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.
Highlights
Aging is a complicated multifactorial process causing a gradual decline in physiological function and the capability of an organism to survive
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 results showed that Prob treatment did not affect body weight and food consumption of mice, suggesting that Prob treatment did not affect the general appearance of mice (Figure 1B and 1C)
Summary
Aging is a complicated multifactorial process causing a gradual decline in physiological function and the capability of an organism to survive. Increasing evidence demonstrate that elevated oxidative stress in central nerve system (CNS) has been implicated to neuronal dysfunction in different kinds of age-related neurodegenerative disorders [2], such as Alzheimer’s disease (AD) [3] and Parkinson's disease (PD) [4]. It is well known that Keap1/Nrf signaling pathway plays a vital role in www.aging-us.com protecting cells from oxidative damage [9, 10]. Increasing evidence has shown that Keap1/Nrf signaling is associated with the pathology of neurodegenerative disorders [11]. Pharmacological activation of Nrf or elevation of Nrf expression by lentiviral ameliorates the phenotypes of AD and PD [12], implying that Keap1/Nrf signaling may serve as a potential target against age-related CNS disorders
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