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

Abstract

Background. Diabetes-associated cognitive decline (DACD) is one of the nervous system dysfunctions induced by diabetes mellitus with cognitive impairment as the major symptom. In a previous preliminary proteomic study, we found that endoplasmic reticulum processing and PI3K-Akt signaling pathway might be impaired in DACD pathogenesis. In addition, growth factor receptor-bound protein 2 might be a crucial protein as a molecular target of the neuroprotective effects of ZiBuPiYin recipe (ZBPYR). Methods. In this study, 6-8 weeks aged db/db mice were treated with excipients or ZBPYR for 6 weeks. Body weight and RBG were recorded weekly. Oral glucose tolerance and insulin tolerance tests were used to assess insulin sensitivity. Morris water maze (MWM) tests were used to assess memory function. The expression of Grb2, Gab2, Akt, and GSK3β in mouse hippocampus and cerebral cortex were analyzed by Western blotting. Results. ZBPYR not only significantly reduced RGB and improved glucose tolerance and insulin resistance, but also improved spatial cognition in DACD mice. The expression of Grb2 and Gab2 in hippocampus and cerebral cortex of db/db mice was upregulated after treated with ZBPYR, and then affected the PI3K/Akt signaling pathway, and inhibited GSK3β overactivity. Conclusions. This study showed that ZBPYR could enhance the memory and learning ability of db/db mice. Such neuroprotective effect might be related to the activation of Grb2-PI3K/Akt signaling which might provide a novel therapeutic target for the clinical treatment of DACD.

The Efficacy and Predictors of Using GPi-DBS to Treat Early-Onset Dystonia: An Individual Patient Analysis

“…We used SPSS 25.0 (IBM, Armonk, NY) to calculate statistics. When no obvious abnormality was found, Student's t test was used after the comprehensive normality test of D'Agostino and Pearson [ 21 ].…”

Targeting Impaired Nutrient Sensing via the Glycogen Synthase Kinase-3 Pathway With Therapeutic Compounds to Prevent or Treat Dementia: A Systematic Review

“…Twenty-two out of 32 studies tested naturally derived compounds, they include: compounds rich in flavonoids such as yuzu extract ( Yang et al, 2013 ), bee pollen extract ( Liao et al, 2019 ), N. incisum extract ( Jiang et al, 2020 ) and flavonoids of okra fruit ( Yan et al, 2021 ); compounds containing alkaloids, such as Puerariae radix ( Huang et al, 2019 ), ZiBuPiYin ( Ren et al, 2021 ), evodiamine ( Wang et al, 2018 ; Chou and Yang, 2021 ) and Peganum harmala ( Saleh et al, 2021 ); aquesous cinnamon extracts ( Madhavadas and Subramanian, 2017 ), which contain type A linked procyanidin trimer; schisandra chinensis extract ( Yan et al, 2017 ), which contains ligand diabenzo [a, c] cyclooctadiene; sea cucumber cerebrosides ( Li et al, 2019 ), which is a class of neural glycospinolipids; osthole ( Yao et al, 2019 ) which is a derivative of coumarin; curcumin ( SoukhakLari et al, 2018 ), which is the main ingredient of turmeric; litchi chinensis seed fraction ( Sun et al, 2020 ), which entails phenolic compounds and glycosides; Asiatic acid ( Ahmad Rather et al, 2019 ), which is a pentacyclic triterpenoid; Yonkenafil ( Zhu et al, 2019 ), which is a novel phosphodiesterase type 5 inhibitor and an analogue of sildenafil; 20(S)-protopanaxadiol, oleanolic acid ( Lin et al, 2021 ), which is an active compound found in ginseng and a Chinese herb gastrodin ( Wang et al, 2021 ).…”

“…Thirteen studies using natural compounds showed an overall positive effect ( Yang et al, 2013 ; SoukhakLari et al, 2018 ; Tang et al, 2018 ; Ahmad Rather et al, 2019 ; Huang et al, 2019 ; Li et al, 2019 ; Yao et al, 2019 ; Jiang et al, 2020 ; Chou and Yang, 2021 ; Ren et al, 2021 ; Saleh et al, 2021 ; Wang et al, 2021 ; Yan et al, 2021 ) on cognition, seven studies a moderately positive ( Madhavadas and Subramanian, 2017 ; Yan et al, 2017 ; Wang et al, 2018 ; Liao et al, 2019 ; Zhu et al, 2019 ; Sun et al, 2020 ; Lin et al, 2021 ) and one a negative effect ( Jiang et al, 2020 ). The effect of natural compounds on cognition were tested in dementia animal models in rat ( n = 7 out of 21 studies); mice ( n = 14 out of 21 studies), and in normal ageing animal model in mice [ n = 1 out of 1 study ( Jiang et al, 2020 )].…”

“…The GSK3 pathway can be inhibited at different stages of the nutrient sensing pathway. For the compounds osthole, sea cucumber cerebrosides, schisandra chinensis extract, brain-derived neurotrophic factor, sodium orthovanodate, diapocynin, ZiBuPiYin and flavonoids of okra fruit, GSK3β is inhibited by activation of the PI3K, and subsequent activation of Akt impaired GSK3 phosphorylation ( Yan et al, 2017 , 2021 ; Xu et al, 2018 ; Li et al, 2019 ; Yao et al, 2019 ; Akhtar et al, 2020 ; Ibrahim et al, 2020 ; Ren et al, 2021 ). The PI3K/Akt pathway is a key for regulating cell survival, growth and metabolism, which is important for cognitive function such as learning and memory ( Shu et al, 2013 ).…”

MiR-27a-3p suppresses cerebral ischemia-reperfusion injury by targeting FOXO1

“…In our study, FOXO1 was found to be targeted by miR-27a-3p. FOXO1 upregulation could inhibit the cell growth [ 11 ], while Grb2 can promote the cell proliferation [ 29 ]. Thus, the different function between FOXO1 and Grb2 might result in this discrepancy.…”