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

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-1,2,3,6tetrahydropyridine (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.

Vanillic Acid, a Bioactive Phenolic Compound, Counteracts LPS-Induced Neurotoxicity by Regulating c-Jun N-Terminal Kinase in Mouse Brain

“…Previously, studies have shown that ligand/RAGE interactions activate a range of intracellular signaling pathways, including the activation of MAPKs/JNK [ 17 , 35 ]. In addition, many studies have reported that LPS treatment increases the expression level of the stress associated kinases; importantly, c-Jun N terminal kinase (p-JNK) [ 24 , 36 ].…”

“…Previously, studies have shown that ligand/RAGE interactions and activated p-JNK protein is critically involved in the upregulation of nuclear factor-kappa B (p-NF-κB; a transcription factor) [ 16 , 17 ], resulting in the production of pro-inflammatory cytokines and causing inflammation [ 37 ]. Importantly, in this regard, a considerable number of studies have also shown that systemic administration of LPS-injection increases the protein expression level of p-NF-κB and its associated neuroinflammatory markers in the initiation of neuroinflammation [ 7 , 36 ].…”

“…Studies have suggested that activation of RAGE via its ligands (ligand-RAGE interaction) triggered a complex cascade of signaling pathways events, including MAPK signaling cascade [ 17 , 52 ]. Of importance, many studies reported that RAGE triggered JNK phosphorylation [ 45 , 52 , 53 ].…”

“…Both in-vivo and in-vitro studies have shown that LPS is a well-known and potent brain macrophage stimulator, which stimulates the immune system [ 13 ] that evokes inflammatory processes in the body and has detrimental effects on many vital organs, including the brain [ 14 ]. RAGE ligation activates a range of intracellular signaling pathways, including the activation of mitogen-activated protein kinases (MAPKs)/c-Jun N-terminal kinase (JNK), or nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway in initiation of the inflammatory process [ 15 , 16 , 17 , 18 ].…”

Narcolepsy in Parkinson's disease with insulin resistance

“…RAGE gene variants have been linked to sporadic PD in an Asian population 34,35 , indicating that RAGE might play a role in the pathogenesis of PD. Moreover, silencing of the RAGE pathway in a mouse model of PD improved neuroinflammation which causes dopaminergic neurodegeneration in PD patients 36 . This is important because the deterioration of dopaminergic neurons in the brain is believed to play a critical role in the development of PD 37 .…”