Shichangpu–Xiyangshen Herb Extract Alleviates Cognitive Dysfunction in Type 1 Diabetes Through Metabolism of Arachidonic Acid Cyclooxygenase and Lipoxygenase

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.