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

doi:10.3389/fphar.2020.00183

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 (mGlu2/3 receptors), which can decrease excitatory glutamate neurotransmission, provides an opportunity to slow down the degeneration of the dopaminergic system. However, the roles of mGlu2/3 receptors in relation to PD pathology were partially recognized. By using mGlu2/3 receptors agonist (LY354740) and mGlu2/3 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 mGlu2/3 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 mGlu2/3 receptors ligands could influence MPTP-induced toxicity, which supported a role for mGlu2/3 receptors in PD pathogenesis.

Highlights

Parkinson’s disease (PD) is a common neurological disorder characterized by degeneration of dopaminergic neurons in the substantia nigra (SN) (Przedborski, 2017)
Excitatory neurons of the subthalamic nucleus send glutamatergic projections to dopaminergic neurons of the substantia nigra pars compacta (SNc), which may contribute to the excitotoxic damage to SNc neurons in PD models (Conn et al, 2005; Duty, 2012; Sebastianutto and Cenci, 2018)
Consideration of mitochondrial respiration deficits and subsequent cellular oxidative stress caused by MPTP, dopaminergic neurons of SNc may not be able to cope with elevation of intracellular Ca2+ followed by extracellular glutamatergic stimulation (Jiang and Dickson, 2018)

Summary

Introduction

Parkinson’s disease (PD) is a common neurological disorder characterized by degeneration of dopaminergic neurons in the substantia nigra (SN) (Przedborski, 2017). MPTP rodent models recapitulate many aspects of the disease and are important tools to investigate the biological fundaments of PD (Meredith and Rademacher, 2011). Studies showed impaired glutamate homeostasis in vivo following MPTP treatment (Robinson et al, 2003; Meredith et al, 2009). Due to the compromise of mitochondrial respiration following MPTP exposure, dopaminergic neurons may not be able to cope with even low levels of glutamate stimulation and subsequent Ca2+ influx (Meredith and Rademacher, 2011). Mechanisms which maintain low concentrations of glutamate in PD models are essential for normal brain function

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Results

Conclusion