Loss of dopamine-producing neurons in Parkinson’s disease (PD) is accompanied by inflammation in surrounding support cells, called glial cells. This inflammatory state in glial cells leads to production of toxic substances that further damage neurons, leading to a viscous cycle of inflammatory damage that ultimately worsens the progression of the disease. New evidence in experimental pre-clincal models indicates that blocking the signaling pathways in glial cells responsible for turning on neurotoxic genes dramatically decreases damage to dopaminergic neurons. The objective of this project is to test the efficacy and mechanism of action of a new class of experimental drug that shows high activity toward blocking neuroinflammation in experimental models of PD.
A novel series of plant-derived compounds with high anti-inflammatory activity has been structurally modified to selectively interact with signaling pathways that regulate the activity of key genes in glial cells responsible for producing neurotoxic substances in PD. We will use the well-established MPTP model of PD examine the efficacy of representative classes of these compounds in order to discover those that best protect dopaminergic neurons from inflammatory injury. We will use a novel transgenic pre-clinical model line that permits a cell-specific readout of inflammatory gene activation to be detected in the brains of affected animals, thus enabling a precise determination to be made of both the mechanism of action and efficacy of these compounds.
Relevance to Diagnosis/Treatment of Parkinson's’s Disease:
Neuroinflammation is now understood to play a critical role in the progression of PD. Unfortunately, current therapies do not address this problem, being focused on ameliorating the symptoms of dopamine loss rather than on the underlying causes of injury to dopaminergic neurons. Targeting the signaling pathways in glial cells responsible for neuroinflammation represents a promising new therapeutic approach designed to preserve remaining neurons in PD patients, thereby extending the window of efficacy of existing Symptoms & Side Effects drugs in order to better maintain quality of life.
Based upon our preliminary studies, we expect to identify 1) which specific class of molecule is most effective in protecting dopaminergic neurons from inflammatory injury in experimental PD and 2) which type of activated glial cell is most effectively suppressed. Based upon these outcomes, we will select a lead compound to move forward into pre-clinical studies.
Neuroinflammation is an unresolved problem in PD that results in a cycle of glial activation and neuronal injury contributing to the progressive loss of dopaminergic neurons. Both microglia and astrocytes produce neurotoxic levels of inflammatory mediators such as TNFα and nitric oxide that are increased in PD patients and in pre-clinical models of the disease but there are presently no approved drugs that prevent this damaging response. The studies in this project funded by the MJFF examined a library of structural variants of a compound originally isolated from cruciferous vegetables and demonstrated that these compounds potently suppressed inflammatory activation of glia both in isolated cells and in the MPTP pre-clinical model of PD. Additionally, there appears to be pathway selectivity in blocking a broad array of neuroinflammatory genes that are regulated by nuclear factor kappa B, a signaling molecule implicated in pathological activation of glial cells in PD.
Publication Based on MJFF Funding:
Roberts RA, Smith RA, Safe S, Szabo C, Tjalkens RB, and Robertson FM. Toxicological and pathophysiological roles of reactive oxygen and nitrogen species. Toxicology, 2010. PMID: 20643181
Grants Made Possible with MJFF Funding:
Dr. Tjalkens received additional support from The Colorado Bioscience Discovery Grant Evaluation Program representing matching funds to the MJFF-funded project from the State of Colorado to enable screening of a larger number of compounds from the library.