Therapeutic potential of targeting group III metabotropic glutamate receptors as a disease modifying strategy in the treatment of Parkinson’s disease
Parkinson’s disease (PD) is characterised by a progressive loss of dopaminergic neurones from the SNpc, leading to numerous downstream changes in the basal ganglia circuitry. Overactivity of the glutamatergic subthalamonigral pathway may underlie this continual degeneration of the nigrostriatal system. With this in mind, this thesis examined whether selective activation of group III metabotropic glutamate receptor subtypes may offer a novel strategy to halt persistent degeneration in PD. Initial distribution studies revealed mGlu4 and 7 group III mGlu receptor subtypes, demonstrated particularly intense immunoreactivity in the SNpc, suggesting these receptors may be ideally positioned to provide neuroprotective effects. Therefore, the first objective was to confirm this neuroprotective possibility using a broad spectrum agonist, L-AP4. Sub-chronic supranigral L-AP4 treatment mediated functional neuroprotection against a unilateral 6-OHDA lesion of the SN, confirmed by behavioural assessment and post-mortem analyses. Secondly, the pharmacological identity of the group III mGlu receptor mediating this protective effect was examined. To investigate mGlu4 receptors, the novel mGlu4 selective PAM VU0155041, was also shown to provide functional neuroprotection in the 6-OHDA rat model to an almost comparable level reached with L-AP4. Whilst these neuroprotective effects are likely mediated by an inhibition of glutamate to protect from glutamate-mediated excitotoxicity, VU015504 also led to a significant reduction in levels of GFAP and IBA-1 suggesting an additional anti-inflammatory action. Further studies revealed little evidence for co-localisation of mGlu4 receptors with GFAP in the SN suggesting this anti-inflammatory component likely reflects an indirect effect via stimulation of neuronal mGlu4 receptors. Finally, to investigate mGlu7 receptors, the selective allosteric agonist AMN082, was also shown to protect the nigrostriatal tract and demonstrate a degree of preservation of motor function. In contrast, mGlu8 receptor activation using the selective agonist DCPG, failed to protect the nigrostriatal tract or preserve motor behaviour. Collectively, these findings demonstrate that, of the group III mGlu receptors investigated, mGlu4 offers the most potential as a promising target for establishing disease modification in PD.
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