NETP Focus Area(s): (i) Environmental exposures and gene - environment interactions at prodromal or clinically diagnosed PD; (ii) Translational outcome measures and animal models

Environmental exposures are closely linked to the development of Parkinson's disease (PD). A number of environmental compounds have been implicated as risk factors for PD, including heavy metals, pesticides and anti-cholinergic chemical warfare agents. A central mechanism of action of many of these agents is the capacity to inhibit mitochondrial energy production in cells, leading to several common pathways of cellular dysfunction associated with PD, including protein misfolding, inflammation, and injury to nerve cells in the brain that regulate movement. It is now known that Veterans of the 1991 and more recent Gulf wars were widely exposed to a number of these agents, particularly pesticides, that has increased the prevalence of PD and PD-like disorders amongst Gulf war service Veterans. It is therefore critical to identify both the cellular mechanisms driving this pathology as well as key signaling pathways that could be therapeutically targeted to interdict further neurological decline in individuals diagnosed with parkinsonism related to environmental exposures.

One promising target for therapeutic intervention to prevent neurotoxic injury in PD-like disorders is a class of receptors that regulate inflammation in cells of the brain. These receptors are present in the support cells of the brain, called glial cells, that surround and maintain the health of the nerve cells within the brain (neurons). Following injury, infection, or neurotoxic exposures, brain glial cells can switch into an inflammatory state and release neurotoxic factors that damage neurons. This occurs both in idiopathic PD and in neurotoxin-induced parkinsonism. Pesticide-mediated mitochondrial damage is a potent activator of inflammatory signaling in glial cells, thus, targeting these inflammatory pathways offers the potential to prevent further injury to dopaminergic neurons associated with PD and PD-like disorders resulting from neurotoxic exposures. However, there are no approved drugs that successfully prevent neuroinflammation in PD and related diseases.

The studies proposed in this application focus on a key receptor in glial cells, called Nuclear Receptor 4A2 (NR4A/Nurr1), which is an important inhibitor of inflammation in the brain. Although there is no known endogenous ligand for NR4A2, a number of synthetic compounds have been shown to modulate its activity. Previous studies have reported that a novel synthetic NR4A2 ligand (CDIM12) protected against loss of dopaminergic neurons in neurotoxin-based models of PD and improved locomotor function, even when delivered subsequent to neurotoxic injury. The efficacy and mechanism of action of second-generation DIM compounds will be evaluated using the pesticide and mitochondrial inhibitor, rotenone, as a model of PD, which closely recapitulates multiple neurobehavioral and pathological features of the disease. The synthetic NR4A2 ligands to be used in these neuroprotection studies are orally bioavailable and distribute to the brain. The mechanism of neuroprotection involves inhibition of inflammatory injury. It is the central hypothesis of these studies that CDIM analogs optimized for higher affinity binding to NR4A2 will reduce inflammation in glial cells, thereby preventing neurotoxic injury to dopamine neurons in the rotenone model of Parkinson's disease. This hypothesis will be tested in the following two Specific Aims over the proposed two-year project period: (1) Identify second-generation CDIM analogs with optimal molecular binding characteristics for NR4A2 that modulate PD-relevant cellular targets in glia and neurons; (2) Characterize the pharmacokinetic properties and the in vivo neuroprotective efficacy of the CDIM analogs displaying the most favorable molecular binding and cytoprotective activity.

At the conclusion of these studies, we expect to identify one or two second-generation CDIM analogs suitable for further evaluation of therapeutic potential. Identifying pharmacologic modulators of NR4A2 with the capacity to prevent neuroinflammatory injury to dopaminergic neurons is the goal of the proposed studies. Because neuroinflammation is now understood to be central to the progression of PD and because there are no available drugs to treat this condition, identification of tractable cellular targets to interdict inflammatory injury to neurons represent an important step toward treating PD and related disorders associated with environmental exposures.