Probucol, a “non-statin” cholesterol-lowering drug, ameliorates D-galactose induced cognitive deficits by alleviating oxidative stress via Keap1/Nrf2 signaling pathway in mice

Abstract

Oxidative stress plays a vital role in the initiation and progression of age-related neurodegenerative diseases. Ameliorating oxidative damage is therefore considered as a beneficial strategy for the treatment of age-related neurodegenerative disorders. Probucol (Prob), a lipid-lowering prototype agent, was reported to treat cardiovascular diseases, chronic kidney disease and diabetes mellitus. However, whether Prob has an effect on age-related neurodegenerative diseases remains unknown. In the study, it was found that Prob ameliorated D-galactose (D-gal) induced cognitive deficits and neuronal loss in the hippocampal CA1 region. Moreover, Prob alleviated ROS and MDA levels by elevating SOD, GSH-PX and HO-1 mRNA and protein expressions, and improving plasmic and cerebral SOD and GSH-PX activities in D-gal treated mice. Furthermore, Prob promoted the dissociation of Keap1/Nrf2 complex leading to the accumulation of Nrf2 in nucleus, implying that the improved anti-oxidant property of Prob is mediated by Keap1/Nrf2 pathway. The study firstly demonstrates the favorable effects of Prob against cognitive impairments in a senescent mouse model, rendering this compound a promising agent for the treatment or prevention of age-related neurodegenerative disease.

The Combination Treatment of Curcumin and Probucol Protects Chondrocytes from TNF‐α Induced Inflammation by Enhancing Autophagy and Reducing Apoptosis via the PI3K‐Akt‐mTOR Pathway

“…At present, some cholesterol regulatory drugs can inhibit the synthesis of cholesterol, thus, being of potential therapeutic significance for OA [ 26 ]. Curcumin and probucol were both reported as cholesterol regulators [ 27 , 28 ]. Specifically, curcumin can inhibit cholesterol metabolism, while probucol can be used to treat atherosclerosis by inhibiting TNF- α -induced cholesterol metabolism [ 29 ].…”

Cullin3 Aggravates The Inflammatory Response of PDLSCs Via Regulation of Shh Signaling and Nrf2

“…In addition, Keleh-like ECHassociated protein 1 (Keap1) could interact with Cullin3, mediating the ubiquitination and degradation of NF-E2-related factor2 (Nrf2) (18,19). Keap1/Nrf2 is a crucial signaling pathway that orchestrates in ammation and oxidative stress (20,21). In this study, we aimed to illustrate the roles of Shh signaling pathways in LPS-induced PDLSCs and evaluate the effect of Cullin3 in the in ammatory process.…”

Ginsenoside Rg1 improves pathological damages by activating the p21‑p53‑STK pathway in ovary and Bax‑Bcl2 in the uterus in premature ovarian insufficiency mouse models

“…However, it remains unknown whether senescence of the reproductive system can be delayed by Rg1 by enhancing the anti-oxidation pathway in a D-galactose (D-gal)-induced rodent aging model. D-gal is an agent that has been widely recognized to induce aging and has been previously used for the establishment of animal models of aging in various organs (19,20). To date, ~400 articles have been reported using this model.…”

“…The mechanisms underlying POI would likely be revealed by investigating individuals with galactosemia (22). Continuous injection of D-gal elevates galactose levels, leading to the further accumulation of free radicals and subsequent oxidative damage, resulting in the acceleration of the aging process of cells (20). The mechanism of this type of aging process is similar to that of natural aging (23).…”

“…D-gal is an agent that has been widely recognized to induce aging and has been previously used for the establishment of animal models of aging in various organs ( 19 , 20 ). To date, ~400 articles have been reported using this model.…”