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

More than 463 million people worldwide suffer from diabetes. One third of diabetics patients are >65 years old, and by 2045, the number of affected individuals may increase to 700 million. T2DM is the most common type of diabetes, accounting for 90% of all diabetes cases (International Diabetes Federation, 2019). Recent epidemiological studies indicated that DM is an independent risk factor for the development of cognitive dysfunction (Biessels and Despa, 2018; Cukierman et al., 2005; Holman et al., 2015; Simó et al., 2017; Spauwen et al., 2013; Nakadate et al., 2008). DACD is a brain injury that is induced by DM, a major symptom of which is cognitive impairment (Moheet et al., 2015; Biessels et al., 2008). The following theories of the pathogenesis of DACD have been put forward: cerebral insulin resistance, cerebrovascular vascular and vascular endothelial dysfunction, mitochondrial damage, oxidative stress, calcium homeostasis imbalance, the inflammatory reaction and non-enzymatic protein glycosylation (Moheet et al., 2015; McCrimmon et al., 2012). The mechanism of chronic psychological stress-induced DM mainly involves emotional circuits in the hypothalamus and limbic system, inducing insulin resistance that leads to higher blood sugar levels. The interaction between neurons, glial cells and endothelial cells plays a major role in energy supply, involving changes of neuronal activity. Mitochondrial dysfunction plays a significant role in this process (Hackett and Steptoe, 2017; Umegaki, 2014; Qi et al., 2013). However, the mechanism by which they participate in DACD remains unclear.

At present, there is still no recognized effective treatment for diabetes-associated cognitive decline (DACD). In traditional Chinese medicine (TCM), DACD belongs to “thirst” (Xiao-ke, in Chinese) combined with “forgetfulness” (Jian-wang, in Chinese) or “dementia” (Dai-zheng, in Chinese). High-efficiency and low-toxicity of TCM, which has the merit of providing multiple pharmacological effects on multiple targets, indicate the feasibility of treatment for DACD. Clinical practice has found that DACD is closely related to Spleen-Yin deficiency syndrome in TCM, so this study chooses ZiBuPiYin recipe (ZBPYR) to treat DACD. ZBPYR is a traditional Chinese medicine formula, which was recorded in the book of Bujuji written by Wu Cheng in the Qing dynasty. And the ZBPYR is derived from the Zicheng Decoction for the clinical treatment of cognitive impairment (Zhu et al., 2014; Bi et al., 2020). In this study, ZBPYR was used to treat DACD based on the theory of “Treating from the Spleen”. The establishment of the DACD animal model is caused by emotional stress, that is, DACD is caused by “Spleen in Storing Idea and Charge of Thought” and “Thinking-Impairing-Spleen”. Based on years of clinical experience, our research group found that ZBPYR can not only improve the symptoms of cognitive impairment such as amnesia and dementia in clinical patients but also improve the cognitive function of Spleen-Yin deficiency dementia rats, aging rats, ZDF rats, diabetic rats induced by high-fat feeding combined with streptozotocin (STZ) injection and db/db mice (Zhou, 2019). Previous studies showed that learning and memory abilities in a rat model of dementia and rats with DACD were improved by the ZBPYR, which was related to improvements in insulin resistance in the brain, the amelioration of endoplasmic reticulum stress, and regulation of the production and degradation of amyloid β and intestinal flora (Chen et al., 2014, 2017; Shi et al., 2011; Zhu et al., 2014; Bi et al., 2020, 2022; Sun et al., 2016; Gu et al., 2016, 2017; Kelly and Ismail, 2015; Liang et al., 2015).

PGC-1α can enhance aerobic respiratory function in different tissues and cells (Chen et al., 2022), which is closely related to the occurrence of metabolic diseases, such as obesity and DM (Sajan et al., 2016). The main function of Mfn2 is to mediate the fusion of the extracorporeal membrane of mitochondria. Mfn2 is involved in the energy metabolism of cells and has been implicated in the development of metabolic diseases, including obesity and T2DM (Zorzano et al., 2010). Reactive astrogliosis can be effectively suppressed by up-regulation of Mfn2, which might be helpful for promising therapeutic intervention of central nervous system disease characterized by glial cell-related injury (Liu et al., 2014). PGC-1α and Mfn2 in myocardial and skeletal muscle cells are involved in the regulation of mitochondrial function (Li et al., 2009; Xu et al., 2020). However, their possible participation in the pathogenesis of chronic psychological stress and DACD in the brain remains unclear.

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.

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