Inhibition of PDE4 Attenuates TNF-α-Triggered Cell Death Through Suppressing NF-κB and JNK Activation in HT-22 Neuronal Cells.

Abstract

Tumor necrosis factor-α (TNF-α) is a critical pro-inflammatory cytokine regulating neuroinflammation. At high concentrations, it is toxic to neurons, and such damage is positively correlated with acute and chronic neurological diseases. Our previous studies showed that inhibition of phosphodiesterase 4 (PDE4) attenuated the production of TNF-α induced by lipopolysaccharides in microglial cells. However, whether PDE4 inhibition can block the neurotoxic effects of TNF-α in neuronal cells is unknown. In this study, we investigated the protective effects of FCPR16, a novel PDE4 inhibitor, against TNF-α-induced cellular apoptosis in HT-22 hippocampal neuronal cells. We demonstrated that FCPR16 dose-dependently increased the viability of HT-22 cells exposed to TNF-α insult. Propidium iodide/calcein staining and flow cytometry analysis showed that FCPR16 decreased cell apoptosis triggered by TNF-α. Western blot analysis showed that FCPR16 decreased the level of cleaved caspase 3 and caspase 8, but had no effect on caspase 9. Mechanistically, FCPR16 blocked the TNF-α-induced phosphorylation of c-Jun N-terminal kinase (JNK) in HT-22 cells, and inhibition of JNK showed a similar protective effect as FCPR16. Furthermore, FCPR16 decreased the translocation of nuclear factor-κB (NF-κB) p65 from the cytosol into the nucleus. In addition, FCPR16 decreased the expression of inducible nitric oxide synthase and the production of reactive oxygen species in HT-22 cells exposed to TNF-α. Moreover, knockdown of PDE4B by specific small interfering RNA reduced the apoptosis of HT-22 cells treated with TNF-α. Taken together, our findings suggest that FCPR16 promotes the survival of neuronal cells exposed to TNF-α by suppressing the activation of JNK and NF-κB.

• Authors: Jiao Xiao, Rumeng Yao, Bingtian Xu, Huizhen Wen, Jiahong Zhong, Dan Li, Zhongzhen Zhou, Jiangping Xu, Haitao Wang
• Journal: Cellular and molecular neurobiology (Cell Mol Neurobiol) Vol. 40 Issue 3 Pg. 421-435 (Apr 2020) ISSN: 1573-6830 [Electronic] United States
• PMID: 31659561 (Publication Type: Journal Article)

Chemical References

• Benzamides
• N-(2-chlorophenyl)-3-cyclopropylmethoxy-4-di-fluoromethoxybenzamide
• NF-kappa B
• Phosphodiesterase 4 Inhibitors
• Reactive Oxygen Species
• Tumor Necrosis Factor-alpha
• JNK Mitogen-Activated Protein Kinases

Topics

• Animals
• Apoptosis (drug effects)
• Benzamides (pharmacology)
• Cell Death (drug effects)
• Cells, Cultured
• Drug Interactions
• Hippocampus (cytology, drug effects, physiology)
• JNK Mitogen-Activated Protein Kinases (antagonists & inhibitors, metabolism)
• Mice
• NF-kappa B (antagonists & inhibitors, metabolism)
• Neurons (drug effects, physiology)
• Phosphodiesterase 4 Inhibitors (pharmacology)
• Reactive Oxygen Species (metabolism)
• Signal Transduction (drug effects)
• Tumor Necrosis Factor-alpha (pharmacology)