Effects of apigenin on cognitive function and its neuroprotective mechanism in type 2 diabetic KKAy mice
Zhang Yueqi
Liu Xin
Chen Xuecong
Tang Xiaohan
Gao Shichao
Abstract：Objective To investigate the effects of apigenin(Apg)on cognitive impairment in KKAy mice,a model of type 2 diabetes(T2DM),and explore its potential mechanisms.Methods Bioinformatics analysis was performed to identify overlapping target genes of Apg,T2DM,and cerebral small vessel disease(CSVD).Protein-protein interaction(PPI)analysis,Gene Ontology(GO),and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment were conducted using the DAVID database.Ten-week-old SPF grade spontaneous type 2 diabetic KKAy mice weighing(36±3)g were selected.KKAy mice were randomly divided into four groups(n=10 per group):T2DM model group(Model group),and low-(3 mg/kg),medium-(6 mg/kg),and high-dose(12 mg/kg)Apg intervention groups(intraperitoneal injection).Additionally,10 C57BL/J mice served as the blank control group(Control group).Cognitive function was assessed using the Morris water maze test.The Apg group,which showed the most significant cognitive improvement,was selected for further experiments,including RT-PCR,inflammatory factor detection,and Western blotting.Neuronal apoptosis,tumor protein 53(TP53),interleukin-6(IL-6),tumor necrosis factor-α(TNF-α),IL-1β,B-cell lymphoma-2(Bcl-2),Bcl-2-associated X protein(Bax),and caspase-3 expression levels were measured.Results TNF-α and TP53 were identified as key target genes,with downstream interactions mainly involving Caspase and Bid family proteins.The MWM test showed that mice in the high-dose Apg group exhibited significantly increased platform crossings[(4.42±0.76)vs.(1.80±0.41)times,t=9.59,P＜0.05]and longer residence time in the target quadrant[(33.5±6.1)vs.(16.1±4.1)s,t=7.49,P＜0.05]compared with the Model group,indicating improved cognitive function.Thus,the high-dose group was selected for subsequent studies(named as Apg group).Further experiments showed that compared with the Model group,Apg intervention significantly reduced the expression of TNF-α[(50.4±9.6)vs.(29.3±7.1)pg/ml,t=6.28,P＜0.01],IL-1β[(60.4±13.6)vs.(28.7±7.1)pg/ml,t=6.56,P＜0.01],IL-6[(3.4±0.5)vs.(1.8±0.3),t=5.58,P＜0.01]and TP53[(4.4±0.9)vs.(2.3±0.4),t=6.18,P＜0.01]in mouse hippocampus.It also decreased the expression of Bax[(2.74±0.60)vs.(1.60±0.30),t=5.18,P＜0.05]and Caspase-3 proteins[(3.14±0.60)vs.(1.80±0.40),t=5.58,P＜0.05],increased Bcl-2 protein expression[(0.61±0.10)vs.(0.78±0.10),t=4.46,P＜0.05],and reduced neuronal apoptosis[(30.4±5.6)%vs.(18.0±2.1)%,t=6.56,P＜0.01].Conclusions Apg may exert neuroprotective effects against T2DM-induced cognitive impairment through anti-inflammatory(downregulating TNF-α,IL-1β,IL-6),anti-apoptotic(regulating Bax/Bcl-2/Caspase-3),and TP53 signaling pathway modulation mechanisms.
Keywords：ApigeninType 2 diabetes mellitusKKAy miceCognitive functionCerebral small vessel diseaseNeuroprotection
Publication Date：2025-09-20
Online Publishing Date：2025-09-23(First online date of this platform, not the publication date of the document)
Pages：7( 645-651 )