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

  • Biochem Pharmacol. 2019 May;163:234-249. doi: 10.1016/j.bcp.2019.02.023.
Bingtian Xu  1 ,  Tiantian Wang  1 ,  Jiao Xiao  1 ,  Wenli Dong  1 ,  Hui-Zhen Wen  2 ,  Xinyi Wang  1 ,  Yunyun Qin  1 ,  Ningbo Cai  1 ,  Zhongzhen Zhou  1 ,  Jiangping Xu  3 ,  Haitao Wang  4
Affiliations
  • 1. Department of Neuropharmacology and Drug Discovery, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
  • 2. Central Laboratory, Southern Medical University, Guangzhou 510515, China.
  • 3. Department of Neuropharmacology and Drug Discovery, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China; Central Laboratory, Southern Medical University, Guangzhou 510515, China; Center for Brain Science and Brain-Inspired Intelligence, Guangdong-Hong Kong-Macao Greater Bay Area, Southern Medical University, Guangzhou 510515, China; Key Laboratory of Mental Health of the Ministry of Education, Southern Medical University, Guangzhou 510515, China. Electronic address: [email protected].
  • 4. Department of Neuropharmacology and Drug Discovery, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China; Center for Brain Science and Brain-Inspired Intelligence, Guangdong-Hong Kong-Macao Greater Bay Area, Southern Medical University, Guangzhou 510515, China; Key Laboratory of Mental Health of the Ministry of Education, Southern Medical University, Guangzhou 510515, China. Electronic address: [email protected].
PMID: 30797872 DOI: 10.1016/j.bcp.2019.02.023
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. 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.

Keywords
AKT; FCPR03; Ischemic stroke; Neuroprotection; Phosphodiesterase 4.
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