RAGE Inhibitors in Neurodegenerative Diseases

Abstract

Nonenzymatic reactions of reducing sugars with primary amino groups of amino acids, proteins, and nucleic acids, followed by oxidative degradations would lead to the formation of advanced glycation endproducts (AGEs). The AGEs exert multifactorial effects on cell damage leading to the onset of neurological disorders. The interaction of AGEs with the receptors for advanced glycation endproducts (RAGE) contribute to the activation of intracellular signaling and the expression of the pro-inflammatory transcription factors and various inflammatory cytokines. This inflammatory signaling cascade is associated with various neurological diseases, including Alzheimer’s disease (AD), secondary effects of traumatic brain injury (TBI), amyotrophic lateral sclerosis (ALS), and diabetic neuropathy, and other AGE-related diseases, including diabetes and atherosclerosis. Furthermore, the imbalance of gut microbiota and intestinal inflammation are also associated with endothelial dysfunction, disrupted blood–brain barrier (BBB) and thereby the onset and progression of AD and other neurological diseases. AGEs and RAGE play an important role in altering the gut microbiota composition and thereby increase the gut permeability and affect the modulation of the immune-related cytokines. The inhibition of the AGE–RAGE interactions, through small molecule-based therapeutics, prevents the inflammatory cascade of events associated with AGE–RAGE interactions, and thereby attenuates the disease progression. Some of the RAGE antagonists, such as Azeliragon, are currently in clinical development for treating neurological diseases, including AD, although currently there have been no FDA-approved therapeutics based on the RAGE antagonists. This review outlines the AGE–RAGE interactions as a leading cause of the onset of neurological diseases and the current efforts on developing therapeutics for neurological diseases based on the RAGE antagonists.

A Fisetin Delivery System for Neuroprotection: A Co-Amorphous Dispersion Prepared in Supercritical Carbon Dioxide

“…With its documented neuroprotective and antioxidant properties, supplementation with fisetin emerges as a strategic and promising intervention. Fisetin's multifunctional effects on AGEs inhibition, its role in disrupting RAGE-ligand interactions, and its impact on gut microbiota collectively position it as a valuable candidate for preventing neurodegenerative diseases [23]. This aligns with the broader strategy of supplementing dietary polyphenols to modulate the AGEs-RAGE and microbiota-gut-brain axes, presenting a holistic and forward-thinking approach to neuroprotection.…”

Erjingwan and Alzheimer’s disease: research based on network pharmacology and experimental confirmation

“…Interestingly, RAGE can also facilitate the transport of Aβ across the blood-brain barrier (BBB) into the brain. Additionally, AGE-RAGE binding triggers the activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, leading to increased production of reactive oxygen species (ROS), malondialdehyde (MDA), and superoxide anion, thus exacerbating oxidative stress and AGE levels ( Reddy et al, 2023 ). Studies have shown that overexpression of proteins in the AGEs/RAGE/NF-κB pathway in the brains of SD rats injected with lipopolysaccharide (LPS) results in elevated levels of IL-1β, IL-6, and TNF-α, alongside increased oxidative stress ( Li et al, 2022 ).…”

Plasma Concentrations of High Mobility Group Box 1 Proteins and Soluble Receptors for Advanced Glycation End-Products Are Relevant Biomarkers of Cognitive Impairment in Alcohol Use Disorder: A Pilot Study

“…In fact, HMGB-1 and sRAGE have been described to correlate inversely in the blood circulation of healthy individuals [ 51 ]. As a brain aging hallmark under pathological conditions, reduced levels of sRAGE have been specifically described to be a risk biomarker of neurodegenerative conditions [ 52 ], including mild cognitive impairment, early cognitive decline in type-2 diabetes, AD, and vascular dementia, among others [ 28 , 29 , 30 , 31 , 32 , 53 ]. However, increased sRAGE levels were also described to prevent harmful effects of HMGB1–RAGE interaction as an antioxidant response to the amplification of pathological pro-inflammatory processes and exacerbated oxidative stress conditions [ 31 , 54 ].…”