Assessing Inhibition of NLRP3 to Reduce Brain Inflammation in Parkinson’s Disease

Study Rationale: 
Recent studies indicate that brain inflammation caused by activation of a protein complex called the NLRP3 inflammasome worsens Parkinson’s disease (PD). Although multiple drugs that target this inflammasome are under development or entering clinical trials, many are not able to enter the brain. This project will establish a straightforward pre-clinical model for screening newly developed anti-NLRP3 drugs for their ability to reach the brain and to treat the inflammatory symptoms of PD. 

Hypothesis:
We hypothesize that NLRP3 inhibitors that are able to enter the brain will have a therapeutic advantage in suppressing neuroinflammation compared with drugs that are restricted to peripheral tissues.  

Study Design:
The study will establish a pre-clinical model in which the NLRP3 inflammasome is produced specifically in the brain. Using this model, we will establish an efficient panel of measurements that can be used to monitor the brain activity in NLRP3. We will then test our hypothesis by comparing the anti-inflammatory effects of NLRP3 inhibitors that are either restricted to peripheral tissues or are able to penetrate into the brain. The major advance in this project is the optimization of a rapid drug-screening protocol that relies on a newly developed model in which NLRP3 is activated specifically in brain tissue.  

Impact on Diagnosis/Treatment of Parkinson’s Disease:
Previous research has identified a role for NLRP3 during the progression of PD and established tests for the measurement of inflammasome-related processes in people with Parkinson’s. This project will speed the pre-clinical evaluation of new drugs to target NLRP3, driving the development of these new treatments towards clinical application.  

Next Steps for Development:
Near-term, we provide a model for selecting peripherally or centrally acting NLRP3 inhibitors for transition into clinical trials. A long-term goal is to define the molecular basis of the subtypes of PD that involve neuroinflammation and use this information to design clinical trials with an increased likelihood of success.