Journal
FRONTIERS IN PHARMACOLOGY
Volume 11, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fphar.2020.00183
Keywords
Parkinson's disease; 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; metabotropic glutamate receptor; NMDA receptor; Fyn kinase; Polo-like kinase; pS129 alpha-synuclein
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Funding
- National Natural Science Foundation of China [81974200, 81171193, 81671108, 81873734]
- National Key R&D Program of China [2017YFC1310300]
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Glutamate overactivity in basal ganglia critically contributes to the exacerbation of dopaminergic neuron degeneration in Parkinson's disease (PD). Activation of group II metabotropic glutamate receptors (mGlu(2/3) receptors), which can decrease excitatory glutamate neurotransmission, provides an opportunity to slow down the degeneration of the dopaminergic system. However, the roles of mGlu(2/3) receptors in relation to PD pathology were partially recognized. By using mGlu(2/3) receptors agonist (LY354740) and mGlu(2/3) receptors antagonist (LY341495) in mice challenged with different cumulative doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), we demonstrated that systemic injection of LY354740 reduced the level of extracellular glutamate and the extent of nigro-striatal degeneration in both acute and sub-acute MPTP mice, while LY341495 amplified the lesions in sub-acute MPTP mice only. LY354740 treatment improved behavioral dysfunctions mainly in acute MPTP mice and LY341495 treatment seemed to aggravate motor deficits in sub-acute MPTP mice. In addition, ligands of mGlu(2/3) receptors also influenced the total amount of glutamate and dopamine in brain tissue. Interestingly, compared with normal mice, MPTP-treated mice abnormally up-regulated the expression of polo-like kinase 2 (PLK2)/pS129 alpha-synuclein and phosphorylation of Fyn/N-methyl-D-aspartate receptor subunit 2A/2B (GluN2A/2B). Both acute and sub-acute MPTP mice treated with LY354740 dose-dependently reduced all the above abnormal expression. Compared with MPTP mice treated with vehicle, mice pretreated with LY341495 exhibited much higher expression of p-Fyn Tyr416/p-GluN2B Tyr1472 and PLK2/pS129 alpha-synuclein in sub-acute MPTP mice models. Thus, our current data indicated that mGlu(2/3) receptors ligands could influence MPTP-induced toxicity, which supported a role for mGlu(2/3) receptors in PD pathogenesis.
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