Metformin protects against neuroinflammation through integrated mechanisms of miR-141 and the NF-ĸB-mediated inflammasome pathway in a diabetic mouse model.

The brain responds to diabetic stress by inducing the inflammatory response. Under normal circumstances this process is tightly regulated. However, uncontrolled inflammatory responses lead to compromised function and eventual neurodegeneration. The microRNA (miR)-200 family, specifically miR-141, is differentially expressed in diseased states including cognitive decline, thereby triggering changes in downstream genes. We hypothesised that Metformin (MF) regulates the miR-141/protein phosphatase 2A (PP2A) axis, and associated NF-ĸB-mediated inflammasome expression in diabetic mice brain. Diabetes was induced by intraperitoneal injection of Streptozotocin (STZ), thereafter mice were treated with MF (20 mg/kg BW). Whole brain tissue was harvested for further analysis. In silico analysis showed that Sirt1 and PP2A are prediction targets of miR-141. Selected protein and gene expressions were established through western blotting and qPCR, respectively. Diabetic mice brain tissue demonstrated overexpression of miR-141 and related pro-inflammatory factors as well as decreased PP2A gene expression. MF was able to counteract this by regulating expression of miR-141, PP2A, and p-tau at Ser396 protein expressions. Further experimentation revealed MF's inhibitory action on the inflammasome system by regulating the expression of the upstream controller NLRP3, related cytokines and NF-κB signalling pathway. Collectively, we demonstrate that MF promotes neuroprotection in diabetic mice by dampening inflammatory responses through its inhibitory effects on various signalling pathways. CATEGORIES: Inflammation and Immunopharmacology, Metabolic Disorders and Endocrinology, Neuropharmacology.