Effect of the ZiBuPiYin Recipe on Diabetes-Associated Cognitive Decline in Zucker Diabetic Fatty Rats After Chronic Psychological Stress

Abstract

Background: Cognitive impairment is a complication of type 2 diabetes mellitus (T2DM) that affects the central nervous system (CNS). Studies have shown that chronic psychological stress may promote the development of T2DM into diabetes-associated cognitive decline (DACD). Previously, cognitive impairment in T2DM was correlated predominantly with insulin resistance in the medial prefrontal cortex (mPFC). Aims:We examined the effect of the ZiBuPiYin recipe (ZBPYR) on Zucker diabetic fatty (ZDF) rats and explored the impact of chronic stress on altered b-amyloid (Ab) metabolism through insulin receptor substrate (IRS) 1/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway after the induction of chronic psychological stress.Main Methods: After chronic psychological stress and drug treatment, cognitive function was observed via behavioral experiments. The activation of the hypothalamus-pituitaryadrenal (HPA) axis and levels of Ab were detected by enzyme-linked immunosorbent assay, and the expression of related proteins was evaluated by Western blotting.Key Findings: ZBPYR treatment significantly decreased anxious-like behaviors and plasma corticosterone (CORT) levels, and ameliorated learning and memory impairments of ZDF rats after chronic psychological stress. ZBPYR also reduced the deposition of Ab in the mPFC, improved brain insulin resistance, and modulated the mTOR-autophagy pathway.Significance: ZBPYR may be a potential therapeutic application for the treatment of DACD induced by chronic psychological stress.

Neuroprotective Effects of ZiBuPiYin Recipe on db/db Mice via PI3K-Akt Signaling Pathway by Activating Grb2

“…ZiBuPiYin recipe (ZBPYR) is derived from a modification of ZiCheng decoction, a TCM recipe recorded in a TCM monograph named Bujuji written by Wu Cheng during Qing dynasty. Our preliminary study suggested that ZBPYR improved learning and memory ability in multiple animal models of diabetes [ 10 – 12 ]. We also found that ZBPYR protected hippocampal neurons against glutamate and amyloid beta-peptide- (A β -) induced neurotoxicity through blocking the serum-inducible kinase and spine-associated Rap GTPase-activating protein (SNK-SPAR) pathway [ 13 , 14 ].…”

ZiBuPiYin Recipe Prevented and Treated Cognitive Decline in ZDF Rats With Diabetes-Associated Cognitive Decline via Microbiota–Gut–Brain Axis Dialogue

“…Brain Aβ deposition is a hallmark of DACD and AD pathogenesis, as well as an important cause of cognitive decline (Sui et al, 2017). Recent studies have also confirmed the similarities between the changes seen in ZDF rats and brain samples from people with AD, namely, Aβ accumulation and insulin resistance in the brain causing neuronal injury and ultimately cognitive decline (Bi et al, 2020;Jash et al, 2020). The insulindependent IRS2-AKT signaling pathway is the main pathway of insulin resistance (Zhang L. et al, 2020).…”

“…The spatial memory ability of 15-week-old rats was performed by the MWM test as described in our previous study (Bi et al, 2020). All rats were trained in a round water pool at 22 ± 2 • C with four equal quadrants.…”

“…Compelling evidence supports the hypothesis that the interactions between TCM and gut microbiota could lead to changes in microbiota and metabolic components . ZiBuPiYin recipe (ZBPYR), an ancient TCM formula recorded in the book of Bujuji written by Wu Cheng in the Qing dynasty, is derived from Zicheng Decoction and has been widely used for the treatment of T2DM and DACD in clinical practice (Sun et al, 2016;Bi et al, 2020). Its chemical characterization, quality control standard, and pharmacokinetics have been reported in our previous studies (Zhu et al, 2014;Dong et al, 2016).…”

“…Here, we characterized the phenotype of microbiome and metabolome in ZDF rats and identified the key biomarkers and metabolic structures of ZBPYR against DACD by using a comprehensive strategy combining 16S rRNA genetic sequencing and ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS) techniques. It is worth noting that the ZDF rat is a leptin receptor-deficient model, which develops into a stable T2DM model at 9 weeks of age (Zhou et al, 2019) and has symptoms of cognitive dysfunction at 15 weeks of age (Bi et al, 2020). Leptin is involved in the development of the rat embryonic brain (Udagawa et al, 2006), and the lack of leptin receptors may not be the main cause of cognitive decline (Dinel et al, 2011).…”