LY354740 Reduces Extracellular Glutamate Concentration, Inhibits Phosphorylation of Fyn/NMDARs, and Expression of PLK2/pS129 α-Synuclein in Mice Treated With Acute or Sub-Acute MPTP

Yang Tan; Yan Xu; Chi Cheng; Cong Zheng; Weiqi Zeng; Ji Wang; Xiaoqian Zhang; Xiaoman Yang; Jialing Wang; Xiaomei Yang; Shuke Nie; Xuebing Cao

doi:10.3389/fphar.2020.00183

LY354740 Reduces Extracellular Glutamate Concentration, Inhibits Phosphorylation of Fyn/NMDARs, and Expression of PLK2/pS129 α-Synuclein in Mice Treated With Acute or Sub-Acute MPTP

Front Pharmacol. 2020 Feb 28:11:183. doi: 10.3389/fphar.2020.00183. eCollection 2020.

Authors

Yang Tan¹, Yan Xu¹, Chi Cheng¹, Cong Zheng², Weiqi Zeng¹, Ji Wang¹, Xiaoqian Zhang¹, Xiaoman Yang¹, Jialing Wang¹, Xiaomei Yang¹, Shuke Nie³, Xuebing Cao¹

Affiliations

¹ Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
² Institute of Neuroscience, Chinese Academy of Sciences, Shanghai, China.
³ Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, China.

Abstract

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 α-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 α-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.

Keywords: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Fyn kinase; NMDA receptor; Parkinson’s disease; Polo-like kinase; metabotropic glutamate receptor; pS129 α-synuclein.