The phosphodiesterase 10 inhibitor papaverine exerts anti-inflammatory and neuroprotective effects via the PKA signaling pathway in neuroinflammation and Parkinson’s disease mouse models
Abstract Background Neuroinflammation plays a pivotal role in the pathogenesis of Parkinson’s disease (PD). Thus, the development of agents that can control neuroinflammation has been suggested as a promising therapeutic strategy for PD. In the present study, we investigated whether the phosphodiest...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2019-12-01
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| Series: | Journal of Neuroinflammation |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12974-019-1649-3 |
| _version_ | 1818562715544715264 |
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| author | Yu-Young Lee Jin-Sun Park Yea-Hyun Leem Jung-Eun Park Do-Yeon Kim Youn-Hee Choi Eun-Mi Park Jihee Lee Kang Hee-Sun Kim |
| author_facet | Yu-Young Lee Jin-Sun Park Yea-Hyun Leem Jung-Eun Park Do-Yeon Kim Youn-Hee Choi Eun-Mi Park Jihee Lee Kang Hee-Sun Kim |
| author_sort | Yu-Young Lee |
| collection | DOAJ |
| description | Abstract Background Neuroinflammation plays a pivotal role in the pathogenesis of Parkinson’s disease (PD). Thus, the development of agents that can control neuroinflammation has been suggested as a promising therapeutic strategy for PD. In the present study, we investigated whether the phosphodiesterase (PDE) 10 inhibitor has anti-inflammatory and neuroprotective effects in neuroinflammation and PD mouse models. Methods Papaverine (PAP) was utilized as a selective inhibitor of PDE10. The effects of PAP on the expression of pro-inflammatory molecules were examined in lipopolysaccharide (LPS)–stimulated BV2 microglial cells by ELISA, RT-PCR, and Western blot analysis. The effects of PAP on transcription factors were analyzed by the electrophoretic mobility shift assay, the reporter gene assay, and Western blot analysis. Microglial activation and the expression of proinflammatory molecules were measured in the LPS- or MPTP-injected mouse brains by immunohistochemistry and RT-PCR analysis. The effect of PAP on dopaminergic neuronal cell death and neurotrophic factors were determined by immunohistochemistry and Western blot analysis. To assess mouse locomotor activity, rotarod and pole tests were performed in MPTP-injected mice. Results PAP inhibited the production of nitric oxide and proinflammatory cytokines in LPS-stimulated microglia by modulating various inflammatory signals. In addition, PAP elevated intracellular cAMP levels and CREB phosphorylation. Treatment with H89, a PKA inhibitor, reversed the anti-inflammatory effects of PAP, suggesting the critical role of PKA signaling in the anti-inflammatory effects of PAP. We verified the anti-inflammatory effects of PAP in the brains of mice with LPS-induced systemic inflammation. PAP suppressed microglial activation and proinflammatory gene expression in the brains of these mice, and these effects were reversed by H89 treatment. We further examined the effects of PAP on MPTP-injected PD model mice. MPTP-induced dopaminergic neuronal cell death and impaired locomotor activity were recovered by PAP. In addition, PAP suppressed microglial activation and proinflammatory mediators in the brains of MPTP-injected mice. Conclusions PAP has strong anti-inflammatory and neuroprotective effects and thus may be a potential candidate for treating neuroinflammatory disorders such as PD. |
| first_indexed | 2024-12-14T01:07:24Z |
| format | Article |
| id | doaj.art-737990ad3c024dda8bde9d798848e82e |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-12-14T01:07:24Z |
| publishDate | 2019-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-737990ad3c024dda8bde9d798848e82e2022-12-21T23:22:54ZengBMCJournal of Neuroinflammation1742-20942019-12-0116111710.1186/s12974-019-1649-3The phosphodiesterase 10 inhibitor papaverine exerts anti-inflammatory and neuroprotective effects via the PKA signaling pathway in neuroinflammation and Parkinson’s disease mouse modelsYu-Young Lee0Jin-Sun Park1Yea-Hyun Leem2Jung-Eun Park3Do-Yeon Kim4Youn-Hee Choi5Eun-Mi Park6Jihee Lee Kang7Hee-Sun Kim8Department of Molecular Medicine and Tissue Injury Defense Research Center, School of Medicine, Ewha Womans UniversityDepartment of Molecular Medicine and Tissue Injury Defense Research Center, School of Medicine, Ewha Womans UniversityDepartment of Molecular Medicine and Tissue Injury Defense Research Center, School of Medicine, Ewha Womans UniversityDepartment of Molecular Medicine and Tissue Injury Defense Research Center, School of Medicine, Ewha Womans UniversityDepartment of Molecular Medicine and Tissue Injury Defense Research Center, School of Medicine, Ewha Womans UniversityDepartment