Triggering of inflammasome by impaired autophagy in response to acute experimental Parkinson’s disease: involvement of the PI3K/Akt/mTOR pathway

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Several lines of evidence suggest that the inflammasome activation is involved in the progression of neurodegenerative diseases. However, the relation between Parkinson’s disease (PD) and the inflammasome is still unclear. This study was designed to assess the involvement of inflammasome in acute experimental PD. Specifically, acute PD was induced in C57BL/6 mice by an injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). At seven days from MPTP induction, mice were euthanized and the midbrains were sampled to carry out immunohistochemical evaluations and western blot analysis. Our results show the activation of Nod-like receptor-3 inflammasome in acute MPTP mice, as suggested by the increase of nuclear factor-κB expression, which represents the first signal for inflammasome induction. The Nod-like receptor-3 assembly induces the activation of caspase-1, which in turn activates interleukin-1β and interleukin-18 production, as confirmed by our evaluations. A dysregulation of autophagy system was also found in acute MPTP mice by looking at the expression of Beclin-1, LC-3, and Bcl-2, chosen as markers of autophagy. Thus, in an effort to identify the molecular mechanism underlying the well-known crosstalk between autophagy and the inflammasome, we evaluated the involvement of the phosphoinositide-3 kinase/protein kinase-B/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway, which plays a key role in autophagy. Our results showed a clear upregulation of this signaling after MPTP induction. Taken together, our findings suggest that the triggering of inflammasome could be linked to impaired autophagy because of aberrant upstream activation of the PI3K/Akt/mTOR pathway. Finally, our results propose the inflammasome as a new potential therapeutic target in the management of PD.

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