Parkinson’s disease (PD) is a progressive neurodegenerative disorder that is caused by loss of dopaminergic neurons in the basal ganglia, the brain center for movement initiation and coordination. mGluR4 receptors are strategically localized to counteract neurotransmitter imbalance and restore motor behavior in patients.
Parkinson’s disease is characterized by motor symptoms such as slowness in initiating and executing movements (akinesia and bradykinesia, respectively), muscular rigidity, resting tremor, postural instability, gait dysfunction and freezing. These symptoms are caused by the degeneration of dopaminergic neurons in the substantia nigra and depletion of dopamine in the striatum. Actually, in a healthy brain, there is a balance between the direct and indirect pathways of the basal ganglia. The direct pathway stimulates the initiation of movements through an activation of the thalamocortical neurons. By contrast, the indirect pathway leads to the inhibition of the thalamocortical neurons, and then an inhibition of movements. These two pathways are modulated by the dopaminergic neurons from the substantia nigra, that activate the direct pathway and inhibit the indirect pathway. In PD, these dopaminergic neurons degenerate, and dopamine loss in the striatum leads to an over-stimulation of glutamate transmission at the subthalamo-nigral synapses, and then an over-inhibition of the thalamocortical neurons. The ability to carry out voluntary movements is impaired and this leads to the motor symptoms of PD.
Current treatments are aimed at replacing dopamine or mimicking its effects by chronically administering patients with the dopamine precursor L-DOPA, inhibitors of dopamine catabolic enzymes or direct dopamine receptor agonists. Although these treatments provide good symptomatic relief in the early to middle stages of PD, they lose their efficacy as the disease progresses and their chronic administration is associated with invalidating side effects (dyskinesia, motor fluctuations, behavior disturbances). Finally, none of the compounds of the current pharmacopeia for PD have demonstrated neuroprotection which would delay disease progression. Therefore, to address these important unmet medical needs, efforts are required to develop new treatments for PD that target the neurochemical systems downstream dopamine itself in the basal ganglia.
Within the basal ganglia, mGluR4 receptors are strategically localized to counteract neurotransmitter imbalance in PD. Actually, they are localized presynaptically on the striato-pallidal neurons and on the subthalamo-nigral projections. By decreasing GABAergic and glutamatergic transmission in the indirect pathway, mGluR4 activation is expected to restore the equilibrium between the direct and indirect pathways, and then to restore motor behaviours in PD, as demonstrated in animal models.
We are developing positive allosteric modulators, or PAMs, to increase mGluR4 activity while minimizing the likelihood of adverse effects. Several studies in animal models have demonstrated that this strategy is promising for the treatment of motor and non-motor symptoms of PD, as well as for disease modification.