A Novel, Multi-Target Natural Drug Candidate, Matrine, Improves Cognitive Deficits in Alzheimer’s Disease Transgenic Mice by Inhibiting Aβ Aggregation and Blocking the RAGE/Aβ Axis

Abstract

The treatment of AD is a topic that has puzzled researchers for many years. Current mainstream theories still consider Aβ to be the most important target for the cure of AD. In this study, we attempted to explore multiple targets for AD treatments with the aim of identifying a qualified compound that could both inhibit the aggregation of Aβ and block the RAGE/Aβ axis. We believed that a compound that targets both Aβ and RAGE may be a feasible strategy for AD treatment. A novel and small natural compound, Matrine (Mat), was identified by high-throughput screening of the main components of traditional Chinese herbs used to treat dementia. Various experimental techniques were used to evaluate the effect of Mat on these two targets both in vitro and in AD mouse model. Mat could inhibit Aβ42-induced cytotoxicity and suppress the Aβ/RAGE signaling pathway in vitro. Additionally, the results of in vivo evaluations of the effects of Mat on the two targets were consistent with the results of our in vitro studies. Furthermore, Mat reduced proinflammatory cytokines and Aβ deposition and attenuated the memory deficits of AD transgenic mice. We believe that this novel, multi-target strategy to inhibit both Aβ and RAGE, is worthy of further exploration. Therefore, our future studies will focus on identifying even more effective multi-target compounds for the treatment of AD based on the molecular structure of Mat.

The influence of two functional genetic variants of GRK5 on tau phosphorylation and their association with Alzheimer's disease risk

“…For the mice, the hippocampus on both sides was detached from the deep cortical layer and homogenized with RIPA complexes and cell lysis solution. The following steps were performed similarly regardless of the source of the protein (cells or tissues) as previously described [ 41 ]. The only differences were the antibody used and their dilution ratios, which included phosphorylated tau, or p-tau, (Abcam; 1:1000), tau (Cell Signaling; 1000), GRK5 (Abcam; 1:600) and beta-actin (Solarbio; 1:1000).…”

Impact of HMGB1, RAGE, and TLR4 in Alzheimer’s Disease (AD): From Risk Factors to Therapeutic Targeting

“…Moreover, several HMGB1 inhibition approaches, including TTP488, sRAGE-mesenchymal stem cells (MSCs), FPS-ZM1, matrine, pentamidine, hesperidin, and linguizhugan, have revealed promising outcomes in experimental AD models mainly by inhibiting RAGE expression, decreasing production of Aβ, reducing Aβ deposition, oxidative stress, and inflammatory cytokines, while improving spatial learning and memory (Table 2) [113][114][115][116][117][118].…”

Targeting the Receptor for Advanced Glycation Endproducts (RAGE): A Medicinal Chemistry Perspective

“…In AD transgenic mice model studies, 14 (ip 100 mg/kg) is transported across the BBB, reduces brain Aβ, NF-κB, BACE1 levels, and downregulates proinflammatory cytokines (TNF-α and IL-1β) as well as attenuates memory deficits. 135 …”

“… 135 14 reduces proinflammatory cytokines and Aβ deposition, attenuating the memory deficits of AD transgenic mice. 135 Molecular docking analysis of 14 demonstrated its binding pattern to the V domain through hydrophobic interactions with Val35, Leu36, and Ile26 as well as hydrogen bonds with Lys37 ( Figure 7 ). 135 However, the three binding regions of 1 – 14 involved in the interaction with RAGE have been proposed solely based on molecular docking simulations ( Figure 7 ).…”

“… 135 Molecular docking analysis of 14 demonstrated its binding pattern to the V domain through hydrophobic interactions with Val35, Leu36, and Ile26 as well as hydrogen bonds with Lys37 ( Figure 7 ). 135 However, the three binding regions of 1 – 14 involved in the interaction with RAGE have been proposed solely based on molecular docking simulations ( Figure 7 ). Therefore, the elucidation of structures of RAGE–inhibitor complexes by X-ray or NMR should confirm the proposed binding mode and provide useful tools for future design of more stable and/or potent inhibitors.…”