Inhibition of phosphodiesterase 4 by FCPR16 protects SH-SY5Y cells against MPP+-induced decline of mitochondrial membrane potential and oxidative stress

摘要: Abstract Phosphodiesterase 4 (PDE4) is a promising target for the treatment of Parkinson's disease (PD). However, underlying mechanism has not yet been well elucidated. Additionally, most current PDE4 inhibitors produce severe nausea and vomiting response in patients, which limit their clinical application. FCPR16 novel inhibitor with little emetic potential. In present study, neuroprotective effect against cellular apoptosis induced by 1-methyl-4-phenylpyridinium (MPP+) were examined SH-SY5Y cells. (12.5–50 μM) dose-dependently reduced MPP+-induced loss cell viability, accompanied reductions nuclear condensation lactate dehydrogenase release. The level cleaved caspase 3 ratio Bax/Bcl-2 also decreased after MPP+-treated Furthermore, (25 μM) significantly suppressed accumulation reactive oxygen species (ROS), prevented decline mitochondrial membrane potential (Δψm) attenuated expression malonaldehyde level. Further studies disclosed that enhanced levels cAMP exchange protein directly activated (Epac) Western blotting analysis revealed increased phosphorylation element-binding (CREB) kinase B (Akt) down-regulated MPP+ Moreover, inhibitory effects on production ROS Δψm could be blocked PKA H-89 Akt KRX-0401. Collectively, these results suggest attenuates dopaminergic degeneration via lowering preventing Mechanistically, cAMP/PKA/CREB Epac/Akt signaling pathways are involved processes. Our findings indicate pre-clinical candidate PD possibly other oxidative stress-related neuronal diseases.