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The Potent PDE10A Inhibitor MP-10 (PF-2545920) Suppresses Microglial Activation in LPS-Induced Neuroinflammation and MPTP-Induced Parkinson’s Disease Mouse Models
- Title
- The Potent PDE10A Inhibitor MP-10 (PF-2545920) Suppresses Microglial Activation in LPS-Induced Neuroinflammation and MPTP-Induced Parkinson’s Disease Mouse Models
- Authors
- Kim D.-Y.; Park J.-S.; Leem Y.-H.; Park J.-E.; Kim H.-S.
- Ewha Authors
- 김희선; 임예현
- SCOPUS Author ID
- 김희선; 임예현
- Issue Date
- 2021
- Journal Title
- Journal of Neuroimmune Pharmacology
- ISSN
- 1557-1890
- Citation
- Journal of Neuroimmune Pharmacology vol. 16, no. 2, pp. 470 - 482
- Keywords
- Microglia; Molecular mechanism; MP-10; Neuroinflammation; Neuroprotection; Parkinson’s disease
- Publisher
- Springer
- Indexed
- SCIE; SCOPUS
- Document Type
- Article
- Abstract
- MP-10 (PF-2545920) is a selective inhibitor of phosphodiesterase 10A (PDE10A), an enzyme highly enriched in the striatum, nucleus accumbens, olfactory tubercle, and substantia nigra. The therapeutic effect of MP-10 has been reported in psychiatric and neurodegenerative disorders such as schizophrenia, depression, and Huntington’s disease. However, the effect of MP-10 in Parkinson’s disease (PD) has not been reported to date. In this study, we examined the effect of MP-10 in neuroinflammation and PD mouse models. MP-10 inhibited nitric oxide, tumor necrosis factor alpha, and interleukin (IL)-6 production, while it promoted IL-10 production in lipopolysaccharide (LPS)-stimulated BV2 microglial cells. Subsequent western blot and reverse transcription polymerase chain reaction analyses showed that MP-10 reduced the mRNA and protein levels of inducible nitric oxide synthase, cyclooxygenase-2, proinflammatory cytokines, and matrix metalloproteinase-3, −8, and − 9 in LPS-stimulated BV2 cells. Further mechanistic studies revealed that MP-10 exerts anti-inflammatory effects by inhibiting the phosphorylation of c-Jun N-terminal kinase and Akt, reducing the activity of nuclear factor-kappa B/activator protein-1, and upregulating the nuclear factor erythroid 2-related factor 2/antioxidant response element and protein kinase A/cAMP response element-binding protein signaling pathways. The anti-inflammatory effect of MP-10 was confirmed in vivo. Specifically, MP-10 inhibited microglial activation and proinflammatory gene expression in the brains of LPS-injected mice. Moreover, MP-10 rescued behavioral deficits and recovered dopaminergic neuronal cell death in the brains of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced PD mice. MP-10 also reduced microglial activation in this PD mouse model. These data collectively suggest that MP-10 may have therapeutic potential in PD and other neuroinflammatory disorders. [Figure not available: see fulltext.] © 2020, Springer Science+Business Media, LLC, part of Springer Nature.
- DOI
- 10.1007/s11481-020-09943-6
- Appears in Collections:
- 의과대학 > 의학과 > Journal papers
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