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

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

  • Redox Biol. 2018 Jun:16:47-58. doi: 10.1016/j.redox.2018.02.008.
Jiahong Zhong 1,  Hui Yu 1,  Chang Huang 1,  Qiuping Zhong 1,  Yaping Chen 1,  Jinfeng Xie 1,  Zhongzhen Zhou 1,  Jiangping Xu 2,  Haitao Wang 3
Affiliations

Affiliations

  • 1 Department of Neuropharmacology and Drug Discovery, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China; Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
  • 2 Department of Neuropharmacology and Drug Discovery, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China; Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China. Electronic address: jpx@smu.edu.cn.
  • 3 Department of Neuropharmacology and Drug Discovery, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China; Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China. Electronic address: wht821@smu.edu.cn.
PMID: 29475134 DOI: 10.1016/j.redox.2018.02.008
Abstract

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

Keywords

FCPR16; Mitochondrial membrane potential; Oxidative stress; Parkinson's disease; Phosphodiesterase 4.

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