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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
The phosphodiesterase 10 inhibitor papaverine exerts anti-inflammatory and neuroprotective effects via the PKA signaling pathway in neuroinflammation and Parkinson's disease mouse models
Authors
Lee, Yu-YoungPark, Jin-SunLeem, Yea-HyunPark, Jung-EunKim, Do-YeonChoi, Youn-HeePark, Eun-MiKang, Jihee LeeKim, Hee-Sun
Ewha Authors
이지희김희선박은미최윤희박진선임예현
SCOPUS Author ID
이지희scopus; 김희선scopus; 박은미scopus; 최윤희scopus; 박진선scopus; 임예현scopus
Issue Date
2019
Journal Title
JOURNAL OF NEUROINFLAMMATION
ISSN
1742-2094JCR Link
Citation
JOURNAL OF NEUROINFLAMMATION vol. 16, no. 1
Keywords
Parkinson's diseaseNeuroinflammationNeuroprotectionMicrogliaPDE10 inhibitorPapaverinePKA signaling
Publisher
BMC
Indexed
SCIE; SCOPUS WOS scopus
Document Type
Article
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 antiinflammatory 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.
DOI
10.1186/s12974-019-1649-3
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의과대학 > 의학과 > Journal papers
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