Relationship Between Parkinson's Disease And Metabotropic Glutamate Receptors On The Glia

Parkinson's disease (PD) is a progressive neurodegenerative disease of the central nervous system. The pathological hallmarks of PD are the loss of nigrostriatal dopaminergic neurons and the presence of intraneuronal proteinacious cytoplasmic inclusions, termed "Lewy Bodies" (LBs). Oxidative stress, mitochondrial respiration defect and excitotoxicity are three types of cellular dysfunction that play important roles in the pathogenesis of PD. Glutamate is considered as the major excitatory neurotransmitter in the central nervous system. Over-activation of glutamate receptors by elevated extracellular concentration of glutamate may cause neurotoxicity.In this study, we investigated whether activation of astroglial group II and III mGluRs could exert neuroprotection and whether the neuroprotection was related to glutamate uptake. We also detected the expression of mGluRs on C6 glioma cells and investigated the effect of group II and III mGluRs agonists on MPP+-induced glutamate uptake inhibition to confirm the research of astroglial function. Our results showed that 150 μ M MPP+ added directly to midbrain neurons couldn't increase apoptotic rate, whereas conditioned medium (CM) from astrocytes treated with 150μ M MPP+ significantly increased the apoptotic rate. After preincubation with DCG-IV, a group II mGluRs agonist, and L-AP4, a group III mGluRs agonist, for Ih, we treated te midbrain neurons with CM from astrocytes treated with 150 μ M MPP+, no decrease was observed. But CM from astrocytes pretreated with DCG-IV and L-AP4 significantly inhibited neuronal apoptosis. Toelucidate the mechanism, we investigated glutamate uptake into astrocytes by using radio-ligand binding assay method. We found that MPP+ decreased glutamate uptake of cultured astrocytes and C6 glioma cells, and this glutamate uptake inhibition was recovered by DCG-IV or L-AP4. APICA or MSOP, which was specific group II or III mGluRs antagonist respectively, completely abolished the enhancement of glutamate uptake of DCG-IV or L-AP4. Our results for the first time demonstrated that C6 glioma cells expressed receptor proteins for group I mGluRl, group II mGluR2/3, group III mGluR4, mGluR6 and mGluR7, and we confirmed that activation of astroglial mGluRs exerted neuroprotection, and the mechanism underlying this protective role was, at least partly, related to the enhancement of glutamate uptake.In conclusion, we reported for the first time activation of astroglial group II and III mGluRs could exert neuroprotection and the neuroprotection was related to glutamate uptake; C6 glioma cells expressed receptor proteins for group I mGluRl, group II mGluR2/3, group III mGluR4, mGluR6, and mGluR7.