Current therapy for PD is focused on dopamine replacement by the use of L-DOPA and
dopamine agonists, which relieve the Parkinsonian motor symptoms led by the
degeneration of dopaminergic neurons in the substantia nigra par compacta (SNc).
However, the long-term use of these agents could induce side effects and fail to slow
down the progression of the nigral dopaminergic neuronal loss. Thus, there is an
increasing demand for neuroprotective agents that can relieve the symptoms and alter
the dopaminergic neuronal death in PD. Excitotoxicity, due to the excessive glutamate
release from subthalamic nucleus (STN) to the SNc, could jeopardize the
neurodegeneration in the SNc. Thus, the modulation of the glutamate could prevent the
cellular loss in PD SNc. Accordingly, the selective ligands acting on metabotropic
glutamate receptors (mGluRs) were proved to be anti-Parkinsonian in PD models.
Furthermore, the group III mGluR agonist, L-(+)-2-amino-4-phosphonobutyric acid
(L-AP4), was proved to be neuroprotective in the 6-OHDA PD model. In this study,
therefore, the subtypes of group III mGluRs, such as mGluR4, 6, 7 and 8, was examined
in order to provide a more specific neuroprotection. Thus,
N-phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxamide (PHCCC) and
(S)-3,4-dicarboxyphenylglycine ((S)-DCPG) were utilized for the activation of
mGluR4 and 8 respectively which are expressed prevalently in basal ganglia. Herein,
the concentration-dependent and receptor mediated neuroprotection of PHCCC and
(S)-DCPG against 6-OHDA toxicity in rodent model of PD were demonstrated.
Furthermore, PHCCC and (S)-DCPG are neuroprotective when administered to animal
systemically. Moreover, the neuroprotective potential of PHCCC and (S)-DCPG were
putatively demonstrated in another PD model of lactacystin, an ubiquitin-proteasome
inhibitor. In this study, we also reported the effect of PHCCC and (S)-DCPG on the
glial cells involved in the PD models, elucidating the underlying neuroprotective
mechanism of these ligands. Thus, mGluR4 and 8 may be a promising therapeutic
target for further pharmacological development.