ArticleMolecular neurobiology2016
NF-κB Upregulates Type 5 Phosphodiesterase in N9 Microglial Cells: Inhibition by Sildenafil and Yonkenafil.
Article in Molecular neurobiology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers, 1 of them a synthesis that pooled it.
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Who cites it
15 citing papers in PubMed, 1 synthesis or guideline pooled it, 23 citations in OpenAlex.
- Analysis of Phosphodiesterase-5 (PDE5) Inhibitors in Modulating Inflammatory Markers in Humans: A Systematic Review and Meta-Analysis.International journal of molecular sciences · 2025Pooled it
- M2 microglial exosomal miR-1949 ameliorates sepsis-associated encephalopathy through DKK1/Wnt/β-catenin-mediated microglial repolarization.Archives of pharmacal research · 2026Article
- Treatment with Sildenafil Promotes Angiogenesis and Modulates Immune Response in Ischemic Muscle Tissue.Current issues in molecular biology · 2026Article
- Structure matters: commensalFrontiers in cellular neuroscience · 2026Article
- RNA Interference Unleashed: Current Perspective of Small Interfering RNA (siRNA) Therapeutics in the Treatment of Neuropathic Pain.ACS pharmacology & translational science · 2024Review
- Potential of Neuroinflammation-Modulating Strategies in Tuberculous Meningitis: Targeting Microglia.Aging and disease · 2024Review
- The Role of Sildenafil in Treating Brain Injuries in Adults and Neonates.Frontiers in cellular neuroscience · 2022Review
- Mechanisms Involved in Microglial-Interceded Alzheimer's Disease and Nanocarrier-Based Treatment Approaches.Journal of personalized medicine · 2021Review
- The CNS-penetrant soluble guanylate cyclase stimulator CYR119 attenuates markers of inflammation in the central nervous system.Journal of neuroinflammation · 2021Article
- Regulation of pathological blood-brain barrier for intracranial enhanced drug delivery and anti-glioblastoma therapeutics.Oncology research · 2021Review
- Effects of Microglial Activation and Polarization on Brain Injury After Stroke.Frontiers in neurology · 2021Review
- Microglial autophagy defect causes parkinson disease-like symptoms by accelerating inflammasome activation in mice.Autophagy · 2020Article
- Lipopolysaccharide induces neuroinflammation in microglia by activating the MTOR pathway and downregulating Vps34 to inhibit autophagosome formation.Journal of neuroinflammation · 2020Article
- Pharmacological Targeting of Microglial Activation: New Therapeutic Approach.Frontiers in cellular neuroscience · 2019Review
- Pharmacological Modulation of Functional Phenotypes of Microglia in Neurodegenerative Diseases.Frontiers in aging neuroscience · 2017Review
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Authors and funding
9 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Our previous studies showed that the phosphodiesterase-5 (PDE5) inhibitor sildenafil inhibited the microglial activation induced by lipopolysaccharide (LPS). However, whether yonkenafil, a novel PDE5 inhibitor, also inhibits microglial activation and the underlying mechanism of inhibition remain elusive. Here we found that yonkenafil significantly suppressed the production of NO, interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α) and the protein expression of inducible NO synthase (iNOS) induced by LPS in microglial cells in a concentration-dependent manner. Knockdown of PDE5 inhibits NO and iNOS protein expression in LPS-stimulated N9 microglia. Moreover, we observed that the nuclear factor-κB (NF-κB) transcriptionally upregulated PDE5 expression, which was inhibited by sildenafil and yonkenafil in LPS-stimulated N9 microglia. Therefore, sildenafil and yonkenafil may exert their inhibitory effects on microglial activation by reducing the expression of PDE5. Furthermore, sildenafil and yonkenafil increased the cyclic guanosine monophosphate (cGMP) level in N9 microglia, and 8-Br-cGMP, an analogue of cGMP, downregulates extracellular signal-regulated kinases 1 and 2 (ERK1/2)/the NF-κB pathway, suggesting that sildenafil and yonkenafil inhibit microglial activation by decreasing PDE5 expression and increasing the cGMP level. Importantly, sildenafil and yonkenafil significantly alleviated the death of SH-SY5Y neuroblastoma cells and primary cortical neurons induced by the conditioned medium from activated microglia. Together, these findings position PDE5 as a potential therapy target for the treatment of neuroinflammation accompanied by microglial activation.
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