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

Free Radical Biology & Medicine
Jiahong ZhongHaitao Wang

Abstract

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 pote...Continue Reading

Citations

Sep 1, 2020·American Journal of Physiology. Endocrinology and Metabolism·Xiao Wen WangWen-Fang Chen
Sep 22, 2020·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Xiang SunShizhong Zhang
Jul 17, 2020·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Abid BhatMeena Kishore Sakharkar
Jun 23, 2021·Movement Disorders : Official Journal of the Movement Disorder Society·Roberto ErroKailash P Bhatia

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