Papaverine inhibits ?-synuclein aggregation by modulating neuroinflammation and matrix metalloproteinase-3 expression in the subacute MPTP/P mouse model of Parkinson’s disease - 27/10/20
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Graphical abstract |
Highlights |
• | PAP attenuated behavioral deficits and showed neuroprotection in subacute PD mice. |
• | PAP ameliorated microglia/astrocyte activation in the striatum and SN of PD mice. |
• | PAP inhibited α-synuclein expression, aggregation, and phosphorylation. |
• | PAP reduced the expression of MMP-3, and co-labeling of MMP-3 with thioflavin-S. |
• | PAP inhibits α-synuclein aggregation by suppressing neuroinflammation and MMP-3. |
Abstract |
Parkinson’s disease (PD) is a neurodegenerative disorder characterized by motor impairments. Most PD drugs act by improving motor impairments, whereas very few drugs that efficiently recover PD-related neuropathological features, particularly α-synuclein-related toxicity, have been developed. In this study, we found that papaverine (PAP) attenuated behavioral deficits and protected against nigrostriatal dopaminergic degeneration in the subacute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/probenecid (MPTP/P) mouse model of PD. Histological analysis of tissue dissected from mice sacrificed nearly 3 weeks after the completion of treatment revealed that PAP significantly ameliorated microglia/astrocyte activation in the striatum and substantia nigra of MPTP/P-treated mice. In addition, PAP diminished α-synuclein expression and aggregation in this model. Furthermore, PAP inhibited the phosphorylation of α-synuclein at serine 129, which may underlie the observed reduction in α-synuclein aggregation. PAP also reduced the expression of matrix metalloproteinase-3 (MMP-3), and the MMP3-positive area co-labeled with thioflavin-S. Taken together, our data suggest that PAP inhibits dopaminergic neuronal cell death and α-synuclein aggregation by suppressing neuroinflammation and MMP-3 expression in the subacute MPTP/P mouse model of PD. Accordingly, PAP may be a promising drug for the treatment of PD.
Le texte complet de cet article est disponible en PDF.Abbreviations : DA, DAergic, GFAP, Iba-1, LPS, MMP, MPTP, MPTP/P, PAP, PD, PDE, SN, SNpc, TH, TUNEL
Keywords : Parkinson’s disease, MPTP/probenecid, α-Synuclein, Neuroinflammation, Matrix metalloproteinase-3, Papaverine
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