FCPR03, a novel phosphodiesterase 4 inhibitor, alleviates cerebral ischemia/reperfusion injury through activation of the AKT/GSK3β/ β-catenin signaling pathway

Bingtian Xu, Tiantian Wang, Jiao Xiao, Wenli Dong, Hui-Zhen Wen, Xinyi Wang, Yunyun Qin, Ningbo Cai, Zhongzhen Zhou, Jiangping Xu, Haitao Wang
Biochemical Pharmacology 2019 February 21, 163: 234-249
Inhibition of phosphodiesterase 4 (PDE4) is a promising strategy for the treatment of ischemic stroke. However, the side effects of nausea and vomiting from the current PDE4 inhibitors have limited their clinical applications. FCPR03 is a novel PDE4 inhibitor with little emetic potential. This study aimed to investigate the effects of FCPR03 on neuronal injury after cerebral ischemia/reperfusion and the underlying signaling pathway. The effects of FCPR03 on cellular apoptosis, intracellular accumulation of reactive oxygen species (ROS), and mitochondrial membrane potential (MMP) were evaluated in HT-22 neuronal cells and cortical neurons exposed to oxygen-glucose deprivation (OGD). The impact of FCPR03 on brain injury, neurological scores and behavioral performance was investigated in rats subjected to middle cerebral artery occlusion (MCAO). The protein kinase B (AKT) inhibitor MK-2206 and β-catenin siRNA were used to investigate the underlying pathways. FCPR03 dose-dependently protected against OGD-induced cellular apoptosis in both HT-22 cells and cortical neurons. The levels of MMP and ROS were also restored by FCPR03. FCPR03 increased the levels of phosphorylated AKT, glycogen synthase kinase-3β (GSK3β), and β-catenin. Interestingly, the role of FCPR03 was reversed by MK-2206 and β-catenin siRNA. Consistently, FCPR03 reduced the infarct volume and improved neurobehavioral outcomes in rats following MCAO. Moreover, FCPR03 increased the levels of phosphorylated AKT, GSK3β and β-catenin within the ischemic penumbra of rats following cerebral ischemia-reperfusion. Taken together, FCPR03 has therapeutic potential in cerebral ischemia-reperfusion. The neuroprotective effects of FCPR03 are mediated through activation of the AKT/GSK3β/β-catenin pathway.

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