of Physiology and Tissue Injury Defense Research Center, School of Medicine, Ewha Womans UniversityDepartment of Pharmacology and Tissue Injury Defense Research Center, School of Medicine, Ewha Womans UniversityDepartment of Physiology and Tissue Injury Defense Research Center, School of Medicine, Ewha Womans UniversityDepartment of Molecular Medicine and Tissue Injury Defense Research Center, School of Medicine, Ewha Womans UniversityAbstract Background Neuroinflammation plays a pivotal role in the pathogenesis of Parkinson’s disease (PD). Thus, the development of agents that can control neuroinflammation has been suggested as a promising therapeutic strategy for PD. In the present study, we investigated whether the phosphodiesterase (PDE) 10 inhibitor has anti-inflammatory and neuroprotective effects in neuroinflammation and PD mouse models. Methods Papaverine (PAP) was utilized as a selective inhibitor of PDE10. The effects of PAP on the expression of pro-inflammatory molecules were examined in lipopolysaccharide (LPS)–stimulated BV2 microglial cells by ELISA, RT-PCR, and Western blot analysis. The effects of PAP on transcription factors were analyzed by the electrophoretic mobility shift assay, the reporter gene assay, and Western blot analysis. Microglial activation and the expression of proinflammatory molecules were measured in the LPS- or MPTP-injected mouse brains by immunohistochemistry and RT-PCR analysis. The effect of PAP on dopaminergic neuronal cell death and neurotrophic factors were determined by immunohistochemistry and Western blot analysis. To assess mouse locomotor activity, rotarod and pole tests were performed in MPTP-injected mice. Results PAP inhibited the production of nitric oxide and proinflammatory cytokines in LPS-stimulated microglia by modulating various inflammatory signals. In addition, PAP elevated intracellular cAMP levels and CREB phosphorylation. Treatment with H89, a PKA inhibitor, reversed the anti-inflammatory effects of PAP, suggesting the critical role of PKA signaling in the anti-inflammatory effects of PAP. We verified the anti-inflammatory effects of PAP in the brains of mice with LPS-induced systemic inflammation. PAP suppressed microglial activation and proinflammatory gene expression in the brains of these mice, and these effects were reversed by H89 treatment. We further examined the effects of PAP on MPTP-injected PD model mice. MPTP-induced dopaminergic neuronal cell death and impaired locomotor activity were recovered by PAP. In addition, PAP suppressed microglial activation and proinflammatory mediators in the brains of MPTP-injected mice. Conclusions PAP has strong anti-inflammatory and neuroprotective effects and thus may be a potential candidate for treating neuroinflammatory disorders such as PD.https://doi.org/10.1186/s12974-019-1649-3Parkinson’s diseaseNeuroinflammationNeuroprotectionMicrogliaPDE10 inhibitorPapaverine |
| spellingShingle | Yu-Young Lee Jin-Sun Park Yea-Hyun Leem Jung-Eun Park Do-Yeon Kim Youn-Hee Choi Eun-Mi Park Jihee Lee Kang Hee-Sun Kim The phosphodiesterase 10 inhibitor papaverine exerts anti-inflammatory and neuroprotective effects via the PKA signaling pathway in neuroinflammation and Parkinson’s disease mouse models Journal of Neuroinflammation Parkinson’s disease Neuroinflammation Neuroprotection Microglia PDE10 inhibitor Papaverine |
| title | The phosphodiesterase 10 inhibitor papaverine exerts anti-inflammatory and neuroprotective effects via the PKA signaling pathway in neuroinflammation and Parkinson’s disease mouse models |
| title_full | The phosphodiesterase 10 inhibitor papaverine exerts anti-inflammatory and neuroprotective effects via the PKA signaling pathway in neuroinflammation and Parkinson’s disease mouse models |
| title_fullStr | The phosphodiesterase 10 inhibitor papaverine exerts anti-inflammatory and neuroprotective effects via the PKA signaling pathway in neuroinflammation and Parkinson’s disease mouse models |
| title_full_unstemmed | The phosphodiesterase 10 inhibitor papaverine exerts anti-inflammatory and neuroprotective effects via the PKA signaling pathway in neuroinflammation and Parkinson’s disease mouse models |
| title_short | The phosphodiesterase 10 inhibitor papaverine exerts anti-inflammatory and neuroprotective effects via the PKA signaling pathway in neuroinflammation and Parkinson’s disease mouse models |
| title_sort | phosphodiesterase 10 inhibitor papaverine exerts anti inflammatory and neuroprotective effects via the pka signaling pathway in neuroinflammation and parkinson s disease mouse models |
| topic | Parkinson’s disease Neuroinflammation Neuroprotection Microglia PDE10 inhibitor Papaverine |
| url | https://doi.org/10.1186/s12974-019-1649-3 |
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