Neuroprotective effects and mechanisms of the activation of group III metabotropic glutamate receptor in rodent models of Parkinson's Disease.

Abstract

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.