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Inhibition of Protease-Activated Receptor-2 Activation in Parkinson's Disease Using 1-Piperidin Propionic Acid
Santina Quarta1, Michele Sandre2, Mariagrazia Ruvoletto1
1Department of Medicine, University of Padova, 35122 Padova, Italy.
Abstract:
In Parkinson's disease, neuroinflammation is a double-edged sword; when inflammation occurs it can have harmful effects, despite its important role in battling infections and healing tissue. Once triggered by microglia, astrocytes acquire a reactive state and shift from supporting the survival of neurons to causing their destruction. Activated microglia and Proteinase-activated receptor-2 (PAR2) are key points in the regulation of neuroinflammation. 1-Piperidin Propionic Acid (1-PPA) has been recently described as a novel inhibitor of PAR2. The aim of our study was to evaluate the effect of 1-PPA in neuroinflammation and microglial activation in Parkinson's disease. Protein aggregates and PAR2 expression were analyzed using Thioflavin S assay and immunofluorescence in cultured human fibroblasts from Parkinson's patients, treated or untreated with 1-PPA. A significant decrease in amyloid aggregates was observed after 1-PPA treatment in all patients. A parallel decrease in PAR2 expression, which was higher in sporadic Parkinson's patients, was also observed both at the transcriptional and protein level. In addition, in mouse LPS-activated microglia, the inflammatory profile was significantly downregulated after 1-PPA treatment, with a remarkable decrease in IL-1β, IL-6, and TNF-α, together with a decreased expression of PAR2. In conclusion, 1-PPA determines the reduction in neuroglia inflammation and amyloid aggregates formation, suggesting that the pharmacological inhibition of PAR2 could be proposed as a novel strategy to control neuroinflammation.
Insights
1-Piperidin Propionic Acid (1-PPA) reduces neuroinflammation and amyloid aggregates in Parkinson's disease models. This novel inhibitor of Proteinase-activated receptor-2 (PAR2) shows potential for controlling neuroinflammation.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Neuroinflammation plays a dual role in Parkinson's disease (PD), contributing to neuronal damage.
- Microglia activation and Proteinase-activated receptor-2 (PAR2) signaling are critical in PD neuroinflammation.
- Reactive astrocytes, triggered by microglia, can promote neuronal destruction.
Purpose of the Study:
- To investigate the therapeutic potential of 1-Piperidin Propionic Acid (1-PPA), a novel PAR2 inhibitor, in Parkinson's disease.
- To evaluate the effects of 1-PPA on neuroinflammation and microglial activation in PD.
- To assess 1-PPA's impact on amyloid aggregates and PAR2 expression in PD models.
Main Methods:
- Cultured human fibroblasts from PD patients were treated with 1-PPA and analyzed for amyloid aggregates and PAR2 expression using Thioflavin S assay and immunofluorescence.
- Transcriptional and protein levels of PAR2 were assessed.
- LPS-activated mouse microglia were treated with 1-PPA to analyze inflammatory markers (IL-1β, IL-6, TNF-α) and PAR2 expression.
Main Results:
- 1-PPA treatment significantly reduced amyloid aggregates in PD patient fibroblasts.
- A notable decrease in both transcriptional and protein levels of PAR2 was observed post-1-PPA treatment.
- In mouse microglia, 1-PPA significantly downregulated inflammatory markers and PAR2 expression.
Conclusions:
- 1-PPA effectively reduces neuroinflammation and amyloid aggregate formation in experimental models of Parkinson's disease.
- Pharmacological inhibition of PAR2 using 1-PPA presents a promising strategy for managing neuroinflammation in PD.
- Targeting PAR2 offers a potential novel therapeutic avenue for Parkinson's disease treatment.
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