Prediction And Primary Validation Of Naringin As A Potential GABAergic Synapse Agent Against Alzheimer’s Disease

Naringin,the primary active ingredient in citrus peel,exhibits favorable characteristics such as good permeability through the blood-brain barrier,antiinflammatory properties,and antioxidant activities.Previous studies have shown that naringin possesses potential to prevent Alzheimer’s disease(AD),although its precise mechanism of action remains unclear.This thesis aims to investigate the effects of naringin,extracted from citrus peel,on AD.The main research objectives are as follows:Meta-analysis and network pharmacology were employed to explore the mechanisms underlying naringin’s preventive effects on AD.The meta-analysis revealed that naringin improves memory,ameliorates cholinergic disorders,and reduces oxidative stress.Network pharmacology identified GABAergic synapse as a potential key pathway for naringin.GABRA3,GABRA5,and GABRA1 were identified as potential targets for naringin.Through WGCNA analysis,testing,and ROC analysis,it was observed that GABRA3,GABRA1,and GABRA5 were strongly negatively associated with the disease,with high positive rates for GABRA3 and GABRA5.Furthermore,the protein interaction network map revealed direct associations of GABRA1,GABRA3,and GABRA5 with 23 upstream targets.Pharmacokinetic predictions indicated that naringenin and hydroxylated naringenin methyl ether exhibited excellent penetration of the blood-brain barrier and absorption in the human intestine,suggesting that they may be key naringin derivatives.Naringenin,hydroxylated naringenin,and naringin exhibited strong binding properties with GABRA3 and GABRA5,with naringin showing the highest affinity among the three compounds.Animal experiments were conducted to verify the interaction between naringin and GABAergic synapse.Immunofluorescence analysis of the hippocampal CA1 region in SD rats demonstrated that naringin reduced the deposition of Aβ1-42 and suppressed the expression of GFAP.Western blotting confirmed that naringin upregulated the expression of GABRA1,GABRA3 and GABRA5.Consequently,naringin could modulate the GABAergic synapse pathway and nerve excitability by up-regulating GABRA1,GABRA3,and GABRA5,resulting in reduced GFAP expression and Aβ142 deposition,thereby preventing AD.In conclusion,this thesis elucidated the effects of naringin on memory,antioxidant capacity,and cholinergic function,thus facilitating further research on naringin.The study revealed that naringin exhibits significant effects on improving the GABAergic synapse and the expression of GABRA1,GABRA3,and GABRA5 in an Aβ1-42 rat model.These findings provide valuable directions for investigating Alzheimer’s disease and serve as a basis for the development of naringin-related products.