No abstract

Diabetic encephalopathy is a common consequence of diabetes mellitus that causes cognitive dysfunction and neuropsychiatric disorders. Praeruptorin C (Pra‐C) from the traditional Chinese medicinal herb Peucedanum praeruptorum Dunn. is a potential antioxidant and neuroprotective agent. This study was conducted to investigate the molecular mechanisms underlying the effect of Pra‐C on diabetic cognitive impairment. A novel object recognition test and the Morris water maze test were performed to assess the behavioral performance of mice. Electrophysiological recordings were made to monitor synaptic plasticity in the hippocampus. A protein–protein interaction network of putative Pra‐C targets was constructed, and molecular docking simulations were performed to predict the potential mechanisms of the action of Pra‐C. Protein expression levels were detected by western blotting. Pra‐C administration significantly lowered body weight and fasting blood glucose levels and alleviated learning and memory deficits in type 2 diabetic mice. Network pharmacology and molecular docking results suggested that Pra‐C affects the PI3K/AKT/GSK3β signaling pathway. Western blot analysis confirmed significant increases in phosphorylated PI3K, AKT, and GSK3β levels in vivo and in vitro upon Pra‐C administration. Pra‐C alleviated cognitive impairment in type 2 diabetic mice by activating PI3K/AKT/GSK3β pathway.

IntroductionFerroptosis has recently been recognized as a new cause of ischemia reperfusion injury due to blood–brain barrier (BBB) disruption followed by secondary iron‐loaded transferrin (TF) influx. As a novel and independent cell death pathway, ferroptosis was characterized by iron‐dependent lipid peroxidation, decline of GSH, GPX4, and shrinking mitochondria. Cottonseed oil (CSO), a liposoluble solvent, can alleviate ischemia stroke injuries and oxidative stress. However, the effect of CSO on ischemic stroke–induced ferroptosis has not been explored. In this study, we investigated the effect of CSO on ferroptosis caused by cerebral ischemic injury in rats.MethodsWe conducted the subcutaneous injection of 1.3 mL/kg CSO every other day for 3 weeks on rats with middle cerebral artery occlusion–reperfusion (MCAO‐R) injury. We used Garcia Test, TTC staining, HE, Nissl and NeuN staining, Evans blue test, 68Ga‐citrate PET, Western blot, immunofluorescence staining, Elisa kits, and transmission electron microscopy to detect the infarct volume, neural injuries, and ferroptosis‐related indexes.ResultsCSO treatment could significantly ameliorate MCAO‐R‐induced neurological dysfunction in a male rat model. Furthermore, it reduced infarct volume and neuronal injuries; protected BBB integrity; reduced the influx of iron ion, TF, and TF receptors; up‐regulated anti‐ferroptosis proteins (GPX4, xCT, HO1, FTH1), while down‐regulating ferroptosis‐related protein ACSL4; increased the activity of GSH and SOD; and decreased MDA and LPO levels. Mitochondrial destruction induced by ischemic stroke was also alleviated by CSO treatment.ConclusionCSO treatment can alleviate ischemic stroke injury via ferroptosis inhibition, which provides a new potential therapeutic mechanism for CSO neuroprotection against ischemic stroke.