RAGE Silencing Ameliorates Neuroinflammation by Inhibition of p38-NF-κB Signaling Pathway in Mouse Model of Parkinson’s Disease

Xiaoli Wang,Xiaoxuan Sun,Anmu Xie,Jing Wang,Xiaona Zhang,Chang Zhou,Mengyue Niu

doi:10.3389/fnins.2020.00353

Abstract

Accumulating evidence suggested that neuroinflammation played a crucial role in dopaminergic neuronal death in Parkinson’s disease (PD). The receptor for advanced glycation end products (RAGE), a multi-ligand receptor of the immunoglobulin superfamily, has been proposed as a key molecule in the onset and sustainment of the inflammatory response. Engagement of RAGE contributed to neuroinflammation by upregulating nuclear factor-κB (NF-κB) as well as cytokines. The aim of the present study was to investigate the expression of RAGE in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice and elucidate the RAGE signal pathway involved in the inflammation. Results showed that RAGE protein and pro-inflammatory cytokines cyclooxygenase type 2 (COX-2) were upregulated in MPTP-treated mice. Further experiments showed that RAGE ablation inhibited phosphorylation of IκB and p38 and protected nigral dopaminergic neurons against cell death in the substantia nigra (SN). These results suggested that RAGE participated in the pathogenesis of PD by neuroinflammation and p38MAPK-NFκB signal pathway may be involved in the process. Moreover, interfering with RAGE signaling pathway may be a reasonable therapeutic option in slowing PD development and progression.

Highlights

Parkinson’s disease (PD) is the second most common neurodegenerative disorder characterized by progressive loss of dopaminergic neurons and accumulation of aggregated α-synuclein in the substantia nigra (SN)
The latency time in the receptor for advanced glycation end products (RAGE)-NC group and RAGE-siRNA group had no difference compared to the control group, respectively
Further studies showed that the motor deficits of mice partly improved in the MPTP + RAGE siRNA when compared with the MPTP + RAGE-NC group (185.1 ± 17.3s vs. 95.29 ± 8.9, p < 0.05)

Summary

Introduction

Parkinson’s disease (PD) is the second most common neurodegenerative disorder characterized by progressive loss of dopaminergic neurons and accumulation of aggregated α-synuclein in the substantia nigra (SN). PD seems to result from a complicated interplay of genetic and environmental factors affecting numerous fundamental cellular processes (Lees et al, 2009; Kalia and Lang, 2015). Increasing evidence has demonstrated that neuroinflammatory mechanisms might contribute to the cascade of events leading to neuronal degeneration (Qian et al, 2010; Herrero et al, 2015). Both cerebrospinal fluid and post-mortem brain were investigated and found accumulation of pro-inflammatory cytokines, including cyclooxygenase type 2 (COX-2), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β) (Nagatsu et al, 2000; Frank-Cannon et al, 2009). Activated microglia was recently reported in the SN and putamen of PD patients

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