AbstractThe loss of nigrostriatal dopamine neurones in Parkinson’s disease causes characteristic motor symptoms resulting from signalling alterations in the basal ganglia. An important consequence of this is increased firing of the glutamatergic subthalamic nucleus (STN). Since the STN innervates dopaminergic neurones in the substantia nigra pars compacta (SNc), any increased firing could perpetuate degeneration of these cells by promoting excitotoxicity. Activation of group III mGlu receptors reportedly reduces glutamatergic transmission at the subthalamonigral synapse suggesting activation of these receptors might provide neuroprotection in PD.
The results reported in this thesis support site-directed targeting of the group III receptor subtype mGlu4 in the SNc as a neuroprotective approach in the 6-hydroxydopamine lesioned rat; however while one mGlu4 positive allosteric modulator tested was successful another was not, highlighting several future considerations for the use of these agents. Unexpectedly, activation of group III and mGlu4 receptors increased, rather than reduced glutamate release in the intact SNc. However, this effect was lost in the 6-hydroxydopamine lesioned SNc, reassuring us that in the parkinsonian state activation of these receptors should not exacerbate excitotoxicity. Further experiments are required to define the mechanisms by which the mGlu4-mediated protection is afforded. Additional studies are also required to shed light on why these protective effects were lost in a subsequent study following systemic injection of an mGlu4 PAM (LuAF21934); might this relate to severity of lesion, or a detrimental effect of activating mGlu4 receptors outside the SNc, for example? The lack of protective efficacy subsequently found with a systemically administered mGlu7 agonist (AMN082) against a severe 6-hydroxydopamine lesion also points towards partial lesion models for future testing.
Finally, since other antiglutamatergic strategies have proven successful, we investigated mGlu4 activation as a means to inhibit L-DOPA-induced dyskinesia expression or development in rodents. While this approach was ineffective at reversing established dyskinesia there was a hint that it might be efficacious at delaying the onset of this complication that will be worth investigating further.
In conclusion, targeting the mGlu4 receptor has shown some beneficial effects in relation to Parkinson’s disease but much remains to be discovered about the actions of these agents both within and outside of the basal ganglia before any clear potential is revealed.
|Date of Award
|Susan Duty (Supervisor)