Systematic review and meta-analysis of Kai-xin-san in animal models of Alzheimer's disease

ContextAlzheimer’s disease (AD) is the most common neurodegenerative disorder, which is associated with impaired cognition. Kai-xin-san (KXS), a classic Chinese herbal formula, has been widely used to treat cognitive disorders.ObjectivesThis study aimed to investigate the therapeutic potential and underlying mechanisms of KXS for AD.MethodsA systematic search of 7 databases was conducted from inception to October 2025, with language restrictions in both Chinese and English. Behavior and biomarkers were assessed as measures of efficacy and mechanism. The risk of bias was assessed by the SYRCLE’s risk of bias tool. The meta-analysis was performed by STATA version 15.0 software packages and RevMan 5.4 software. Subgroup, meta-regression, and sensitivity analyses were used to ascertain the robustness of primary analyses, Egger’s test and funnel plots were used to assess potential publication bias, and the evidence of evidence was assessed by the modified GRADE approach.ResultsThis study included 44 studies, involving a total of 2,681 animals, 3 behavioral tests, such as Morris water maze (MWM), novel object recognition (NOR), Y maze, and 9 biomarkers, such as β-amyloid peptide (Aβ), tau protein, tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6), malondialdehyde (MDA), superoxide dismutase (SOD), acetylcholinesterase (AchE), and acetylcholine (ACh). KXS could significantly shorten escape latency from the target quadrant, and elevate entry frequency into the target quadrant and time spent in the target quadrant in MWM; meanwhile, KXS could also significantly enhance the relative recognition index in NOR, and improve spontaneous alternation performance in Y-maze. Moreover, KXS could decrease Aβ, tau and AchE in the hippocampus, and TNF-α, IL-1β, IL-6, and MDA in both serum and hippocampus, while increase ACh in the hippocampus and SOD in both serum and hippocampus.ConclusionThese findings suggest that KXS may alleviates cognitive deficits in AD animal models, which may be attributed to its modulation of multiple mechanisms, including Aβ and tau pathology, inflammation, oxidative stress, and cholinergic function. However, due to the high risk of bias, indicating that the true effects of KXS may be smaller than those reported. Therefore, high-quality preclinical studies are essential before clinical efficacy can be considered.