Efficacy and Safety of Natural Apigenin Treatment for Alzheimer's Disease: Focus on In vivo Research Advancements

Abstract

Background: Alzheimer's Disease (AD) is the most common dementia in clinics. Despite decades of progress in the study of the pathogenesis of AD, clinical treatment strategies for AD remain lacking. Apigenin, a natural flavonoid compound, is present in a variety of food and Chinese herbs and has been proposed to have a wide range of therapeutic effects on dementia.

Objective: To clarify the relevant pharmacological mechanism and therapeutic effect of apigenin on animal models of AD.

Methods: Computer-based searches of the PubMed, Cochrane Library, Embase, and Web of Science databases were used to identify preclinical literature on the use of apigenin for treating AD. All databases were searched from their respective inception dates until June 2023. The meta-analysis was performed with Review manager 5.4.1 and STATA 17.0.

Results: Thirteen studies were eventually enrolled, which included 736 animals in total. Meta-analysis showed that apigenin had a positive effect on AD. Compared to controls, apigenin treatment reduced escape latency, increased the percentage of time spent in the target quadrant and the number of plateaus traversed; apigenin was effective in reducing nuclear factor kappa-B (NF-κB) p65 levels; apigenin effectively increased antioxidant molecules SOD and GSH-px and decreased oxidative index MDA; for ERK/CREB/BDNF pathway, apigenin effectively increased BDNF and pCREB molecules; additionally, apigenin effectively decreased caspase3 levels and the number of apoptotic cells in the hippocampus.

Conclusion: The results show some efficacy of apigenin in the treatment of AD models. However, further clinical studies are needed to confirm the clinical efficacy of apigenin.

Keywords: Alzheimer's disease; apigenin; apigenin treatment.; meta-analysis; pharmacological mechanism; systematic review.

Fig. (1)

Main sources and map indicating the functions of apigenin.

Fig. (2)

Flow diagram of the systematic review. The process of paper inclusion was divided into three steps: searching, de-duplication, and manual screening.

Fig. (3)

(A) Table based on SYRCLE document quality assessment. (B) Graph-based on SYRCLE document quality assessment.

Fig. (4)

(A) Meta-analysis forest plot comparing apigenin versus vehicle treatment. Outcome: Morris water maze, escape latency (sec). (B) Sensitivity analysis demonstrated the reliability of AP to affect escape latency.

Fig. (5)

(A) Meta-analysis forest plot comparing apigenin versus vehicle treatment. Outcome: Morris water maze, the percentage of residence time in the target quadrant. (B) Sensitivity analysis demonstrated the reliability of AP in affecting the percentage of residence time in the target quadrant.

Fig. (6)

(A) Meta-analysis forest plot comparing apigenin versus vehicle treatment. Outcome: Morris water maze, the number of crossings in the right quadrant. (B) Meta-analysis forest plot comparing apigenin versus vehicle treatment. Outcome: NF-κB.

Fig. (7)

(A) Meta-analysis forest plot comparing apigenin versus vehicle treatment. Outcome: BDNF levels. (B) Meta-analysis forest plot comparing apigenin versus vehicle treatment. Outcome: pCREB levels.

Fig. (8)

(A) Meta-analysis forest plot comparing apigenin versus vehicle treatment. Outcome: SOD levels. (B) Meta-analysis forest plot comparing apigenin versus vehicle treatment. Outcome: GSH-px levels. (C) Meta-analysis forest plot comparing apigenin versus vehicle treatment. Outcome: MDA levels.

Fig. (9)

(A) Meta-analysis forest plot comparing apigenin versus vehicle treatment. Outcome: caspase 3 levels. (B) Meta-analysis forest plot comparing apigenin versus vehicle treatment. Outcome: Apoptotic neurons in the hippocampus.

Fig. (10)

Subgroup analyses of the escape latency. (A) The dose of intervention on the effect size of the outcome measure; (B) The methods of intervention on the effect size of the outcome measure.

Fig. (11)

Subgroup analyses of the percentage of residence time in the target quadrant. (A) The dose of intervention on the effect size of the outcome measure; (B) The methods of intervention on the effect size of the outcome measure.

Fig. (12)

Escape latency. (A) Funnel plot for assessing potential publication bias; (B) Egger’s funnel plot analysis revealed potential publication bias; (C) The trim and fill analysis was used to evaluate the robustness of the results.

Fig. (13)

Percentage of residence time in target quadrant. (A) Funnel plot for assessing potential publication bias; (B) Egger’s funnel plot analysis revealed potential publication bias; (C) The trim and fill analysis was used to evaluate the robustness of the results.

Fig. (14)

Possible mechanism of AP in the treatment of AD: inhibit BACE1 activity, reduce Aβ aggregation and deposition; inhibit GSK-3β to lower p-tau and reduce NFTs production; reduce glial cell activation, inhibit TLR4/NF-κB signaling pathway and reduce inflammatory factor release; improve mitochondrial dysfunction, activate NRF2 signaling pathway, increase antioxidant enzyme expression, reduce intracellular ROS levels and inhibit oxidative stress; increase Bcl2/Bax, downregulate apoptotic factors such as cytochrome C, Bax, caspase 9 and caspase 3 to exert anti-apoptotic effects; upregulate BDNF and its receptors TRKB and pCREB to restore the neurotrophic pathway ERK/CREB/BDNF; increase SYNI expression, inhibit glutamate release and promote synapse formation; inhibit HDAC activity and restores histone acetylation; inhibits AChE activity and increases cortical Ach levels; inhibits NO production and reduces nitrosylation.