Huang-Pu-Tong-Qiao Formula Ameliorates the Hippocampus Apoptosis in Diabetic Cognitive Dysfunction Mice by Activating CREB/BDNF/TrkB Signaling Pathway

Abstract

Background. Huang-Pu-Tong-Qiao formula (HPTQ), a traditional Chinese medicine (TCM) formula used to improve cognitive impairment. However, the underlying neuroprotective mechanism of HPTQ treated for diabetic cognitive dysfunction (DCD) remains unclear. The purpose of this study was to investigate the neuroprotective mechanism of HPTQ in DCD mice based on molecular docking. Methods. To investigate the neuroprotective effect of HPTQ in DCD, the Morris water maze (MWM), novel object recognition (NOR) test was used to detect the learning and memory changes of mice; hematoxylin-eosin (HE) staining was used to investigate the damage of hippocampal neurons; the western blot (WB) was used to examine the level of brain-derived neurotrophic factor (BDNF) of hippocampus. To investigate the neuroprotective mechanism of HPTQ in DCD, molecular docking was used to predict the possible target proteins of different active components in HPTQ and then the WB was used to verify the expression of key target proteins in the hippocampus of mice. Results. HPTQ improved the learning and memory ability, hippocampal neuron damage, and the level of BDNF in the hippocampus of the DCD model treated with HFD/STZ for 12 weeks. Besides, the results of molecular docking showed that the main chemical components of HPTQ could be well combined with the targets of Bcl-2-associated X (Bax) and B-cell lymphoma2 (Bcl-2) and caspase-3. The levels of Bax/Bcl-2 protein ratio and caspase-3 increased in the DCD model while the HPTQ inhibited it. In addition, HPTQ restored DCD-induced decline of p-CREB, BDNF, TrkB, and p-Akt in the hippocampus. Conclusions. These data indicated that HPTQ ameliorates the hippocampus apoptosis in diabetic cognitive dysfunction mice by activating CREB/BDNF/TrkB signaling pathway.

Umbelliferone Ameliorates Memory Impairment and Enhances Hippocampal Synaptic Plasticity in Scopolamine-Induced Rat Model

“…The activation of CREB by phosphorylation is required for long-term memory formation [ 69 ]. Furthermore, CREB phosphorylation upregulates the expression of BDNF [ 70 ]. In our study, the upregulated p-CREB/CREB ratio demonstrated the association between BDNF and CREB.…”

Polyphenols and Neurodegenerative Diseases: Potential Effects and Mechanisms of Neuroprotection

“…In addition, the CREB pathway positively affects cognitive health, neuronal survival, neurogenesis, synaptic plasticity, and general neuronal activation. In this regard, polyphenols can bind to the estrogen receptor (ER) and activate neurotrophic effects through protein kinase C (PKC) pathways (path-way 2 in Figure 3 ) [ 13 , 23 , 27 , 70 , 78 , 82 , 83 , 84 , 85 ].…”

“…Another neuroprotective effect of polyphenols in the brain is the elimination of ROS. Polyphenols induce an antioxidant effect by activating protein kinases that signal molecular pathways, such as Keap1/Nrf-2/ARE, the main protection pathways against endogenous and exogenous ROS [ 84 , 85 , 86 ]. Polyphenols interact and activate receptor kinases ERK1/2, JNK, and p38 protein, to disrupt the Keap1/Nrf2 complex and allow the translocation of nuclear factor 2 (Nrf2)-related transcription factor to the nucleus, where it binds to receptors rich in adenylate and uridylate (ARE), and promotes the expression of antioxidant proteins and enzymes (GSH, GST, GPX, SOD, and CAT) (path-way 3 in Figure 3 ).…”