Sennoside A ameliorates cognitive impairment by inhibiting USP14/ERK1/2 pathway in a mouse model of type 2 diabetes mellitus

Type 2 diabetes mellitus (T2DM) is considered a serious public health issue globally, and cognitive impairment (CI) is a severe complication in diabetic patients. Sennoside A (SA) is considered the main active ingredient of Rhubarb and is a highly promising drug for the treatment of T2DM. The study aims to assess whether SA improves cognitive impairments in T2DM mice and the its specific molecular mechanisms of action. We identified the SA effective targets and signal pathways for treating CI in T2DM by the network pharmacology method, then validated using experimental data. The key genes included in the protein-protein interaction (PPI) network are MAPK1(ERK2), CASP3(caspase-3) and postsynaptic density protein-95 (PSD95). The potential function of ubiquitin-mediated proteolysis and MAPK signaling pathway was analyzed by pathway enrichment analysis. Since ubiquitin-specific protease 14 (USP14) is emerging as a therapeutic target for T2DM, previous studies have indicated that USP14 is important for neurodevelopment and hippocampal synaptic plasticity; we were curious if the USP14/ERK1/2 pathway influences SA improves CI in T2DM mice models. Molecular docking results showed that SA had a good affinity with USP14/ERK1/2. Experimental results confirmed that SA improved glucose homeostasis, suppressed the ERS, reduced apoptosis, and attenuated Aβ formation in hippocampal CA1 and CA3 regions through the USP14/ERK1/2 pathway. The same results were acquired using IU1, a USP14 inhibitor. This study investigated the mechanism of SA in T2DM cognitive dysfunction, and provided more theoretical basis for the in-depth development and clinical promotion of SA.