FCPR03, a novel phosphodiesterase 4 inhibitor, alleviates cerebral ischemia/reperfusion injury through activation of the AKT/GSK3β/ β-catenin signaling pathway
| Autor: | Haitao Wang, Zhong-Zhen Zhou, Wenli Dong, Huizhen Wen, Bingtian Xu, Xinyi Wang, Jiao Xiao, Yunyun Qin, Ningbo Cai, Tiantian Wang, Jiangping Xu |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Male Cell Survival Ischemia Pharmacology Biochemistry Neuroprotection Brain Ischemia Cell Line Rats Sprague-Dawley 03 medical and health sciences Mice 0302 clinical medicine medicine Animals Glycogen synthase Protein kinase B beta Catenin chemistry.chemical_classification Neurons Reactive oxygen species Glycogen Synthase Kinase 3 beta biology Dose-Response Relationship Drug medicine.disease Rats 030104 developmental biology chemistry Gene Expression Regulation Apoptosis 030220 oncology & carcinogenesis Reperfusion Injury Benzamides biology.protein Phosphodiesterase 4 Inhibitors Signal transduction Reactive Oxygen Species Reperfusion injury Proto-Oncogene Proteins c-akt |
| Zdroj: | Biochemical pharmacology. 163 |
| ISSN: | 1873-2968 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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