This grant builds upon the research from a prior grant: Use of NR2D-selective NMDA Receptor Modulators in the Treatment of PD
Objective/Rationale:
The NMDA receptor is a protein that helps to mediate communication between neurons. The brain makes several different kinds of NMDA receptors, sometimes termed NR2A, NR2B, NR2C, and NR2D. The NR2D subtype of NMDA receptor is expressed in key brain structures that are affected in Parkinson’s disease. The goal of this project is to test whether new drugs that reduce the activity of this neurotransmitter receptor might be effective new treatments for Parkinson’s disease.
Project Description:
We have searched for new drugs using model systems in which we can study the effect of many molecules on the NR2D subtype of NMDA receptor in non neuronal cells at the same time. The first experiment to be performed will be to confirm that these new potential drugs that we have discovered act on NMDA receptors in neurons in the same fashion as in our tests systems. The second experiment to be performed will be to evaluate their actions in an animal model of Parkinson’s disease. Rats injected with the neurotoxin 6-hydroxydopamine develop motor disturbances that involve the same circuitry as Parkinson’s disease. These animals can be tested for their response to new potential therapies, and if the responses are positive, it provides evidence for further study in humans.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
If the experiments we perform show that the new drugs that act on the NR2D subtype of the NMDA receptor are potentially effective new treatments for Parkinson’s disease as modeled in animals, this result could lead to a clinical trial of these or similar compounds in humans. The clinical trial would test whether the new compounds can alleviate or reduce the movement disorders associated Parkinson’s disease.
Anticipated Outcome:
We expect that the new potential drugs that we have discovered will show properties in animals that suggest they would be effective in humans. Moreover, we expect that these compounds will cause few side effects, and generally be well-tolerated. We also expect this work will increase interest in this strategy for treatment, making it possible to accelerate testing of similar compounds in humans.
Final Outcome
***NOTE: This grant is related to CFT2005 and CFT2005 Supplement grants to Dr. Traynelis.
We have shown that subthalamic neurons in a pre-clinical model express and utilize functional NMDA receptors that contain the NR2D subunit. The expression of NR2D in STN does not dramatically change with dopaminergic cell loss in pre-clinical models of Parkinson’s disease. Moreover, manipulation of NR2D-containing NMDA receptors with newly discovered subunit-selective NMDA receptor potentiators and inhibitors can control the firing rate of the subthalamic neurons. Thus, the NR2D subunit represents a potentially useful target for controlling subthalamic output and perhaps motor function in Parkinson’s patients.
Publication Based on MJFF Funding:
Mosley CA, Acker TM, Hansen KB, Mullasseril P, Andersen KT, Le P, Vellano KM, Brauner-Osborne H, Liotta DC, Traynelis SF (2010) Quinazolin-4-one derivatives: a novel class of noncompetitive NR2C/D subunit-selective NMDA receptor antagonists. J Med Chem 53: 5476-90, 2010.
Mullasseril P, Hansen KB, Vance KM, Ogden KK, Yuan H, Kurtkaya NL, Santangelo R, Orr AG, Le P, Vellano KM, Liotta D, Traynelis SF (2010) A subunit-selective potentiator of NR2C- and NR2D-containing NMDA receptors. Nature Communication, 1(7):1-8, 2010.
Grants Made Possible with MJFF Funding:
NIH/NINDS R01 NS065371 (PI Traynelis) “Mechanism of action of novel subunit-selective NMDA receptor modulators