PMID- 31659561 OWN - NLM STAT- MEDLINE DCOM- 20201207 LR - 20201214 IS - 1573-6830 (Electronic) IS - 0272-4340 (Linking) VI - 40 IP - 3 DP - 2020 Apr TI - Inhibition of PDE4 Attenuates TNF-alpha-Triggered Cell Death Through Suppressing NF-kappaB and JNK Activation in HT-22 Neuronal Cells. PG - 421-435 LID - 10.1007/s10571-019-00745-w [doi] AB - Tumor necrosis factor-alpha (TNF-alpha) 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-alpha induced by lipopolysaccharides in microglial cells. However, whether PDE4 inhibition can block the neurotoxic effects of TNF-alpha in neuronal cells is unknown. In this study, we investigated the protective effects of FCPR16, a novel PDE4 inhibitor, against TNF-alpha-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-alpha insult. Propidium iodide/calcein staining and flow cytometry analysis showed that FCPR16 decreased cell apoptosis triggered by TNF-alpha. 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-alpha-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-kappaB (NF-kappaB) 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-alpha. Moreover, knockdown of PDE4B by specific small interfering RNA reduced the apoptosis of HT-22 cells treated with TNF-alpha. Taken together, our findings suggest that FCPR16 promotes the survival of neuronal cells exposed to TNF-alpha by suppressing the activation of JNK and NF-kappaB. FAU - Xiao, Jiao AU - Xiao J AD - Department of Neuropharmacology and Drug Discovery, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China. FAU - Yao, Rumeng AU - Yao R AD - Department of Neuropharmacology and Drug Discovery, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China. FAU - Xu, Bingtian AU - Xu B AD - Department of Neuropharmacology and Drug Discovery, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China. FAU - Wen, Huizhen AU - Wen H AD - Central Laboratory, Southern Medical University, Guangzhou, 510515, China. FAU - Zhong, Jiahong AU - Zhong J AD - Department of Neuropharmacology and Drug Discovery, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China. FAU - Li, Dan AU - Li D AD - Department of Neuropharmacology and Drug Discovery, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China. FAU - Zhou, Zhongzhen AU - Zhou Z AD - Department of Neuropharmacology and Drug Discovery, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China. FAU - Xu, Jiangping AU - Xu J AD - Department of Neuropharmacology and Drug Discovery, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China. jpx@smu.edu.cn. AD - Central Laboratory, Southern Medical University, Guangzhou, 510515, China. jpx@smu.edu.cn. AD - Center for Brain Science and Brain-Inspired Intelligence, Guangdong-Hong Kong-Macao Greater Bay Area, Guangzhou, 510515, China. jpx@smu.edu.cn. AD - Key Laboratory of Mental Health of the Ministry of Education, Southern Medical University, Guangzhou, 510515, China. jpx@smu.edu.cn. FAU - Wang, Haitao AU - Wang H AD - Department of Neuropharmacology and Drug Discovery, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China. wht821@smu.edu.cn. AD - Center for Brain Science and Brain-Inspired Intelligence, Guangdong-Hong Kong-Macao Greater Bay Area, Guangzhou, 510515, China. wht821@smu.edu.cn. AD - Key Laboratory of Mental Health of the Ministry of Education, Southern Medical University, Guangzhou, 510515, China. wht821@smu.edu.cn. LA - eng GR - 81773698/National Natural Science Foundation of China/ GR - IRT_16R37/Program for Changjiang Scholars and Innovative Research Team in University/ GR - 2018B030334001/Science and Technology Program of Guangdong/ GR - 2015B020211007/Science and Technology Program of Guangdong/ GR - 201604020112/Science and Technology Program of Guangzhou/ PT - Journal Article DEP - 20191028 PL - United States TA - Cell Mol Neurobiol JT - Cellular and molecular neurobiology JID - 8200709 RN - 0 (Benzamides) RN - 0 (N-(2-chlorophenyl)-3-cyclopropylmethoxy-4-di-fluoromethoxybenzamide) RN - 0 (NF-kappa B) RN - 0 (Phosphodiesterase 4 Inhibitors) RN - 0 (Reactive Oxygen Species) RN - 0 (Tumor Necrosis Factor-alpha) RN - EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases) SB - IM MH - Animals MH - Apoptosis/drug effects MH - Benzamides/*pharmacology MH - Cell Death/*drug effects MH - Cells, Cultured MH - Drug Interactions MH - Hippocampus/cytology/drug effects/physiology MH - JNK Mitogen-Activated Protein Kinases/antagonists & inhibitors/metabolism MH - Mice MH - NF-kappa B/antagonists & inhibitors/metabolism MH - Neurons/*drug effects/physiology MH - Phosphodiesterase 4 Inhibitors/*pharmacology MH - Reactive Oxygen Species/metabolism MH - Signal Transduction/drug effects MH - Tumor Necrosis Factor-alpha/*pharmacology OTO - NOTNLM OT - FCPR16 OT - JNK OT - NF-kappaB OT - Neuroinflammation OT - Phosphodiesterase 4 EDAT- 2019/10/30 06:00 MHDA- 2020/12/15 06:00 CRDT- 2019/10/30 06:00 PHST- 2019/06/24 00:00 [received] PHST- 2019/10/11 00:00 [accepted] PHST- 2019/10/30 06:00 [pubmed] PHST- 2020/12/15 06:00 [medline] PHST- 2019/10/30 06:00 [entrez] AID - 10.1007/s10571-019-00745-w [pii] AID - 10.1007/s10571-019-00745-w [doi] PST - ppublish SO - Cell Mol Neurobiol. 2020 Apr;40(3):421-435. doi: 10.1007/s10571-019-00745-w. Epub 2019 Oct 28.