Y cells, as evidenced by an increased level of microtubule-associated protein 1 light chain 3 II (LC3-II) and decreased p62. Inhibition of autophagy by 3-MA or chloroquine decreased the effect of FCPR16 on the accumulation of autophagic vacuoles and the fluorescence signal of lysosomes. In SH-SY5Y cells treated with MPP+, we found that FCPR16 increased the level of LC3-II, and 3-MA attenuated the protective effect of FCPR16 against MPP+-induced toxicity. Treatment of SH-SY5Y cells with FCPR16 prevented MPP+-induced production of reactive oxygen species (ROS) and the decline of mitochondrial membrane potential (Δψm). Importantly, we also found that FCPR16 phosphorylated and thus activated AMP-activated protein kinase (AMPK) in SH-SY5Y cells treated with MPP+. In contrast, blockade of the AMPK pathway with compound C blocked the role of FCPR16 in autophagy enhancement. Similarly, the roles of FCPR16 in the production of ROS, decline of Δψm, and neuroprotection were blocked by compound C as well. Similar results were consistently obtained in primary cultured neurons. Taken together, these results suggest that FCPR16 is effective in protecting SH-SY5Y cells and neurons against oxidative stress via AMPK-dependent autophagy. Our findings indicate the potential application of FCPR16 in PD treatment.