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

Biochemical Pharmacology
Bingtian XuHaitao Wang

Abstract

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. Int...Continue Reading

Citations

Jun 27, 2020·The Anatomical Record : Advances in Integrative Anatomy and Evolutionary Biology·Meng ChaoYaping Huang
Dec 20, 2020·The European Journal of Neuroscience·Jéssica M BonatoRúbia Maria Weffort de Oliveira
Jul 29, 2020·Current Drug Targets·Vivek K SharmaShareen Singh

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