Objective/Rationale:
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 models indicates that blocking the signaling pathways in glial cells responsible for turning on neuroinflammatory 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.
Project Description:
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 inflammatory mediators in PD. We will use the well-established MPTP model of PD to 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 that permits a cell-specific readout of inflammatory gene activation to be detected in the brains of affected model, thus enabling a precise determination to be made of both the mechanism of action and efficacy of these compounds. In addition initial studies will be conducted to determine the bioavailability of these compounds in animals to test their suitability for oral drug delivery.
Relevance to Diagnosis/Treatment of Parkinson’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.
Anticipated Outcome:
Based upon our the data from the initial period of funding, we expect to identify which specific class of molecule is most effective in protecting dopaminergic neurons from inflammatory injury in experimental PD and which type of activated glial cell is most effectively suppressed. We also expect to determine which compound possesses the best properties for absorption and distribution to brain based upon bioavailability studies.
PARTNERING PROGRAM
This grant was selected by The Michael J. Fox Foundation staff to be highlighted via the Foundation’s Partnering Program.
Progress Report
Loss of dopamine-producing neurons in Parkinson’s disease (PD) is accompanied by inflammatory activation of surrounding microglia and astrocytes, termed glial cells, that further damage neurons. The objective of this project was to test the efficacy and mechanism of action of a novel series of modified diindolylmethane (C-DIM) compounds that inhibit inflammatory genes in glial cells. Selected C-DIM compounds prevented both loss of dopamine neurons as well as well as glial-specific activation of neuroinflammatory gene expression the subacute MPTP-probenecid model of PD. These studies were designed to fulfill two critical criteria: 1) the drugs were delivered orally once daily and 2) drug administration was not begun until after seven days of dosing with MPTP and probenicid, whereupon no further loss of dopaminergic neurons was observed by day 14. These studies demonstrated that the cDIM compounds investigated were extremely effective at suppressing both neuroinflammatory activation of glia and loss of dopaminergic neurons in the substantia nigra pars compacta, even after onset of dopaminergic neuron loss. Pharmacokinetic studies of these compounds demonstrated oral bioavailability of 30-40%, excellent brain penetration following oral delivery, and sustained plasma levels consistent with therapeutically relevant rates of elimination. These findings demonstrate that orally delivered C-DIM compounds may be promising clinical leads for preventing the progression of PD.
Presentations & Publications
Peer-reviewed manuscripts in preparation:
Trout BR, Lunghofer PJ, Hansen RJ, Miller JA, Safe S, Gustafson DL, Colagiovanni D, and Tjalkens RB. Pharmacokinetic parameters of novel para-phenyl substituted diindolylmethanes in brain and plasma following oral and intravenous dosing (submitted to J. Pharmacol. Exper. Therapeutics; will be resubmitted with neuroprotection data as requested by the editor).
Miller JA, Trout BR, Kirkley KA, Safe S, and Tjalkens RB. Astrocyte-specific inhibition of NF-B Protects against the progressive loss of dopaminergic neurons in a pre-clinical model of Parkinson’s disease (in preparation)
Trout BR, Miller JA, Kirkley KA, Safe S, and Tjalkens RB. The Nurr1 activator 1,1-bis(3’-indolyl)-1-(p-chlorophenyl)methane inhibits NF-B in glial cells and prevents neuronal loss in a pre-clinical model of Parkinson’s disease (in preparation)
Presentations:
2011 (Oct) Michael J. Fox Foundation for Parkinson's Disease Research. Invited plenary speaker at the third annual Therapeutics Conference, held at the New York Academy of Sciences, New York City. Presentation entitled, "Targeting glia in Parkinson’s disease with novel anti-inflammatory therapeutics" Symposium Lecture
2011 (Nov) University of Pittsburgh. Invited lecturer at the University of Pittsburgh Medical Center, Department of Neurology, Center for Neurodegenerative Disorders. Presentation entitled, "Glial inflammatory signaling as a therapeutic target in Parkinson's disease"
Abstracts:
B. R. Trout, J. A. Miller, K. A. Popichak and R. B. Tjalkens. Role of glial activation in a progressive neuroinflammatory model of Parkinson’s disease using MPTP and probenecid. Society of Toxicology, The Toxicologist, Vol 120 (S2), 2011
Kirkley K. and Tjalkens R., Characterization of an Astrocyte Specific IKK-Beta Knockout Mouse. Mountain West Society of Toxicology, Breckenridge, CO, September 08, 2011 (Abstract no. 19)
April 2012