Tetramethylpyrazine ameliorates systemic streptozotocin-induced Alzheimer-like pathology

Diabetes mellitus (DM) and its complications are the main threats to the global disease burden. DM-related cognitive dysfunction is a progressive neurodegenerative disease, similar to Alzheimer's disease (AD). The underlying pathophysiology remains unclear, and an effective treatment is unavailable. Tetramethylpyrazine (TMP) is a bioactive ingredient extracted from the plant Ligusticum wallichii, which has anti-diabetic and neuroprotective properties. In this study, streptozotocin (STZ) injection was used to establish a mouse STZ-AD model, and TMP was administered through the lateral ventricle (ICV) to evaluate the effects of TMP on cognitive ability and neurochemical changes and to explore the underlying cellular and molecular mechanisms. Using MWM and Y-maze behavioral paradigms, we observed that TMP protected against STZ-induced learning and memory impairment. STZ promoted the deposition of amyloid plaques, activation of glial cells, loss of neurons and synapses, and reduction of synaptic plasticity. In contrast, TMP restored these aberrations and improved cognitive deficits in STZ-induced diabetic animals. Moreover, TMP attenuated hippocampal mitochondrial dysfunction and oxidative stress through modulation of the SIRT1/Nrf2/ HO-1 pathway. This evidence shows that TMP exerts its therapeutic effects through multiple pathways. Our study provides new insights into the neuroprotective effects of TMP for the treatment of diabetes-related cognitive failure.