Taohe Chengqi decoction improves diabetic cognitive dysfunction by alleviating neural stem cell senescence through HIF1α-driven metabolic signaling

Objective

Type 2 diabetes mellitus (T2DM) is characterized by numerous long-term complications, in which progressive cognitive decline represents a significant risk factor for dementia and other neurodegenerative disorders. Taohe Chengqi decoction (THCQ) is a common traditional Chinese formula for treating T2DM; however, the neuroprotective effect of THCQ on diabetes-associated cognitive dysfunction remains unclear. Hence, the present study investigated the therapeutic effects of THCQ on cognitive impairment associated with T2DM and elucidated the underlying mechanisms.

Methods

A stable high-fat diet (HFD) and streptozotocin (STZ)-induced T2DM mouse model was established and received intragastrical THCQ administration. Blood and tissue samples were investigated for biochemical parameters and neuropathology, whereas hippocampal tissue underwent transcriptome analyses and the role of neural stem cell (NSC) senescence was detected both in vivo and in vitro. Network pharmacology analysis and subsequent primary NSC experiments were conducted to explore the involvement of the HIF1α signaling pathway in THCQ-mediated hippocampal NSC senescence. Furthermore, a lentivirus vector overexpressing HIF1α was used to verify the THCQ potential therapeutic effects on HIF1α/PDKs metabolic signaling that influenced NSC senescence.

Results

THCQ alleviated cognitive dysfunction and metabolic abnormalities in HFD/STZ mice, and relieved hippocampal neurodegeneration. Transcriptome analyses and validation experiments revealed THCQ-induced neuroprotective effects by targeting high glucose-mediated hippocampal neuropathy and NSC senescence. Bioinformatic analysis indicated that HIF1α signaling played a significant role in THCQ therapeutic outcomes; while HIF1α overexpression impaired the effects of THCQ on high glucose-induced metabolic disorders and NSC senescence.

Conclusion

The present study demonstrated that THCQ improved diabetic cognitive dysfunction and hippocampal neurogenesis, the effects of which were mainly attributed to the restoration of metabolic homeostasis and inhibition of NSC senescence through HIF1α signaling. Our results provide novel insights into the therapeutic framework for diabetic neuropathy and indicate that THCQ might be a promising candidate for the management of T2DM-related cognitive disorders.