Objective/Rationale:
Chronic and persistent inflammation in the brain has been shown to be an underlying driver of Parkinson’s disease (PD). Anti-inflammatory strategies may be beneficial in combatting the progression of PD. We have recently discovered that the enzyme monoacylglycerol lipase (MAGL) breaks down cannabinoid-signaling lipids to the arachidonic acid, which generates a wide range of pro-inflammatory lipids (known as eicosanoids). We have shown that blocking MAGL with small-molecule inhibitors enhances the anti-inflammatory action of cannabinoids, while limiting pro-inflammatory eicosanoids, thereby suppressing inflammation in the brain and eliciting protection against neurodegeneration. Here, we will test whether MAGL inhibitors will protect against inflammation and neurodegeneration in pre-clinical models of PD.
Project Description:
We will test whether MAGL inhibitors are protective in pre-clinical models of PD. Specifically, we will determine whether MAGL inhibitors can lessen the neuroinflammation, neurodegeneration and behavioral deficits conferred by two models of PD. We anticipate that these studies will provide the evidence required to push MAGL inhibitors into clinical development for the treatment of PD.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
We have previously shown that MAGL inhibitors are protective in a toxicant-mediated PD model, as well as in an Alzheimer’s disease model. The original toxicant-mediated PD model is crude and has not thus far been predictive for clinical efficacy. Therefore, we propose here to test MAGL inhibitors in more advanced models of PD. Since we will be testing whether MAGL inhibitors attenuate neuroinflammation, neurodegeneration and behavioral deficits in these PD models, our results will have direct relevance to PD treatment, if we are successful.
Anticipated Outcome:
This study will provide penetrating insights into the efficacy of MAGL inhibitors in combatting PD through lowering inflammation in the brain. We anticipate that our MAGL inhibitors will show neuroprotection in both of our very different models of PD, and as such, provide the necessary pre-clinical validation to advance MAGL inhibitors towards further pre-clinical and clinical development.
Progress Report
In the first year of funding, we have garnered preliminary data showing that MAGL inhibitors protect against behavioral deficits and dopamine depletion in a pre-clinical model of PD driven by both neuroinflammation and genetic PD predispositions, through raising endocannabinoid and lowering pro-inflammatory eicosanoid signaling in the brain. We are also testing the effect of MAGL inhibitors in a 6-hydroxydopamine Parkison’s disease model to determine whether MAGL blockade averts dopaminergic neurodegeneration.
January 2014