Use of NR2D-selective NMDA Receptor Modulators in the Treatment of PD

The frontline pharmacological treatment for Parkinson’s disease is associated with serious side effects, creating a need for new therapeutic strategies.  Recent evidence suggests that selective blockade of one glutamate receptor subtype (receptors containing the NR2D subunit) may be a useful treatment for Parkinson’s disease.

The NR2D subunit is expressed in key brain structures that are affected during Parkinson’s disease, and selective inhibition of these receptors may have therapeutic benefit via several potentially synergistic actions. For example, reduction of glutamate receptor function might reduce the overactivation of three different sets of neurons in Parkinson’s patients, which could synergize to reduce Parkinsonian symptoms. In addition, blockade of NR2D-containing glutamate receptors may slow the disease progression by reducing death in neurons that synthesize and release dopamine. 

The first goal of the proposed experiments is to identify molecules that are subunit-selective NR2D inhibitors for eventual testing in animal models of Parkinson’s disease. The second goal is to validate that NR2D receptors are functionally expressed in basal ganglia nuclei and that the NR2D inhibitors we find can modify the excitability of basal ganglia neurons. Achieving these goals could provide tools and data supporting a new potential target for drug development.