ZiBuPiYin recipe ameliorates diabetes-associated cognitive decline by improving neuronal mitochondrial function in chronic psychologically stressed zucker diabetic fatty rats

Zibu Piyin Recipe (ZBPYR) is a traditional Chinese medicine compound composed of 12 kinds of Chinese herbal medicines including red ginseng and yam. Long-term basic and clinical applications have proved that ZBPYR can prevent and treat cognitive dysfunction. Previous studies showed that chronic psychological stress can increase the risk of type 2 diabetes mellitus (T2DM), and lead to cognitive decline. Mitochondrial dysfunction plays a key role in chronic psychological stress-induced diabetes mellitus. While the mechanism of mitochondrial dysfunction and insulin resistance in diabetes-associated cognitive decline (DACD) is unclear.Our previous research found that a ZiBuPiYin recipe (ZBPYR) has significant pharmacological effects against DACD. The present study investigated changes in mitochondrial dysfunction in the brain and the mechanism of insulin resistance and mitochondrial damage to explore the relationship between neuronal mitochondrial dysfunction and insulin resistance in chronic psychologically stressed DACD rats.Zucker diabetic fatty (ZDF) rats with spontaneous T2DM and rats with diabetic cognitive impairment that was induced by chronic psychological stress were used in in vivo experiments. PC12 cells that were damaged by rotenone were used for the in vitro experiment.The findings indicated that the number of mitochondria decreased, morphology and membrane potential were damaged, and reactive oxygen species increased in the cortex and hippocampus in psychologically stressed DACD rats. Protein kinase Cβ2 (PKCβ2) activation and insulin resistance were markedly induced by chronic psychological stress, together with decreases in peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) and mitochondrial fusion protein 2 (Mfn2). Furthermore, ZBPYR exerted protective effects both in in vivo and in vitro.Mitochondrial damage and insulin resistance were observed in the brain in chronic psychologically stressed DACD rats. The ZBPYR significantly improved brain mitochondrial damage and insulin resistance in chronic psychologically stressed DACD rats. These results provide novel insights for the development of ZBPYR as a traditional Chinese medicine for the treatment of chronic psychological stress and DACD.