Ferulic acid prevents LPS-induced up-regulation of PDE4B and stimulates the cAMP/CREB signaling pathway in PC12 cells

Abstract

Aim: Phosphodiesterase 4 (PDE4) isozymes are involved in different functions, depending on their patterns of distribution in the brain. The PDE4 subtypes are distributed in different inflammatory cells, and appear to be important regulators of inflammatory processes. In this study we examined the effects of ferulic acid (FA), a plant component with strong anti-oxidant and anti-inflammatory activities, on lipopolysaccharide (LPS)-induced up-regulation of phosphodiesterase 4B (PDE4B) in PC12 cells, which in turn regulated cellular cAMP levels and the cAMP/cAMP response element binding protein (CREB) pathway in the cells. Methods: PC12 cells were treated with LPS (1 μg/mL) for 8 h, and the changes of F-actin were detected using laser scanning confocal microscopy. The levels of pro-inflammatory cytokines were measured suing ELISA kits, and PDE4B-specific enzymatic activity was assessed with a PDE4B assay kit. The mRNA levels of PDE4B were analyzed with Q-PCR, and the protein levels of CREB and phosphorylated CREB (pCREB) were determined using immunoblotting. Furthermore, molecular docking was used to identify the interaction between PDE4B2 and FA. Results: Treatment of PC12 cells with LPS induced thick bundles of actin filaments appearing in the F-actin cytoskeleton, which were ameliorated by pretreatment with FA (10-40 μmol/L) or with a PDE4B inhibitor rolipram (30 μmol/L). Pretreatment with FA dose-dependently inhibited the LPS-induced production of TNF-α and IL-1β in PC12 cells. Furthermore, pretreatment with FA dosedependently attenuated the LPS-induced up-regulation of PDE4 activity in PC12 cells. Moreover, pretreatment with FA decreased LPS-induced up-regulation of the PDE4B mRNA, and reversed LPS-induced down-regulation of CREB and pCREB in PC12 cells. The molecular docking results revealed electrostatic and hydrophobic interactions between FA and PDE4B2. Conclusion: The beneficial effects of FA in PC12 cells might be conferred through inhibition of LPS-induced up-regulation of PDE4B and stimulation of cAMP/CREB signaling pathway. Therefore, FA may be a potential therapeutic intervention for the treatment of neuroinflammatory diseases such as AD.

The Neuroprotective Effects of Phenolic Acids: Molecular Mechanism of Action

“…dose-dependent prevention from LPS-induced upregulation of 3′5′-cyclic nucleotide phosphodiesterase 4B, reversion of the LPS-induced downregulation of CREB and pCREB (stimulation the cAMP/CREB signaling pathway) in PC12 cells [ 20 ].…”

The Essential Oil from Acori Tatarinowii Rhizome (the Dried Rhizome of Acorus tatarinowii Schott) Prevents Hydrogen Peroxide‐Induced Cell Injury in PC12 Cells: A Signaling Triggered by CREB/PGC‐1α Activation

“…In this study, the cellular mechanism of ATEO against oxidative stress was investigated. PC12 cells were selected as the cell model due to their phenotypic characteristics of sympathetic neurons [25,26]. We evaluated whether ATEO had a beneficial effect on H 2 O 2 -stressed PC12 cells, including a PGC-1α-mediated increase of cell viability, decrease of ROS level, and upregulation of antioxidant protein expression.…”

An Integrative Pharmacology-Based Strategy to Uncover the Mechanism of Xiong-Pi-Fang in Treating Coronary Heart Disease with Depression

“…Recent studies have shown that the cAMP-PKA-CREB-BDNF signaling pathway is closely related to depression ( Wang et al, 2017 ; Ye et al, 2017 ). Meanwhile, the related proteins in the cAMP-PKA-CREB-BDNF signaling pathway can also improve myocardial microcirculation, improve the ability of myocardial cells to resist ischemia and hypoxia, and effectively prevent the development and deterioration of CHD ( Huang et al, 2016 ). To verify whether XPF works in treating CHD with depression by intervening in the cAMP-PKA-CREB-BDNF signaling pathway and cell apoptosis process, the expression of 5-HT, Ang-II, cAMP, PKA, CREB, BDNF, Bcl-2, Bax, Cyt-c, and caspase-3 in the myocardial and hippocampal tissues were detected.…”