This grant builds upon the research from a prior grant: Activation of Nrf2 neuroprotective pathways for Parkinson’s disease
Objective/Rationale:
Low-risk, easily administered therapies aiming to slow down or stop neurodegeneration in PD are urgently needed. Compounds that activate PPAR gamma receptors have the potential to modulate PD progression. In this study we will test whether a novel selective PPAR gamma receptor agonist, LY554862 (Eli Lilly) can protect against the effects of a PD toxin in mice. Our goals are to better understand the role of these receptors in PD development and to move forward a new non invasive treatment for PD.
Project Description:
This project will consist of two sets of experiments. In the first set, we will analyze whether a PPAR gamma activator can induce neuroprotection. We will give LY554862 twice a day orally to black mice exposed to the parkinsonian agent MPTP. We will assess if the treatment can prevent the harmful brain effects of the neurotoxin. In the second set, we will focus in the specific mechanisms by which LY554862 acts. We will assess the effects of administering LY554862 to mice with different mutations with and without exposure to MPTP. Using different assays we will evaluate the contribution of anti-inflammatory and anti-oxidative pathways to neuroprotection induced by this PPAR gamma activator.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
PD patients need an effective oral, non-invasive, neuroprotective treatment. PPAR gamma agonists have the potential to become neuroprotective PD treatments. These studies will specifically assess whether activation of PPAR gamma receptors can be a therapeutic target. The advantage of using LY554862, compared to other compounds acting on similar receptors, is that it is specific, has good brain penetrance, and is devoided of the insulin sensitizing properties and potential cardiovascular complications. We hope that this research will encourage the development and clinical translation of non invasive therapies aiming to these novel targets.
Anticipated Outcome:
We are excited about this project because it will shed light on pathways that modulate nigrostriatal neurodegeneration while assessing a novel oral neuroprotective strategy. We expect that the compound LY554862 will be able to prevent neurotoxin-induced neurodegeneration in mice. We anticipate that the positive effects will be due to a combination of anti-inflammatory and antioxidative stress activation. Most importantly, if the results validate the target, they will get us one step closer to clinical translation.