Diabetes accelerates memory dysfunction in a continuous, slowly pathological process. Studies suggest that the time course of certain biomarkers can characterize the pathological course of the disease to provide information for early intervention. Thus, there is an urgent need for validated biomarkers to characterize the cognitive impairment induced by DM. We aimed to detect changes in cerebrospinal fluid biomarkers such as amyloid β42, phosphorylated tau protein, interleukin 6, and acetylcholine in diabetic rats over time, and to analyse the relationship between diabetes and cognitive impairment. Rats were injected once intraperitoneally with 1% of streptozotocin to establish a diabetic model. Index changes were investigated longitudinally and all were measured at the end of the experiment at day 75. Aβ42, P-tau, IL-6, and ACh levels in CSF, insulin levels in plasma, and Aβ42 levels in plasma and brain tissue were measured by ELISA. Compared with control, the diabetic model showed ACh in CSF to be decreased by day 15, continuing lower out to day 75. Aβ42 changes in brain and blood showed the same trends but exhibited minima at different time points: day 30 in CSF and day 15 in plasma. After the minimum, Aβ42 in cerebrospinal fluid rose and levelled off lower than in the control group, whereas Aβ42 in plasma rose and went above the controls at day 30, slowly trending upwards for the remainder of the experiment. P-tau protein in CSF in diabetic rats showed an increasing trend, becoming significantly different from the controls at day 60 and day 75. Aβ42 in CSF was strongly negatively correlated with blood glucose at day 15 and was negatively correlated with insulin in serum, particularly at day 45. Our longitudinal research model suggest that changes in the measured biomarkers appear before learning and memory impairments do. Aβ42 and ACh in the diabetes model group clearly changed from day 0 to day 45, and then P-tau and IL-6 varied significantly from day 45 to day 75. The reduced ACh levels observed possibly correlated with the factors common to changes in Aβ42, P-tau, and IL-6.

Background: Long-term diabetes mellitus may precipitate severe complications, including cognitive dysfunction. Existing research has shown that diabetic cognitive impairment (DCI) in rats is characterized by memory deterioration and a disordered arrangement of hippocampal cells. The Shichangpu–Xiyangshen herb pair (SX) effectively improved the pathological changes induced by DCI. However, the role of SX in regulating the physiological and behavioral responses to DCI remains unclear. Methods: We sought to determine the small-molecule metabolites of cerebrospinal fluid (CSF) and delineate the pathways to elucidate the potential mechanism of the effect of SX in the treatment of DCI by metabolomics strategies, focusing on key mechanisms. Behavioral assessments were conducted on DCI rats and the rats treated with SX, as well as an evaluation of neuronal morphology in the hippocampal region. Metabolomics was used to analyze biomarkers in cerebrospinal fluid at different time points during the development of DCI, to uncover the underlying core mechanisms of DCI, and to investigate the regulatory effects of SX on these core mechanisms. The mechanisms of SX on DCI were investigated using quantitative reverse transcription polymerase chain reaction, immunohistochemistry, Western blot, and ELISA. Results: The Morris water maze (MWM) and social interaction test results revealed that SX administration effectively counteracted cognitive impairments in rats with DCI while simultaneously diminishing pathological damage in the CA1, CA3, and DG hippocampal regions. Further analysis showed that SX restored the significantly reduced levels of IL-8, ROX, and TNF-α, and reduced Aβ plaque formation (as indicated by APP and BACE1 protein expression). Simultaneously, SX markedly ameliorated arachidonic acid metabolic disorders in DCI, including significant reductions in arachidonic acid (AA), PGE2, and LTB4 and reduced expression of COX-2 (PTGS2) and 5-LOX (ALOX-5). Conclusions: Our findings indicate that SX effectively counteracted cognitive impairment in rats with DCI by inhibiting AA metabolism through both cyclooxygenase and lipoxygenase pathways, thereby minimizing neuronal damage.