A SIRT1 agonist reduces cognitive decline in type 2 diabetic rats through antioxidative and anti‑inflammatory mechanisms

Abstract

Sirtuin 1 (SIRT1) is an NAD+-dependent protein deacetylase that is involved in cell differentiation, aging, apoptosis, physiological rhythms, metabolic regulation, oxidative stress and numerous other important biological processes. In the present study, the ability of a sirtuin-1 (SIRT1) agonist, SRT1720, to reduce cognitive decline in type 2 diabetes mellitus (T2DM) was investigated. Streptozotocin-induced male Sprague-Dawley rats were used to establish a T2DM model and the protective effect of SRT1720 and its underlying mechanisms were investigated. Body weight and fasting blood glucose (FBG) were recorded and cognitive function was measured with the Morris water maze. Levels of oxidative stress, inflammation, caspase-3 activity and nuclear factor κB (NF-κB) mRNA expression were detected with a series of commercial assay kits and reverse transcription-quantitative polymerase chain reaction, respectively. Western blot analysis was performed to determine the protein expression of NF-κB, endothelial nitric oxide synthase (eNOS), peroxisome proliferator-activated receptor γ (PPARγ), AMP-activated protein kinase (AMPK), heat shock 70 kDa protein (HSP70), SIRT1, nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase 1 (HO-1). The results revealed that SRT1720 significantly increased body weight, decreased FBG, improved cognitive function and reduced the levels of proteins associated with oxidative stress and inflammation damage in T2DM rats. Additionally, SRT1720 significantly decreased NF-κB p65 mRNA expression and increased eNOS and PPARγ expression. SRT1720 significantly reduced caspase-3 activity and HSP70 protein expression, and increased p-AMPK, SIRT1, Nrf2 and HO-1 protein expression. Collectively, the results indicate that SRT1720 may reduce cognitive decline in T2DM rats through antioxidative and anti-inflammatory action via NF-κB and AMPK-dependent mechanisms.

Targeting Oxidative Stress Reduction and Inhibition of HDAC1, MECP2, and NF-kB Pathways in Rats With Experimentally Induced Hyperglycemia by Administration of Thymus marshallianus Willd. Extracts

“…As NFkB modulates ROS levels and the expression of proinflammatory factors (interleukin (IL)-1, intercellular adhesion molecule 1, tumor necrosis factor α (TNF α), therefore, it can be considered to initiate the inflammatory cascade ( Wang et al, 2019 ). Previous studies also revealed that HDACi inhibits NFkB transcription, thus repressing inflammatory response ( Lu et al, 2015 ).…”

Interaction of Nuclear Receptor Subfamily 4 Group A Member 1 (Nr4a1) and Liver Linase B1 (LKB1) Mitigates Type 2 Diabetes Mellitus by Activating Monophosphate-Activated Protein Kinase (AMPK)/Sirtuin 1 (SIRT1) Axis and Inhibiting Nuclear Factor-kappa B (NF-κB) Activation

“…Nr4a1 activated sestrin 2, which in turn activated the AMPK pathway to induce glucose metabolism genes and glucose uptake in C2C12 cells [36]. In addition, SIRT1 agonist SRT1720 treatment can reduce FBG, inflammation, and oxidative stress in T2DM rats by inhibiting NF-kB and upregulating AMPK [22]. The insulin sensitivity and glucose homeostasis of adipose tissue were improved after SIRT1 activation, suggesting that SIRT1 activation is a promising new treatment for T2DM [37].…”

“…Inflammation often occurs during the development of chronic DM. SIRT1 can reduce the levels of FBG, oxidative stress, and inflammatory injury-related proteins in T2DM rats through the antioxidant and anti-inflammatory effects of NF-kB and AMPK-dependent mechanisms [22]. In light of this, we overexpressed Nr4a1 and LKB1 in T2DM rats, and observed the changes in the AMPK/SIRT1/NF-kB axis.…”

Baicalin reverse depressive‐like behaviors through regulation SIRT1‐NF‐kB signaling pathway in olfactory bulbectomized rats

“…It has been reported that SIRT1 deacetylates p65 at lysine residue 310 and inhibits the transcriptional activation of NF‐kB, thereby inhibiting the expression of inflammatory cytokines (Xie et al, ; Wang et al, ; Nishida et al, ). SIRT1 links neurodegenerative disease, psychological stress, and depression, and it has been proposed as a novel strategy for treating depression (Alageel et al, ).…”