Preclinical Evidence and Potential Mechanisms of Tanshinone ⅡA on Cognitive Function in Animal Models of Alzheimer Disease: A Systematic Review and Meta-Analysis

Yuanhang Rong^1,2,3Qingqing Li^2,3Yuzhong Du^2,3,4Wenting Wang^2,3Wenna Su^2,3Junlong Zhang^1,2,3*Wenbin He^2,3*

• ¹Shandong University of Traditional Chinese Medicine, Jinan, China
• ²Shanxi Key Laboratory of Chinese Medicine Encephalopathy, Shanxi University of Chinese Medicine, Jinzhong, China
• ³National International Joint Research Center for Molecular Traditional Chinese Medicine, Jinzhong, China
• ⁴Shanxi Medical University, Jinzhong, China

Background: Tanshinone ⅡA (Tan ⅡA) is a monomer from Salvia miltiorrhiza Bunge.Animal studies have shown its potential in Alzheimer's disease (AD) cognitive protection, but overall effects remain inconclusive and the multi-mechanisms have not been systematically summarized.Objective: This systematic review and meta-analysis (SR/MA) aimed to evaluate Tan ⅡA's overall effects on AD animal cognitive function and to summarize the mechanisms. Methods: Seven databases (PubMed, Embase, Web of Science, China National Knowledge Infrastructure, Chinese Biological Medical Disc, Chongqing VIP and Wanfang databases) and grey literature were retrieved. Risk of bias was evaluated following Systematic Review Center for Laboratory Animal Experiments. The mean difference (MD) or standard mean difference (SMD) with 95% confidence intervals (CI) were used to evaluate the effect of Tan ⅡA on cognitive function, neuropathology, neuroinflammation, oxidative stress, apoptosis, and neural/synaptic plasticity, with P < 0.05 considered as significant difference. The effect and potential mechanisms of Tan ⅡA were demonstrated by performing multiple subgroup analyses. Results: Nineteen studies involving 581 AD animals were identified. The included studies showed satisfactory reporting quality, but had certain risk of bias in methodology. Tan ⅡA ameliorated cognitive deficits, evidenced by reducing escape latency (MD = -17.94s, 95% CI: -22.92 to -12.96) and increasing time spent in the target quadrant (MD = 10.69s, 95% CI: 7.32 to 14.07). It attenuated neuropathological damage by reducing Aβ plaques in Tan IIA in AD Models 4 Thioflavine-S staining (SMD = -3.46, 95% CI: -5.65 to -1.26) and increasing neuronal density in Nissl staining (SMD = 2.82, 95% CI: 2.11 to 3.52) and NeuN staining (SMD = 2.89, 95% CI: 1.71 to 4.08). Tan ⅡA also demonstrated anti-inflammatory effects through downregulation of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6), and antioxidant stress properties by increasing SOD and GSH-Px while reducing ROS and MDA levels. Additionally, they exhibited anti-apoptotic effects via increasing Bcl-2/Bax ratio and decreasing Caspase-3 expression. Moreover, treatment improved neuronal/synaptic plasticity by upregulating PSD-95 and BDNF levels. Conclusion: Tan ⅡA could improve cognitive function and neuropathology through multiple mechanisms. This suggests that Tan IIA may serve as a viable candidate for the development of therapeutic strategies for AD.