Ameliorative effect and underlying mechanism of the Xiaxue Kaiqiao formula on age-related dementia in Samp8 mice

Background: Dementia, a major symptom of several neurodegenerative diseases, can be improved by acetylcholinesterase inhibitors (AChE); however, due to the complex etiology and long course of dementia, the efficacy of these drugs remains limited. Significant empirical evidence shows that traditional Chinese medicine (TCM) markedly ameliorates intractable disease; nevertheless, a suitable regimen has yet to be widely accepted, which is likely the result of gaps in the understanding of its causality. We propose that taking advantage of the TCM theory of collateral activation and prevention of accumulation by purgation may improve dementia treatment; thus, we designed the Xiaxue Kaiqiao formula (XKF) accordingly. Purpose: To explore the ameliorative effect and underlying mechanism of XKF on dementia in a Samp8 mouse model. Methods: Samp8 mice were treated with XKF for eight weeks, and the amelioration of dementia was subsequently assessed using the novel object recognition, Barnes maze, and open-field behavioral tests. Neuropathological alterations were observed by immunofluorescence (IF) and Golgi staining of brain tissue. Drug safety was evaluated by blood biochemical tests, organ coefficients, and hematoxylin-eosin (H&E) staining. Proteomics analysis was performed on frozen brain tissue using liquid chromatography-tandem mass spectrometry (LC-MS/ Results: Behavioral testing revealed that the administration of XKF had significant ameliorative effects on memory discrimination, spatial learning memory, and anxiety in Samp8 mice. IF staining showed that XKF reduced the loss of postsynaptic density protein 95 (PSD95), myelin, neurons, and axons, as well as decreased the proliferation of astrocytes and microglia in the hippocampal and temporal lobe regions. Evaluation of drug safety demonstrated no abnormal organ morphology following XKF treatment. Conclusion: XKF treatment improved the symptoms of dementia in Samp8 mice, indicating the potential for clinical application. The mechanism underlying the ameliorative effect of XKF on dementia is likely increased synaptic transmission between neurons. Our data provide reliable evidence for the TCM theory of collateral activation and prevention of accumulation by purgation.